Essentials Of Postgraduate Cardiology 9788193670347
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Table of contents :
Cover Photo
Copyright
Contributors
Preface
Contents
1 . Jugular Venous Pulse:
2 .How to Measure Blood Pressure
3. Peripheral Signs of Aortic
4. Clinical Examination in Atrial Fibrillation
5. Continuous Murmur
6. Dynamic Auscultation
7 Challenges in the Diagnosisand Management of AcuteRheumatic Fever
8 Pathogenesis of Rheumatic Fever and Rheumatic Heart Disease, What have we Learned?
9. Decline of Rheumatic HeartDisease: Is it Real?
10 Clinical Assessment of Severityof Valvular Heart Disease
11 Subclinical RheumaticHeart Disease
12 Natural History of Mitral andAortic Valve Regurgitation
13 Natural History of RheumaticMitral Stenosis
14 Percutaneous TransvenousMitral Commissurotomy:Tips and Tricks
15 Clinical Diagnosis of TricuspidValve Disease
16 Atrial Fibrillation in RheumaticHeart Disease
17 Prevention of Rheumatic Fever/Rheumatic Heart Disease
18 Newer Valve Guidelines:What Suits Indians andWhat does not?
19 Role of Two- and Threedimensional Echocardiographyin Valvular Lesions
20 Pitfalls in Assessment ofValvular Heart Disease
21 Nonrheumatic MitralRegurgitation
22 Bicuspid Aortic Valve in 2018:What we Must Know?
23 Low-gradient Aortic Stenosis
24 Infective Endocarditis:What is New?
25 Prophylaxis for InfectiveEndocarditis in India
26 Mechanical Prosthetic ValveThrombosis
27 Percutaneous ValveInterventions beyondTranscatheter AorticValve Implantation
28 Epidemiology of CongenitalHeart Disease in India
29 Assessment of Congenital HeartDefects with Left-to-Right Shuntsand Pulmonary Hypertension forOperability
30 Pregnancy and CongenitalHeart Disease
31 A Simplified Approach to theManagement of Congenitally CorrectedTransposition of Great Arteries
32 ECG in Pediatric Cardiology
33 Chest X-ray in CongenitalHeart Disease
34 Traps and Pitfalls inEchocardiographic Diagnosis ofCongenital Heart Disease
35 Fetal Echocardiography: CurrentStatus and Role in Managementof Congenital Heart Defects
36 Advances in CT Angiographyfor Congenital Heart Disease
37 Best Use of Cardiac MRI inCongenital Heart Disease
38 Natural History of VentricularSeptal Defect
39 Ventricular Septal Defect withAortic Regurgitation
40 Imaging of Atrial Septal Defect
41 Lutembacher’s Syndrome
42 Which Device for which PatentDuctus Arteriosus?
43 Aneurysms of the Sinusesof Valsalva
44 Coarctation of Aorta in Adults:Diagnosis and Current ManagementStrategies
45 Approach to Cyanosisin Newborn
46 Cyanosis in Adults
47 Eisenmenger Syndrome:An Update
48 Adults with RepairedTetralogy of Fallot
49 Single Ventricle Pathway:Simplified
50 Fontan Circulation: Simplified
51 Ebstein’s Anomaly:What’s New?
52 Total Anomalous PulmonaryVenous Connection:An Overview
53 Pulmonary ArteriovenousMalformations
54 Systemic Effects of Cyanosis
55 Outcomes of DilatedCardiomyopathy in 2018
56 Genetics of Cardiomyopathies:An Overview
57 Noninvasive Evaluation ofSuspected Heart MuscleDisease
58 Curable Forms of VentricularDysfunction
59 Myocarditis: An Update
60 Tachycardiomyopathy
61 The Role of CardiovascularMagnetic Resonance in RiskStratification of HypertrophicCardiomyopathy
62 Constrictive Pericarditis andRestrictive Cardiomyopathy:How to Differentiate?
63 Tubercular Pericarditis
64 Surgery for Chronic ConstrictivePericarditis, TuberculousPericarditis and EffusiveConstrictive Pericarditis
65 An Update on RestrictiveCardiomyopathy
66 Tropical EndomyocardialFibrosis? A Vanishing CuriousDisease
67 Cardiac Amyloidosis:Diagnosis and Management
68 Cardiac Sarcoidosis
69 Imaging and Classification ofTakayasu’s Arteritis
70 Immunotherapy forNonspecific Aortoarteritis
71 Interventions in TakayasuArteritis(Nonspecific Aortoarteritis)
72 Aortic Diseases: When toProceed with Surgery?
73 Aortic Diseases: When and Howto Proceed for InterventionalManagement?
74 Pulmonary Embolism:When to do What?
75 Evaluation of PulmonaryHypertension: A SimplifiedAlgorithm
76 Recent Advances in theManagement of IdiopathicPulmonary Artery Hypertension
77 Kawasaki Disease:What We Should Know?
78 Common Pitfalls and Artifactsin ECG Interpretation
79 Computerized ECGs:Strengths and Limitations
80 ECG Assessment ofSupraventricular Tachycardia
81 ECG Assessment of WideQRS Tachycardia
82 Atrioventricular Block:Diagnosing the Level of Block
83 STEMI Equivalents
84 Recent Advances inEchocardiographic StrainImaging
85 Hemodynamic Assessment inthe Cardiac CatheterizationLaboratory
86 Interpretation ofCatheterization Traces
87 Interpreting a NuclearStress Test
88 Cardiac Tumors: PracticalApproach and Management
Index
Citation preview
ESSENTIALS OF
POSTGRADUATE CARDIOLOGY
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DISCLAIMER This book contains the views and opinions of a group of experts and does not represent the decisions or stated policies of the Cardiological Society of India or Editors. The authors/contributors are themselves responsible for obtaining appropriate permissions to reproduce data/ illustrations/figures/tables from other sources. The editors and publishers have accepted manuscripts in good faith and on the condition that all authors have adhered to the highest standards of publication ethics. Medicine is an ever-changing science. As new data and drugs become available, treatment concepts and recommendations are constantly changing. The editors and publishers have tried to ensure that the information provided in this book is current and in keeping the present standard of care. Readers are, however, advised to cross check full prescribing information with the product inserts provided by the drug manufacturers. References from the web are provided for informational purposes only and do not constitute endorsement of any website.
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Cardiological Society of India
ESSENTIALS OF
POSTGRADUATE CARDIOLOGY Editor-in-Chief
Kewal C Goswami
MD DM
Professor Department of Cardiology All India Institute of Medical Sciences New Delhi, India
Co-Editors
Rakesh Yadav
MD DM
Professor Department of Cardiology All India Institute of Medical Sciences New Delhi, India
Nitish Naik
MD DM
Professor Department of Cardiology All India Institute of Medical Sciences New Delhi, India
S Ramakrishnan
MD DM
Professor Department of Cardiology All India Institute of Medical Sciences New Delhi, India
New Delhi, India
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© Cardiological Society of India 2019 The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers/ editor(s)/author(s). All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the author(s)/editor(s) will be pleased to make the necessary arrangements at the first opportunity. Essentials of Postgraduate Cardiology / Kewal C Goswami ISBN: 978-81-936703-4-7 Printed in India Published and exclusively distributed by EVANGEL PUBLISHING
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CONTRIBUTORS EDITOR-IN-CHIEF Kewal C Goswami
MD DM
Professor Department of Cardiology All India Institute Of Medical Sciences New Delhi, India
CO-EDITORS Rakesh Yadav
MD DM
Professor Department of Cardiology All India Institute of Medical Sciences New Delhi, India
Nitish Naik
MD DM
Professor Department of Cardiology All India Institute of Medical Sciences New Delhi, India
S Ramakrishnan
MD DM
Professor Department of Cardiology All India Institute of Medical Sciences New Delhi, India
CONTRIBUTING AUTHORS Aayush Goyal
Ajay Bahl
Department of Cardiovascular and Thoracic Surgery All India Institute of Medical Sciences New Delhi, India
Postgraduate Institute of Medical Education and Research Chandigarh, India
Abhinav Singhal
Department of Cardiology Jawaharlal Institute of Postgraduate Medical Education and Research Puducherry, India
Senior Resident Department of Nuclear Medicine All India Institute of Medical Sciences New Delhi, India
Abhishek Goyal Assistant Professor Department of Cardiology Hero DMC Heart Institute Dayanand Medical College and Hospital Ludhiana, Punjab, India
Ahmed Y Salama Research Fellow, Echocardiography Laboratory, Cardiology Division University of Alabama at Birmingham Birmingham, Alabama, USA
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Ajith Ananthakrishna Pillai
Ajit Thachil Consultant Cardiac Electrophysiologist Lisie Hospital Kochi, Kerala, India
Akshyaya Pradhan Assistant Professor Department of Cardiology KG’s Medical University Lucknow, Uttar Pradesh, India
Amit Vora Glenmark Cardiac Centre Swami Krupa CHS Mumbai, Maharashtra, India
Anandaraja Subramanian
Senior Consultant Department of Cardiology Indira Gandhi Government General Hospital and Postgraduate Institute Puducherry, India
Anil Bharani
Former Professor and Head Department of Medicine and Division of Cardiology MGM Medical College and MY Hospital Principal Investigator ICMR RF/RHD Registry Indore, Madhya Pradesh, India
Anita Saxena
Professor All India Institute of Medical Sciences New Delhi, India
Anjali Bharani
Assistant Professor Department of Pediatrics MGM Medical College, MY Hospital and Chacha Nehru Bal Chikitsalaya Indore, Madhya Pradesh, India
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Essentials of Postgraduate Cardiology
Ankit Bansal Associate Professor Department of Cardiology GB Pant Institute of Postgraduate Medical Education and Research Maulana Azad Medical College New Delhi, India
Annu Jose Junior Consultant Pediatric Cardiology Lisie Hospital Kochi, Kerala, India
Arima Nigam Associate Professor Academic Block GB Pant Institute of Postgraduate Medical Education and Research New Delhi, India
Arindam Pande Consultant Interventional Cardiologist Medica Superspecialty Hospital Kolkata, West Bengal, India
Arun K Chopra Director Fortis Escorts Hospital Amritsar, Punjab, India
Arun Sharma Department of Cardiovascular Radiology and Endovascular Interventions All India Institute of Medical Sciences New Delhi, India
Arvind Balaji Senior Resident All India Institute of Medical Sciences New Delhi, India
Avinash Anantharaj Junior Consultant Department of Cardiology Indira Gandhi Government General Hospital and Postgraduate Institute Puducherry, India
Balachander Jayaraman
BRJ Kannan
Department of Cardiology Jawaharlal Institute of Postgraduate Medical Education and Research Puducherry, India
Senior Interventional and Pediatric Cardiologist Vadamalayan Hospitals Madurai, Tamil Nadu, India
Balu Vaidyanathan
B Vinodkumar
Clinical Professor Head Fetal Caardiology Division Amrita Institute of Medical Sciences Amrita School of Medicine Kochi, Kerala, India
BC Srinivas Professor Sri Jayadeva Institute of Cardiovascular Sciences Bengaluru, Karnataka, India
Bhanu Duggal Professor and Head Department of Cardiology All India Institutes of Medical Sciences Rishikesh, Uttarakhand, India
Bharat Dalvi Glenmark Cardiac Centre Mumbai, Mahrashtra, India
Bijesh Viswambaran Junior Consultant Pediatric Cardiology Lisie Hospital Kochi, Kerala, India
Binay Kumar EP Fellow Holy Family Hospital Mumbai, Maharashtra, India
Bishav Mohan Professor Dayanand Medical College and Hospital Unit Hero DMC Heart Institute Ludhiana, Punjab, India
BKS Sastry Senior Consultant Cardiologist CARE Hospitals Hyderabad, Telangana, India
Physician Billroth Hospital Chennai, Tamil Nadu, India
Calambur Narasimhan Director Department of Cardiac Electrophysiology Department of Cardiology CARE Hospital Hyderabad, Telangana, India
Chandramukhi Sunehra Department of Cardiac Imaging Care Hospital Hyderabad, Telangana, India
Chetan D Patel Professor Department of Nuclear Medicine All India Institute of Medical Sciences New Delhi, India
CM Nagesh
Associate Professor Department of Cardiology Sri Jayadeva Institute of Cardiovascular Sciences and Research Bengaluru, Karnataka, India
CN Manjunath
Professor and Director Sri Jayadeva Institute of Cardiovascular Sciences Bengaluru, Karnataka, India
Deepa S Kumar
Assistant Professor Department of Pediatric cardiology SCTIMST Thiruvananthapuram, Kerala, India
Devendra Kanshilal Sharma
Department of Cardiology Jawaharlal Institute of Postgraduate Medical Education and Research Puducherry, India
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Gurpreet S Wander
John Gorcsan III
Pediatric Cardiology Lisie Heart Institute, Lisie Hospital Kochi, Kerala, India
Professor and Head Department of Cardiology Hero DMC Heart Institute Dayanand Medical College and Hospital Ludhiana, Punjab, India
Division of Cardiology Washington University in St. Louis 660 S. Euclid Ave. Campus Box 8086 St. Louis, MO 63110, USA
Ganesan Karthikeyan Professor All India Institute of Medical Sciences New Delhi, India
Ganesh Kumar Kasinadhuni Senior Resident Cardiology Postgraduate Institute of Medical Education and Research Chandigarh, India
Gaurav Choudhary Assistant Professor Department of Cardiology King George’s Medical University Lucknow, Uttar Pradesh, India
Gautam Singal Senior Consultant Department of Cardiology Holy Family Hospital New Delhi, India
GC Khilnani Professor and Head Department of Pulmonary Medicine and Sleep Disorders All India Institutes of Medical Sciences New Delhi, India
Girish Kumar Parida Senior Resident Department of Nuclear Medicine All India Institute of Medical Sciences New Delhi, India
Hanan Fadala Research Fellow, Echocardiography Laboratory, Cardiology Division University of Alabama at Birmingham Birmingham, Alabama, USA
Harkrishnan S Sree Chitra Tirunal Institute for Medical Sciences and Technology Thiruvananthapuram, Kerala, India
Gurpreet S Gulati Department of Cardiovascular Radiology and Endovascular Interventions All India Institute of Medical Sciences New Delhi, India
Justin Paul G Professor Institute of Cardiology Madras Medical College Chennai, Tamil Nadu, India
Kailash Chandra Senior Resident Post Graduate Department of Cardiology Jawahar Lal Nehru Medical College Ajmer, Rajasthan, India
Kanabar Kewal IB Vijayalakshmi Professor Department of Pediatric Cardiology Super Specialty Hospital Bengaluru Medical College and Research Institute Bengaluru, Karnataka, India
Jaganmohan A Tharakan Former Professor and Head Department of Cardiology SCTIMST Trivandrum, Kerala, India
Jagdish C Mohan Chairman Department of Cardiology Institute of Heart and Vascular Diseases Jaipur Golden Hospital New Delhi, India
Girish MP Professor Department of Cardiology GB Pant Institute of Post Graduate Medical Education and Research New Delhi, India
Contributors
Edwin Francis
Jayaranganath M Professor and Head Department of Pediatric Cardiology Sri Jayadeva Institute of Cardiovascular Sciences and Research Bengaluru, Karnataka, India
Jay Relan Senior Resident All India Institute of Medical Sciences New Delhi, India
Senior Resident Department of Cardiology Postgraduate Institute of Medical Education and Research Chandigarh, India
Kartikeya Bhargava Associate Director Medanta Heart Institute Medanta-The Medicity Gurugram, Haryana, India
Kewal C Goswami Professor Department of Cardiology All India Institute of Medical Sciences New Delhi, India
KH Srinivasa Professor Sri Jayadeva Institute of Cardiovascular Sciences and Research Bengaluru, Karnataka, India
KK Talwar Chairman Department of Cardiology Max Healthcare Institute Ltd
KM Krishnamoorthy Professor Pediatric Cardiology SCTIMST Thiruvananthapuram, Kerala, India ix
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Essentials of Postgraduate Cardiology
Krishnakumar S
Madhu Shukla
Monotosh Panja
Sree Chitra Tirunal Institute for Medical Sciences and Technology Thiruvananthapuram, Kerala, India
Senior Clinical Associate Department of Cardiology Institute of Heart and Vascular Diseases Jaipur Golden Hospital New Delhi, India
Senior Consultant Interventional Cardiologist BM Birla Heart Institute Kolkata, West Bengal, India
Krishnam Raju P Cardiologist CARE Outpatient Centre Hyderabad, Telangana, India
Kshitij Sheth Sir HN Reliance Foundation Hospital Mumbai, Maharashtra, India
K Sivakumar Head Department of Pediatric Cardiology Madras Medical Mission Chennai, Tamil Nadu, India
Kumaran S Assistant Professor Institute of Cardoology Madras Medical College Chennai, Tamil Nadu, India
Lakshmi Gopalakrishnan Senior Cardiologist Southern Railway Headquarters Hospital Chennai, Tamil Nadu, India
Lakshmi Kumari Sankhyan Department of Cardiothoracic Surgery All India Institute of Medical Sciences New Delhi, India
Lalit Kumar Department of Medical Oncology All India Institute of Medical Sciences New Delhi, India
Laxmi H Shetty Assistant Professor Department of Cardiology Sri Jayadeva Institute of Cardiovascular Sciences and Research Bengaluru, Karnataka, India
Madhumanti Panja
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Cardiology Trainee RN Tagore International Institute of Cardiac Science Kolkata, West Bengal, India
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Mahesh Kappanayil Clinical Professor Department of Pediatric Cardiology Amrita Institute of Medical Sciences and Research Centre Kochi, Kerala, India
Mahim Saran
Mumun Sinha DM Fellow Department of Cardiovascular Radiology and Endovascular Interventions All India Institutes of Medical Sciences New Delhi, India
M Zulfikar Ahamed
Senior Resident Department of Cardiology King George’s Medical University Lucknow, Uttar Pradesh, India
Professor Senior Consultant Pediatric Cardiology KIMS Hospital Thiruvananthapuram, Kerala, India
Manoj Kumar Rohit
Nageswara Rao Koneti
Professor Department of Cardiology Postgraduate Institute of Medical Education and Research Chandigarh, India
Martin S Maron Director Hypertrophic Cardiomyopathy Center Division of Cardiology Tufts Medical Center 800 Washington Street, Boston Massachusetts 02111
Mohan Nair Coordinator and Head Department of Cardiology Holy Family Hospital New Delhi, India
Mohit Bhutani Senior Resident Department of Cardiology Dr RML Hospital New Delhi, India
Mohit D Gupta Professor Department of Cardiology GB Pant Institute of Post Graduate Medical Education and Research New Delhi, India
Chief Pediatric Cardiologist CARE Hospital Hyderabad, Telangana, India
Narendra Bagri Department of Pediatrics All India Institute of Medical Sciences New Delhi, India
Naveen Kumar Department of Pediatric Cardiology Max Hospital New Delhi, India
Navin C Nanda Research Fellows, Echocardiography Laboratory, Cardiology Division University of Alabama at Birmingham Birmingham, Alabama, USA
Neeraj Awasthy Department of Pediatric Cardiology and Congenital Heart Diseases Max Hospital New Delhi, India
Neeraj Pandit Professor and Head Department of Cardiology Dr RML Hospital New Delhi, India
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Raghavan Subramanyan
Raziye E Akdogan
Assistant Professor Sri Jayadeva Institute of Cardiovascular Sciences and Research Bengaluru, Karnataka, India
Head Department of Pediatric Cardiology Frontier Lifeline Hospital Chennai, Tamil Nadu, India
Research Fellow, Echocardiography Laboratory, Cardiology Division University of Alabama at Birmingham Birmingham, Alabama, USA
Nobuyuki Kagiyama
Raghav Bansal
Rishi Sethi
Postdoctoral Researcher Division of Cardiology Washington University St. Louis, Missouri, USA
Parag Barwad Associate Professor Cardiology Postgraduate Institute of Medical Education and Research Chandigarh, India
Pintu Sharma Department of Cardiology All India Institutes of Medical Sciences Rishikesh, Uttarakhand, India
Associate Consultant Max Super Speciality Hospital New Delhi, India
Rajesh Kalyankar DNB Cardiology CARE Hospitals Hyderabad, Telangana, India
Rajesh Kannan Department of Radiology Amrita Institute of Medical Sciences and Research Centre Kochi, Kerala, India
Rajesh Vijayvergiya Prakash C Negi Professor and Head Cardiology Indira Gandhi Medical College Shimla, Himachal Pradesh, India
Pramod Sagar BK Senior Resident Department of Cardiology Sanjay Gandhi PGIMS Lucknow, Uttar Pradesh, India
Prashant Bhopate Consultant Pediatric Cardiologist Children’s Heart Center Kokilaben Dhirubai Ambani Hospital Mumbai, Maharashtra, India
Preetam Krishnamurthy Senior Resident Department of Cardiology All India Institute of Medical Sciences New Delhi, India
PV Suresh Senior Consultant Pediatric Cardiology Narayana Institute of Cardiac Sciences Bengaluru, Karnataka, India
Professor Department of Cardiology Advanced Cardiac Centre Post Graduate Institute of Medical Education and Research Chandigarh, India
Contributors
Nishanth KR
Professor Department of Cardiology KG’s Medical University Lucknow, Uttar Pradesh, India
RK Gokhroo Principal and Controller Jawahar Lal Nehru Medical College and Associated Group of Hospitals Ajmer, Rajasthan, India
R Krishna Kumar Clinical Professor and Head Department of Pediatric Cardiology Amrita Institute of Medical Sciences Kochi, Kerala, India
R Saileela Consultant Pediatric Cardiologist MIOT Centre for Children’s Cardiac Care Chennai, Tamil Nadu, India
Sachin Sondhi Rajiv Ananthakrishna Associate Professor Department of Cardiology Sri Jayadeva Institute of Cardiovascular Sciences and Research Begaluru, Karnataka, India
Ramalingam Vadivelu Department of Cardiology Advanced Cardiac Centre Post Graduate Institute of Medical Education and Research Chandigarh, India
Ranjit Kumar Nath Professor Department of Cardiology Dr Ram Manohar Lohia Hospital and Postgraduate Institute of Medical Education and Research New Delhi, India
Senior Resident Cardiology Cardiology Indira Gandhi Medical College Shimla, Himachal Pradesh, India
Safal Singh Assistant Professor Department of Cardiology GB Pant Hospital New Delhi, India
Sakshi Sachdeva Senior Resident Pediatric Cardiology All India Institutes of Medical Sciences New Delhi, India
Samhita Kulkarni Registrar SR Mehta Cardiac Insititute and Sir KP Trust Hospital xi
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Essentials of Postgraduate Cardiology
Sandeep S
Saurabh Kumar Gupta
Siddharthan Deepti
Senior Resident Institute of Cardiology Madras Medical College Chennai, Tamil Nadu, India
Associate Professor Department of Cardiology All India Institute of Medical Sciences New Delhi, India
Assistant Professor All India Institute of Medical Sciences New Delhi, India
Sanjay G
Saurabh Mittal
Additional Professor of Cardiology SCTIMST Thiruvananthapuram, Kerala, India
Sanjay Tyagi Director Professor and Head Department of Cardiology GB Pant Institute of Postgraduate Medical Education and Research Maulana Azad Medical College New Delhi, India
Sanjeev Asotra Associate Professor Cardiology Indira Gandhi Medical College Shimla, Himachal, Pradesh, India
Sanjiv Sharma Professor and Head Department of Cardiovascular Radiology and Endovascular Interventions All India Institutes of Medical Sciences New Delhi, India
Assistant Professor Department of Pulmonary Medicine and Sleep Disorders All India Institutes of Medical Sciences New Delhi, India
SB Gupta Consultant Physician Asian Heart Institute and Research Centre Mumbai, Maharashtra, India
Shibba Takkar Chhabra Associate Professor Dayanand Medical College and Hospital Unit Hero DMC Heart Institute Ludhiana, Punjab, India
Shiv Kumar Choudhary Professor and Head Department of Cardiovascular and Thoracic Surgery All India Institute of Medical Sciences New Delhi, India
Santosh Kumar Chellapuram Department of Medical Oncology All India Institute of Medical Sciences New Delhi, India
Santosh Satheesh Additional Professor Department of Cardiology Jawaharlal Institute of Postgraduate Medical Education and Research Puducherry, India
Sasinthar Rangasamy Senior Resident Department of Cardiology JIPMER Puducherry, India
Shomu Bohora Associate Professor of Cardiology UN Mehta Institute of Cardiology and Research Center Ahmedabad, Gujarat, India
Shyam S Kothari Professor Department of Cardiology All India Institute of Medical Sciences New Delhi, India
Siddhant Trehan Artemis Hospital Gurugram, Haryana, India
Sivasubramanian Ramakrishnan Professor All India Institute of Medical Sciences New Delhi, India
SK Dwivedi Professor Department of Cardiology King George’s Medical University Lucknow, Uttar Pradesh, India
Snehal Kulkarni Senior Consultant Pediatric Cardiology Division of Pediatric Cardiology Kokilaben Ambani Hospital Mumbai, Maharashtra, India
Snigdha Boddu Senior Resident Department of Cardiology KG’s Medical University Lucknow, Uttar Pradesh, India
Srinivas B Chikkaswamy Professor Department of Cardiology Sri Jayadeva Institute of Cardiovascular Sciences and Research Bengaluru, Karnataka, India
Sriram Rajagopal Chief Cardiologist Southern Railway Headquarters Hospital Chennai, Tamil Nadu, India
S Shanmugasundaram
Professor Department of Cardiology Emeritus Professor of Cardiology Dr MGR Medical University and Cardiologist, Billroth Hospital Chennai, Tamil Nadu, India
Sudeep Kumar Professor Department of Cardiology Sanjay Gandhi PGIMS Lucknow, Uttar Pradesh, India
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Sudhir S Shetkar
Suresh Kumar Senior Consultant and Head Believers International Heart Centre Thiruvalla, Kerala, India
Usha MK
Associate Professor Department of Pediatric Cardiology Sri Jayadeva Institute of Cardiovascular Sciences and Research Bengalurur, Karnataka, India
Varun S Narain
Sylvia Colaco Fellow, Children’s Heart Center Kokilaben Dhirubai Ambani Hospital Mumbai, Maharashtra, India
Tamiruddin A Danwade Department of Cardiology CARE Hospital Hyderabad, Telangana, India
U Ilayaraja Cardiologist Billroth Hospital
Ujjwal Kumar Chowdhury Professor Cardiothoracic Sciences Centre All India Institute of Medical Sciences New Delhi, India
Vishwas Mohan
Professor and Head Department of Cardiology King George’s Medical University Lucknow, Uttar Pradesh, India
Attending Cardiologist Max Hospital New Delhi, India
Vijaykumar JR
Vivek Chaturvedi
Suruchi Hasija Associate Professor Department of Cardiac Anesthesia All India Institutes of Medical Sciences New Delhi, India
Vishal Batra Assistant Professor Department of Cardiology GB Pant Institute of Post Graduate Medical Education and Research New Delhi, India
Senior Resident Department of Cardiology Sanjay Gandhi PGIMS Lucknow, Uttar Pradesh, India
Senior Consultant Cardiology Director, Cardiac Electrophysiology Narayana Super Specialty Hospital Gurugram, Haryana, India
Vijay Kumar Trehan
V Jacob Jose
Director Professor Department of Cardiology GB Pant Institute of Postgraduate Medical Education and Research Maulana Azad Medical College New Delhi, India
Contributors
Consultant Department of Cardiac Sciences Apollo Hospital Nashik, Mahrashtra, India
Consultant Ministry of Health Brunei
Yash Lokhandwala
Vikas Kataria
Arrhythmia Associates Mumbai, Maharashtra, India
Vineeta Ojha
Assistant Professor Department of Cardiology All India Institutes of Medical Sciences Rishikesh, Uttarakhand, India
Senior Consultant Department of Cardiology Holy Family Hospital New Delhi, India
Department of Cardiovascular Radiology and Endovascular Interventions All India Institute of Medical Sciences New Delhi, India
Yash Shrivastava
Yuko Soyama Washington University Saint Louis
Uma Kumar
Vinoth Doraiswamy
Z Sajan Ahmad
Professor and Head Department of Rheumatology All India Institute of Medical Sciences New Delhi, India
Associate Consultant Pediatric Cardiologist CARE Hospital Hyderabad, Telanagana, India
Assistant Professor Department of Cardiology Pushpagiri Medical College Thiruvalla, Kerala, India
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PREFACE It gives me immense pleasure and satisfaction in presenting the book titled Essentials of Postgraduate Cardiology to be released during the 70th annual conference of CSI 2018. The book covers a wide range of clinical and practical exam-oriented topics covering all essential aspects of cardiology. We tried our best to keep the all the topics practical, up to date, relevant and interesting. I sincerely hope that this update will serve as a ready reckoner for postgraduate students and even the practising cardiologist. Modern-day cardiology is a beast that is difficult to tame—current-day treatment protocols are based on outcomes of large randomized controlled trials that draw strength from complex statistical models (of which, I fear, most cardiologists know very little about). Interventional cardiology has continued its inexorable progress, conquering frontiers that would have been felt impossible to conquer only a decade ago. Cardiac imaging has made even more remarkable progress with 3D imaging, intravascular probes, ultrafast CTs, plaque imaging and what not. Electrophysiology has not been far behind either with newer computer-based technologies seeking to solve questions that would be difficult for physicians to interpret with their minds. My only concern is that the budding cardiologist has, and again I cannot blame him for that, inadvertently chosen to sacrifice clinical and examination skills at the altar of modern medicine. It is certainly more macho to diagnose severe mitral regurgitation by looking at PISA and EROA than to locate the hyperdynamic apex shifted into the axilla or assess the split of S2. The palpable P2 in the second intercostal space or dilated pulmonary artery on the chest X-ray will draw only cursory, fleeting glance; greater time and skill would be spent on memorizing echo parameters of PAH. This tectonic shift in our perception of relevant clinical skills is there for all of us to see—clinical cardiology seems to be on a deathbed. I was dismayed to read articles writing obituary for the stethoscope, the only instrument cardiologists wielded with considerable pride only two decades ago. It is for this very reason that I draw immense pride and satisfaction to see this book delve largely on matters of clinical cardiology. Galaxy of national and international experts have penned down their thoughts, observations and clinical experience, and I feel this book would stand the test of time. I am really thankful from the bottom of my heart and really appreciate their enthusiasm for this endeavor. In the present scenario, a lot of literature is available in the field of cardiology. The problems we encounter in India are at times unique and offer specific challenges. We realize the lack of consolidated literature focusing on ‘Indian’ and developing world problems like rheumatic heart disease, unoperated adults with congenital heart disease, pericardial diseases, EMF, etc, which must be known to each and every fellow training in cardiology in India. Therefore, our goal was to create an academic resource to address the needs of a fellow preparing for the examinations. I am sure students taking up either DM/ DNB in cardiology will find it useful. An undertaking of this magnitude requires a team approach with immense dedication and coordination among all the team members. The editorial team played a pivotal role in the planning, executing and editing the book. I would like to place on record my sincere appreciation to my publishers, Evangel Publishing, for putting in their heart in making this book possible. I would be failing in my duty if I do not acknowledge my family including my wife and mother for putting up with my prolonged absences from home.
Kewal C Goswami
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CONTENTS Section 1
CLINICAL CARDIOLOGY Chapter 1. Jugular Venous Pulse: Elusive but Adorable...............................................3 Varun S Narain, Gaurav Choudhary
Examination of the Jugular Venous Pulse 3
Interpretation of the Jugular Venous Pulse 4
Identification of Waves 6
Abnormal Contours: What They Say 7
Chapter 2. How to Measure Blood Pressure in Children and Adults? A Guide ...................................................................... 11 Justin Paul G, Sandeep S, Kumaran S
History of Blood Pressure Measurement 11
Noninvasive Techniques 11
Present-day Methods
Practical Points in Blood Pressure Measurement 13
Procedure of Measuring Blood Pressure 13
Ambulatory Blood Pressure Monitoring 14
Blood Pressure Measurement in Special Populations 14
12
Chapter 3. Peripheral Signs of Aortic Regurgitation: Revisited .............................. 17 S Shanmugasundaram, B Vinodkumar, U Ilayaraja
Typical Arterial Pulse of Significant Aortic Regurgitation
Peripheral Signs of Aortic Runoff 18
Investigations 20
17
Chapter 4. Clinical Examination in Atrial Fibrillation.................................................. 21 Ganesh Kumar Kasinadhuni, Parag Barwad
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Physical Examination 21
Systemic Examination 22
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Chapter 5. Continuous Murmur ........................................................................................ 25 Essentials of Postgraduate Cardiology
Ranjit Kumar Nath
Physiologic Classification 25
Differential Diagnosis 26
Chapter 6. Dynamic Auscultation ..................................................................................... 32 Rishi Sethi, Akshyaya Pradhan, Snigdha Boddu
Section 2
Physiological Maneuvers 32
Pharmacological Maneuvers 36
VALVULAR HEART DISEASE—RHEUMATIC HEART DISEASE Chapter 7. Challenges in the Diagnosis and Management of Acute Rheumatic Fever .................................................. 39 Anita Saxena
Diagnosis of Rheumatic Fever 39
Major Criteria 40
Minor Manifestations 41
Management 42
Chapter 8. Pathogenesis of Rheumatic Fever and Rheumatic Heart Disease: What have we Learned?.............................. 46 Santhosh Satheesh, Sasinthar Rangasamy
Three Components of Rheumatic Fever Pathogenesis
46
Immunological Mechanisms in Acute Rheumatic Fever and Rheumatic Heart Disease 47 Controversies in Pathogenesis of Acute Rheumatic Fever/ Rheumatic Heart Disease 49 Evolution into Chronic Rheumatic Heart Disease 50 Recent Conflicting Evidences in Rheumatic Heart Disease Pathogenesis 50 Knowing the Pathogenesis of RHD: How Does it Help in Tackling the Disease? 50
Chapter 9. Decline of Rheumatic Heart Disease: Is it Real? ..................................... 53 Prakash C Negi, Sanjeev Asotra, Sachin Sondhi
Methods of Detection
Data Sources for Estimation of Burden of RF/RHD 53
53
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Epidemiological Trends of Burden of RHD in India 54
Decline of Rheumatic Heart Disease: Is it Real? 56
Estimated Burden of Disease 57
Contents
Challenges and Opportunities for Prevention and Control of Rheumatic Fever/Rheumatic Heart Disease 57
Chapter 10. Clinical Assessment of Severity of Valvular Heart Disease ................................................................................ 60 Ajith Ananthakrishna Pillai, Devendra Kanshilal Sharma, Balachander Jayaraman
Mitral Stenosis
Mitral Regurgitation
64
Aortic Regurgitation
66
Acute Aortic Regurgitation 69
Aortic Stenosis
Tricuspid Stenosis
Tricuspid Regurgitation
Pulmonary Stenosis
Pulmonary Regurgitation
Multivalvular Lesions
60
69 71 71
72 72
72
Chapter 11. Subclinical Rheumatic Heart Disease ........................................................ 74 RK Gokhroo, Kailash Chandra
Prevalence of Clinical and Subclinical RHD 74
Is Early Recognition Beneficial? 74
Diagnostic Criteria for Latent RHD 75
Definite RHD 75
Borderline RHD 76
Limitations for WHF Criteria 76
Targets for Screening
The Natural History of Subclinical RHD 77
Management of Definite RHD 77
Management of Borderline RHD 77
77
Chapter 12. Natural History of Mitral and Aortic Valve Regurgitation ................... 79 Sudhir S Shetkar, Sivasubramanian Ramakrishnan, Kewal C Goswami
Natural History of Mitral Regurgitation 79
Natural History of Aortic Regurgitation 81 xix
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Chapter 13. Natural History of Rheumatic Mitral Stenosis ......................................... 87 Essentials of Postgraduate Cardiology
Vivek Chaturvedi
Natural History of Mitral Stenosis in the Era Prior to Definitive Therapy 87
Chapter 14. Percutaneous Transvenous Mitral Commissurotomy: Tips and Tricks............................................................... 92 CN Manjunath, Vijaykumar JR, BC Srinivas
Anatomy and Pathophysiology 92
Indications for BMV 92
Contraindications 92
Technique 92
BMV Technique 93
Percutaneous Transvenous Mitral Commissurotomy (PTMC) in Left Atrium Clot
96
Manjunath’s Classification of LA Clot 98 Lutembacher’s—ASD/RHD Severe MS with Severe Submitral Disease 99
Chapter 15. Clinical Diagnosis of Tricuspid Valve Disease ........................................106 Sudeep Kumar, Pramod Sagar BK
Clinical Anatomy of Tricuspid Valve 106
Physiology 106
Etiology of Tricuspid Valve Abnormalities 107
Tricuspid Stenosis 107
Tricuspid Regurgitation 107
Symptoms of Tricuspid Valve Disease 110
Physical Signs
Effect of Various Maneuvers 112
Electrocardiogram 113
Chest X-ray 113
110
Chapter 16. Atrial Fibrillation in Rheumatic Heart Disease ......................................115 Krishnakumar S, Harkrishnan S
Pathophysiology
Inflammation and Structural Remodeling 115
Pulmonary Veins, Electrical Remodeling and Stretch 115
Thromboembolism and Anticoagulation 116
Management 116
115
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Correction of Underlying Disorder 116
Control of Ventricular Rate 116
Rhythm Control 117
Contents
Chapter 17. Prevention of Rheumatic Fever/ Rheumatic Heart Disease .............................................................................119 Anil Bharani, Anjali Bharani
Section 3
Epidemiology 119
Diagnosis of Rheumatic Fever 119
Prevention of Rheumatic Fever/Rheumatic Heart Disease 119
VALVULAR HEART DISEASE—OTHERS Chapter 18. Newer Valve Guidelines: What Suits Indians and What does not? ........................................................................127 Rajiv Ananthakrishna, Srinivas B Chikkaswamy
Valvular Heart Disease: The Indian Perspective 127
General Considerations in Evaluating Valvular Heart Disease 127
Specific Valvular Lesions
Other Considerations 131
Common Case Scenarios in Routine Clinical Practice
The Future 132
128 131
Chapter 19. Role of Two- and Three-dimensional Echocardiography in Valvular Lesions .....................................................133 Raziye E Akdogan, Ahmed Y Salama, Hanan Fadala, Navin C Nanda
Mitral Stenosis and Regurgitation 133
Aortic Stenosis and Regurgitation 138
Tricuspid Stenosis and Regurgitation 141
Pulmonary Stenosis and Regurgitation 145
Chapter 20. Pitfalls in Assessment of Valvular Heart Disease ..................................148 Jagdish C Mohan, Vishwas Mohan, Madhu Shukla
Assessment of Mitral Regurgitation 148
Methods to Assess Severity of Rheumatic Mitral Regurgitation 150
Assessment of Mitral Stenosis 156
Assessment of Aortic Valve 165
Assessment of Aortic Regurgitation 172 xxi
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Essentials of Postgraduate Cardiology
Chapter 21. Nonrheumatic Mitral Regurgitation .........................................................180 CM Nagesh, Laxmi H Shetty
Mitral Valve Anatomy
Etiology
Pathophysiology
Clinical Features 182
Diagnosis
Quantitation of Primary and Ischemic Mitral Regurgitation 183
Treatment
Treatment in Primary Mitral Regurgitation 186
Treatment in Secondary Mitral Regurgitation 186
Percutaneous Techniques
180
180 181
183 185
186
Chapter 22. Bicuspid Aortic Valve in 2018: What we Must Know?.........................190 KM Krishnamoorthy, Deepa S Kumar
Embryology
Anatomy
Dysfunction of BAV
192
Anomalies of Aorta
192
Pathophysiology of Aortopathy
Genetics
Natural History
Diagnosis
Intervention
Balloon Valvuloplasty
Surgical Aortic Valvuloplasty 196
Indications of Surgery for Aortopathy
Pregnancy and BAV
Exercise and BAV
190
190
192
192 192
193 194 194 196
196
197
Chapter 23. Low-gradient Aortic Stenosis .....................................................................199 Vishal Batra, Mohit D Gupta, Girish MP
Technical Pitfalls and Measurement Errors
199
Classical (Reduced Left Ventricular Ejection Fraction) Low-flow, Low-gradient Aortic Stenosis 200 Paradoxical (Preserved Left Ventricular Ejection Fraction) Low-flow, Low-gradient Aortic Stenosis 202 Normal-flow, Low-gradient Aortic Stenosis
202
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Chapter 24. Infective Endocarditis: What is New? .......................................................204
Prevention 204
Impact of Guideline Change 204
Prevention of Health Care-associated IE 205
Diagnosis 205
Imaging 205
Microbiology 206
Prognostic Assessment 206
Management 207
Antimicrobial Therapy 207
Surgical Indications 208
IE in Special Subgroups 208
Contents
SK Dwivedi, Mahim Saran
Chapter 25. Prophylaxis for Infective Endocarditis in India .....................................212 KH Srinivasa, Nishanth KR
Rationale for Prophylaxis Against IE 212
Cardiac Conditions at Risk for IE 212
Chapter 26. Mechanical Prosthetic Valve Thrombosis ...............................................216 Ganesan Karthikeyan
Incidence of Left-sided PVT 216
Clinical Presentation and Diagnosis of Left-sided PVT 216
Management of Left-sided PVT 217
Recommendations for Management 217
Chapter 27. Percutaneous Valve Interventions beyond Transcatheter Aortic Valve Implantation ................................................219 Vijay Kumar Trehan, Safal Singh, Siddhant Trehan
Mitral Valve Repair 220
Mitral Valve Replacement 225
Percutaneous Therapies for Tricuspid Valve 229
Transcatheter Pulmonary Valve Implantation 231
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Section 4
CONGENITAL HEART DISEASE—KEY ISSUES Chapter 28. Epidemiology of Congenital Heart Disease in India...........................235 Anita Saxena
Risk Factors
Incidence and Prevalence
Prevention
Current Status of CHD Care in India 239
235 235
237
Chapter 29. Assessment of Congenital Heart Defects with Left-to-Right Shunts and Pulmonary Hypertension for Operability ......................................................................243 R Krishna Kumar
Objectives of the Review
244
Correlating Preoperative Hemodynamics with Lung Biopsy Findings and Clinical Outcomes 244 Clinical and Noninvasive Correlates of Hemodynamic Changes in Left-to-Right Shunts 245 Accurate Hemodynamic Assessment in Shunt Lesions: Who Needs it Most? 245 Role of Clinical Examination, ECG, Chest X-ray, Echocardiography and Arterial Blood Gas 246 Hemodynamic Assessment in the Catheterization Laboratory 247
Chapter 30. Pregnancy and Congenital Heart Disease..............................................252 Arima Nigam
Physiological Changes During Pregnancy
Maternal and Fetal Risk
High-risk Pathophysiologic States
High-risk Anatomic Lesions
Cardiovascular Drugs in Pregnancy
Recommendations Regarding Anticoagulation Management
Thrombolytic Therapy in Pregnancy
Percutaneous Intervention/Surgery During Pregnancy
Genetic Counseling
Mode of Delivery
Care in Puerperium
252
253 254
255 255 255
256 257
257 257 257
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R Suresh Kumar, R Saileela
Section 5
Clinical Presentation and Natural History Management 259 Heart Block in CCTGA 263 Pregnancy in CCTGA 263
259
Contents
Chapter 31. A Simplified Approach to the Management of Congenitally Corrected Transposition of Great Arteries ...................259
CONGENITAL HEART DISEASE—EVALUATION OF CHD Chapter 32. ECG in Pediatric Cardiology .........................................................................267 BRJ Kannan
Basics of Recording and Interpretation 267 Normal Variations and Related Abnormalities Analysis of P Wave 271 Analysis of PR Segment 271 Analysis of QRS Complex 273 Cardiac Position-related QRS Changes 274 Analysis of ST Segment 274 Analysis of T Wave 274 Some Disease-specific ECG Changes 275
267
Chapter 33. Chest X-ray in Congenital Heart Disease ................................................281 Arun Sharma, Vineeta Ojha, Sanjiv Sharma
Technical Consideration 281 Sequential Approach for Interpretation 281 Chest X-ray and CHD Classification: Simplified Approach
284
Chapter 34. Traps and Pitfalls in Echocardiographic Diagnosis .............................289 of Congenital Heart Disease K Sivakumar
Anatomical Errors 289 Functional Errors 294
Chapter 35. Fetal Echocardiography: Current Status and Role in Management of Congenital Heart Defects .............................296 Balu Vaidyanathan
Concept of Universal Screening of Fetal Heart 296 3D/4D Stic Fetal Echocardiography 296 Impact of Fetal Echocardiography and Prenatal Diagnosis of CHD 297 xxv
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Chapter 36. Advances in CT Angiography for Congenital Heart Disease ......................................................................302 Arun Sharma, Gurpreet S Gulati
Challenges to Cardiac Imaging
Technical Improvements in Cardiac CT
Choosing the Optimal Imaging Modality in CHD
Clinical Applications of CT in CHD 303
Limitations
302 302 302
306
Chapter 37. Best Use of Cardiac MRI in Congenital Heart Disease ........................309 Mahesh Kappanayil, Rajesh Kannan
Section 6
Cardiac MRI 309
ACYANOTIC CONGENITAL HEART DISEASE Chapter 38. Natural History of Ventricular Septal Defect .........................................319 Sakshi Sachdeva, Shyam S Kothari
Natural History of Ventricular Septal Defect 319
Chapter 39. Ventricular Septal Defect with Aortic Regurgitation..........................326 Manoj Kumar Rohit, Kanabar Kewal
History
Epidemiology
326
Pathogenesis
326
Morphology
Physiological Effects
Natural History
Clinical Presentation
Treatment
326
327 327
327 327
328
Chapter 40. Imaging of Atrial Septal Defect ..................................................................332 Kshitij Sheth, Bharat Dalvi
Embryology of Interatrial Septum
Anatomy of Ostium Secundum Atrial Septal Defect
Types of Atrial Septal Defect 332
Echocardiographic Imaging of the Atrial Septal Defect 333
Three-dimensional Transesophageal 336
332 332
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Chapter 41. Lutembacher’s Syndrome ............................................................................340
Epidemiology 340
Clinical Features 340
Investigations
Contents
Bhanu Duggal, Yash Shrivastava, Pintu Sharma
341
Chapter 42. Which Device for which Patent Ductus Arteriosus? ...........................344 IB Vijayalakshmi
Selection of Various Devices 344
Morphologic Classification of PDA 344
When is Each Device Used?
Amplatzer Vascular Plugs
Which Device in PDA With PAH? 347
Feasibility Test for Device Closure
344 347 348
Chapter 43. Aneurysms of the Sinuses of Valsalva ......................................................351 Kewal C Goswami, Sivasubramanian Ramakrishnan, Siddharthan Deepti
Epidemiology 351
Pathological Anatomy and Etiology
Clinical Presentation
Diagnosis 352
Management
351
352
357
Chapter 44. Coarctation of Aorta in Adults: Diagnosis ............................................. 360 and Current Management Strategies PV Suresh
Section 7
Classification
Clinical Presentation
Diagnostic Evaluation
Indications of Intervention 362
360 360 361
CYANOTIC CONGENITAL HEART DISEASE Chapter 45. Approach to Cyanosis in Newborn ...........................................................371 Anita Saxena
Normal Cardiopulmonary Adaptation at Birth 371
Causes of Central Cyanosis in the Newborn
372 xxvii
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Essentials of Postgraduate Cardiology
Initial Evaluation of the Newborn with Cyanosis 372
Hyperoxia Test
Approach to a Newborn with Cyanotic Congenital Heart Disease 373
Role of Pulse Oximetry 374
Chest Radiograph
Electrocardiography 374
Echocardiography
Initial Management
373
374 374 375
Chapter 46. Cyanosis in Adults ...........................................................................................378 Raghavan Subramanyan, R Saileela
Pathophysiology
Methemoglobinemia 379
Differential Diagnosis of Cyanosis 379
Hemoglobin Work-up in a Cyanotic Patient 381
Treatment Strategy 382
378
Chapter 47. Eisenmenger Syndrome: An Update........................................................384 Sylvia Colaco, Prashant Bobhate
Definition and Classification 384
Epidemiology 384
Classification 384
Pathophysiology
Natural History 387
Clinical Features 388
Cerebrovascular Events 389
Pulmonary Dysfunction
Renal Function and Uric Acid Clearance 389
Other Miscellaneous Organ Involvement 389
Investigations
Management Strategy
Other Conventional Therapies 391
Targeted Therapy 391
Surgical Management 393
Future Trends 393
385
389
389 390
Chapter 48. Adults with Repaired Tetralogy of Fallot .................................................397 Snehal Kulkarni
Surgical Repair of Unoperated TOF in Adults
Subsets Who Do Better On Long-term Follow-up 397
397
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Issues on Long-term Follow-up in Adults
Periodic Holter Monitoring
Computed Tomography
Magnetic Resonance Imaging 400
Nuclear Scintigraphy 400
Cardiac Catheterization and Angiography
Serial Estimation of Brain Natriuretic Peptide 401
Electrophysiology Study for Risk Stratification
Standardized Clinical Assessment and Management Plans
Pregnancy in Patients with TOF 401
Predictors of Complications on Follow-up 401
Reoperations in Adults with Repaired TOF
Percutaneous Pulmonary Valve Replacement/Implantation
398 Contents
399
399
401 401 401
401 401
Chapter 49. Single Ventricle Pathway: Simplified ........................................................403 Nageswara Rao Koneti, Vinoth Doraiswamy
Morphology 403
Hemodynamics 404
Clinical Features 404
Investigations 404
Management 405
Long-term Follow-up of Fontan
408
Chapter 50. Fontan Circulation: Simplified ....................................................................410 Jay Relan, Saurabh Kumar Gupta
Fontan Physiology 410
Indications for Fontan Operation 410
Selecting a Patient for Fontan Operation 411
Preparing for Fontan Operation 411
To Stage or Not to Stage Cavopulmonary Connection 412
Different Types of Fontan Circulation 414
Clinical Effects of Fontan Circulation 415
Long-term Effects and Complications 415
Outcome 417
Chapter 51. Ebstein’s Anomaly: What’s New?................................................................419 Jayaranganath M, Usha MK
Anatomy 419
Embryology 419 xxix
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Arrhythmias 420
Etiology and Genetic Factors 421
Differential Diagnosis 421
Pathophysiology
Natural History 421
Examination 422
Treatment 424
421
Chapter 52. Total Anomalous Pulmonary Venous Connection: An Overview ............................................................428 Sivasubramanian Ramakrishnan, Arvind Balaji, Kewal C Goswami
History 428
Prevalence and Etiology 428
Embryology 428
Morphology
Associated Lesions 429
Pathophysiology
Natural History 430
Clinical Features 430
Other Imaging
Management 433
428 429
433
Chapter 53. Pulmonary Arteriovenous Malformations .............................................435 Edwin Francis, Annu Jose, Bijesh Viswambaran
History 435
Etiology 435
Clinical Features 435
Investigations
Management 436
436
Chapter 54. Systemic Effects of Cyanosis .......................................................................439 Neeraj Awasthy, Naveen Kumar
Systemic Problems with Cyanosis 439
Failure to Thrive
Cyanotic Spell
440
Brain Abscess
440
Hematological Complications
Vascular Complications
Renal Problems
439
441
441
442
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Rheumatological Complications
Bacterial Endocarditis
Pulmonary Complications
Gallbladder stones
Ventricular Dysfunction
Dental abnormalities 444
442
443
Contents
Section 8
443
443 444
CARDIOMYOPATHY Chapter 55. Outcomes of Dilated Cardiomyopathy in 2018....................................449 KK Talwar, Raghav Bansal
Epidemiology and Natural History 449
Etiological Classification of DCM 450
Evaluation of DCM 451
Management of DCM 452
Specific Considerations for Common Secondary Etiologies 454
Chapter 56. Genetics of Cardiomyopathies: An Overview .......................................460 Ajay Bahl
General Principles 460
Dilated Cardiomyopathy 461
Hypertrophic Cardiomyopathy 462
Idiopathic Restrictive Cardiomyopathy 462
Arrhythmogenic Right Ventricular Cardiomyopathy 462
Indian Context 462
Chapter 57. Noninvasive Evaluation of Suspected Heart Muscle Disease ..............................................................464 Krishnam Raju P, Chandramukhi Sunehra
Echocardiography 464
Cardiac Magnetic Resonance Imaging 466
Nuclear Cardiac Imaging 467
Cardiac Computed Tomography 467
Dilated Cardiomyopathy
Hypertrophic Cardiomyopathy 468
Noncompaction Cardiomyopathy 470
Restrictive Cardiomyopathy 471
Idiopathic Restrictive Cardiomyopathy 472
467
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Cardiac Amyloidosis 472
Cardiac Magnetic Resonance Imaging 474
Nuclear Imaging in Cardiac Amyloidosis 474
Cardiac Sarcoidosis 474
Electrocardiogram
475
Echocardiography
475
Cardiac Magnetic Resonance 475
Positron Emission Tomography (PET) 475
Anderson-Fabry Disease 476
Echocardiographic Features 476
Cardiac Magnetic Resonance Imaging 476
Nuclear Imaging in Fabry Disease 476
Endomyocardial Fibrosis and Löffler’s Endocarditis 477
Echocardiography
Cardiac Magnetic Resonance Imaging 477
Arrhythmogenic Right Ventricular Dysplasia 477
Reversible Cardiomyopathies
Chemotherapy and Radiation-induced Cardiomyopathy 478
477
478
Chapter 58. Curable Forms of Ventricular Dysfunction .............................................481 Tamiruddin A Danwade, Calambur Narasimhan
Ischemic Cardiomyopathy (Coronary Artery Disease) 481
Hypertensive Heart Disease 482
Diabetes Mellitus 483
Valvular Heart Disease 483
Alcoholic Cardiomyopathy 483
Cocaine
Medications
Infectious Cardiomyopathy
484 484 484
Chapter 59. Myocarditis: An Update ................................................................................492 Neeraj Pandit, Mohit Bhutani
Etiopathogenesis 492
Classification of Myocarditis 492
Clinical Features 492
Investigations
Natural Course of Disease 494
Management 495
Future Directions 497
493
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Chapter 60. Tachycardiomyopathy ...................................................................................500
Introduction 500
Definition
Epidemiology 503
Pathophysiology 503
Clinical Features 503
Contents
Vikas Kataria, Gautam Singal, Mohan Nair 501
Chapter 61. The Role of Cardiovascular Magnetic Resonance in Risk Stratification of Hypertrophic Cardiomyopathy ....................506 Martin S Maron
Introduction 506 Cardiovascular Magnetic Resonance Characterization of Left Ventricular Hypertrophy and Impact on Risk Assessment 506
Left Ventricular Apical Aneurysm: High-risk Subgroup 506
CMR Tissue Characterization in HCM 507
Late Gadolinium Enhancement and Sudden Death Risk
Pattern of Late Gadolinium Enhancement 510
Additional CMR Methods of Tissue Characterization 511
Quantification of Late Gadolinium Enhancement 512
Late Gadolinium Enhancement and Systolic Dysfunction 512
508
Chapter 62. Constrictive Pericarditis and Restrictive Cardiomyopathy: How to Differentiate? .................................................514 V Jacob Jose
Pathophysiology of Constriction 514
Echo Doppler Signs 515
Cardiac Computed Tomography 517
Cardiac Magnetic Resonance (CMR) 517
Multimodality Imaging 517
Invasive Hemodynamics (Cardiac Catheterization) 520
Chapter 63. Tubercular Pericarditis ...................................................................................523 GC Khilnani, Saurabh Mittal
Epidemiology 523
Pathogenesis 523
Clinical features 523
Diagnosis 524
Differential Diagnosis 525
Treatment 525 xxxiii
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Chapter 64. Surgery for Chronic Constrictive Pericarditis, Tuberculous Pericarditis and Effusive-Constrictive Pericarditis ...............................526 Ujjwal Kumar Chowdhury, Lakshmi Kumari Sankhyan, Suruchi Hasija
Etiological Search 526
Clinical Challenge and Diagnostic Dilemma of CCP 526
Surgical Techniques and Results 530
Post-pericardiectomy Low Cardiac Output Syndrome 530
Specific Disease Entities 531
Management 532
Tuberculous Pericarditis 532
Tuberculous Pericardial Effusion 532
Treatment 533
Chapter 65. An Update on Restrictive Cardiomyopathy ...........................................536 Ramalingam Vadivelu, Rajesh Vijayvergiya
Etiology 536
Clinical Presentation 536
Diagnosis 536
Echocardiographic Findings in RCM 536
Hemodynamic in RCM 539
Common Causes of RCM 540
Chapter 66. Tropical Endomyocardial Fibrosis?............................................................546 A Vanishing Curious Disease Jaganmohan A Tharakan, Shomu Bohora, Sanjay G
Epidemiology
Endomyocardial Fibrosis in India 547
Etiology of Endomyocardial Fibrosis
Clinical Presentation 548
Laboratory Investigations 548
Natural History and Management
546 548
549
Is the Incidence and Prevalence of EMF on the Decline— A Vanishing and Curious Disease? 550
Chapter 67. Cardiac Amyloidosis: Diagnosis and Management ............................552 Santosh Kumar Chellapuram, Lalit Kumar
Pathophysiology
Clinical features 552
552
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AL Amyloidosis 553
Cardiac Magnetic Resonance and Radionuclear Testing 553
Cardiac Biomarkers 554
Management of Cardiac Failure 555
Transthyretin-related Amyloidosis 557
Novel Strategies 557
Cardiac Transplantation 557
Contents
Chapter 68. Cardiac Sarcoidosis .........................................................................................559 Ajit Thachil
Section 9
Incidence and Prevalence 559
Presentations 559
Prognosis 560
Diagnosis 561
Differential Diagnosis 563
Imaging in Cardiac Sarcoidosis 563
Treatment 566
VASCULAR SYSTEM Chapter 69. Imaging and Classification of Takayasu’s Arteritis ...............................575 Monotosh Panja, Arindam Pande, Madhumanti Panja
Imaging in Takayasu’s Arteritis 575
Chest Radiographic Features 575
Ultrasonography 575
Chapter 70. Immunotherapy for Nonspecific Aortoarteritis ...................................581 Narendra Bagri, Uma Kumar
Disease Activity and Severity
Immunotherapy 582
Corticosteroids 582
Nonbiological Disease Modifying Antirheumatic Drugs 582
Other DMARDs
Biologic Disease Modifying Anti-rheumatic Drugs 584
Other Biological agents
Immunotherapy During Surgery and Perioperative Period
Follow-up 584
581
583 584 584
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Essentials of Postgraduate Cardiology
Chapter 71. Interventions in Takayasu Arteritis (Nonspecific Aortoarteritis) ....586 Sanjay Tyagi, Ankit Bansal
Pathophysiology
Imaging for Interventions in Takayasu Arteritis 586
Interventions in Takayasu Arteritis 587
ARCH Artery Interventions 589
Recent Advances 593
586
Chapter 72. Aortic Diseases: When to Proceed with Surgery? ................................598 Shiv Kumar Choudhary, Aayush Goyal
Aortic Aneurysms 599
Acute Aortic Syndromes 601
Traumatic Aortic Injury 604
Arteritis
604
Chapter 73. Aortic Diseases: When and How to Proceed for Interventional Management? .............................................607 Mumun Sinha, Sanjiv Sharma
Imaging of Aortic Diseases 607
Steno-occlusive Lesions of Aorta 608
Dilatative or Aneurysmal Lesions 609
Aortitis
Aortic Dissection 610
Diseases Specific to Aortic Root and Ascending Aorta 611
609
Chapter 74. Pulmonary Embolism: When to do What? .............................................615 Bishav Mohan, Shibba Takkar Chhabra
Anticoagulation
Systemic Thrombolytic Therapy
Catheter-based Therapy 616
615 616
Chapter 75. Evaluation of Pulmonary Hypertension: A Simplified Algorithm..................................................................................624 Abhishek Goyal, Gurpreet S Wander
Definition and Classification 624
Algorithmic Approach to Pulmonary Hypertension 624
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Rajesh Kalyankar, BKS Sastry
Pharmacotherapy 630
Combination Therapy 630
Oral Anticoagulants 630
Stem Cell Therapy 632
Pulmonary Artery Denervation
Potts Shunt 632
Experimental Therapies 632
Contents
Chapter 76. Recent Advances in the Management of Idiopathic Pulmonary Artery Hypertension ..........................................630
632
Chapter 77. Kawasaki Disease: What We Should Know? ...........................................635 M Zulfikar Ahamed, Z Sajan Ahmad
Historical Perspective 635
Epidemiological Perspective 635
Pathology 636
Clinical Diagnosis 636
Laboratory Evaluation
Cardiovascular Manifestations in KD 638
Other Abnormalities 640
Other Investigations 640
Natural History 640
Special Concerns in KD 640
Treatment of KD 641
Standard Protocol Followed in Our Institution 642
Long-term Management
Protocol for Management
Interventions in KD 644
Natural History 645
Long-term Cardiac Damage 645
Indications for Coronary Angiography
637
643 644
645
Section 10 ELECTROCARDIOLOGY Chapter 78. Common Pitfalls and Artifacts in ECG Interpretation ........................651 SB Gupta
Limitations 651
Normal ECG in Pathological Conditions 651 xxxvii
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Essentials of Postgraduate Cardiology
Common Pitfalls in Diagnosis of Coronary Artery Disease on ECG 652
Abnormal ECG with Normal Hearts 654
Common Artifacts in ECG Interpretation 654
Lead Misplacements 656
Chapter 79. Computerized ECGs: Strengths and Limitations..................................663 Kartikeya Bhargava
Computerized ECG: Methodology and Technical Aspects 663
Accuracy of Computer-Interpreted Electrocardiograms 664
Utility of Computer-Interpreted ECG in Specific Diagnosis 664
Computerized ECGs: Strengths and Limitations— General Comments and Concluding Remarks 667
Chapter 80. ECG Assessment of Supraventricular Tachycardia...............................675 Amit Vora, Samhita Kulkarni
Steps in the ECG Analysis of SVTs 675
ECG Analysis of Different SVTs 675
Chapter 81. ECG Assessment of Wide QRS Tachycardia ............................................684 Binay Kumar, Yash Lokhandwala
Types of Wide QRS Tachycardia 684
Steps for Ventricular Tachycardia Discrimination 684
Assessment of QRS Regularity 685
Identification of P Wave 687
Relationship between P and QRS 687
Morphologic Analysis of the Wide QRS Complex: Comparison with Sinus Rhythm 688
Chapter 82. Atrioventricular Block: Diagnosing the Level of Block.......................692 Avinash Anantharaj, Anandaraja Subramanian
Localization of the Site of Block 693
Chapter 83. STEMI Equivalents ...........................................................................................699 Arun K Chopra
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Isolated True Posterior Myocardial Infarction 699
Hyperacute T Waves 699
De Winter Sign 700
Isolated ST Depression in AVL 700
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Wellens’ Syndrome 700
Isolated ST Elevation in AVR 700
New or Presumed New Left Bundle Branch Block 701
Stemi Equivalents in Paced Patients 703
Contents
Section 11 LET’S FACE THE VIVA Chapter 84. Recent Advances in Echocardiographic Strain Imaging ...................709 Nobuyuki Kagiyama, Yuko Soyama, John Gorcsan III
Fundamentals of Strain Imaging 709
Global Longitudinal Strain 709
Normal Longitudinal Strain Values 709
Relationship of GLS to Ejection Fraction 710
GLS in Heart Failure with Reduced Ejection Fraction 710
GLS in Heart Failure with Preserved Ejection Fraction 712
GLS in Acute Heart Failure 712
Longitudinal Strain in Cardiac Amyloidosis 712
GLS in Monitoring Cardiotoxicity for Chemotherapy
GLS in Valvular Heart Disease 713
713
Chapter 85. Hemodynamic Assessment in the Cardiac Catheterization Laboratory .........................................................716 Jaganmohan A Tharakan, Sanjay G
How to Perform an Invasive Hemodynamic Study? 716
General Cues Obtained During any Hemodynamic Study 716
Provocative Maneuvers in Cardiac Catheterization Laboratory 717
Evaluation of Patients with Congenital Heart Diseases 719
Evaluation of a Patient with Pulmonary Hypertension 721
Transpulmonary Gradient, Diastolic Pulmonary Gradient 721
Heart Failure and Transplantation 721
Pericardial Diseases 722
Evaluation of Obstructive Lesions 722
Evaluation of Patients with Ischemic Heart Disease 725
Postmyocardial Infarction 728
Chapter 86. Interpretation of Catheterization Traces .................................................729 Sriram Rajagopal, Lakshmi Gopalakrishnan
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Steps in the Process of Interpretation 729
Normal Physiology 729
Technical Aspects 730
Correlation of Pressure Traces with Electrocardiographic Events 731
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Chapter 87. Interpreting a Nuclear Stress Test..............................................................736 Essentials of Postgraduate Cardiology
Girish Kumar Parida, Abhinav Singhal, Chetan D Patel
Patient Preparation 736
Stress Protocols 736
Radiotracers and Image Acquisition Protocol 737
Image Display 737
Interpretation 737
Gated SPECT Parameters 741
Final Reporting of MPS 743
Chapter 88. Cardiac Tumors: Practical Approach and Management ....................746 Kewal C Goswami, Preetam Krishnamurthy
Epidemiology 746
Classification 746
Histopathology 747
Clinical Features 747
Examination 749
Clinical Diagnosis 749
Diagnostic Evaluation 751
Management 753
Benign Cardiac Tumors
Malignant Cardiac Tumors 755
753
Index .................................................................................................................................................... 761
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Clinical Cardiology Jugular Venous Pulse: Elusive but Adorable
Varun S Narain, Gaurav Choudhary How to Measure Blood Pressure in Children and Adults? A Guide
Justin Paul G, Sandeep S, Kumaran S Peripheral Signs of Aortic Regurgitation: Revisited
S Shanmugasundaram, B Vinodkumar, U Ilayaraja Clinical Examination in Atrial Fibrillation
Ganesh Kumar Kasinadhuni, Parag Barwad Continuous Murmur
Ranjit Kumar Nath Dynamic Auscultation
Rishi Sethi, Akshyaya Pradhan, Snigdha Boddu
S E C T I O N
1 KG-1 (Sec-1).indd 1
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Jugular Venous Pulse: CHAPTER 1 Elusive but Adorable Varun S Narain, Gaurav Choudhary
INTRODUCTION Examination of the jugular venous pulse (JVP) is an important initial step in the examination of the cardiovascular system. It is a treasure-chest of diagnostic possibilities. It is also the trickiest part of the examination, often misinterpreted, underused, and even ignored. One must learn to use JVP, not only for its merit of giving clues to the diagnosis, but also to understand the underlying hemodynamics of the condition, which would ultimately help in guiding management of the case in question. This review will look at the anatomical, physiological, technical, and applied aspects of the JVP. The systemic veins are thin walled mildly distensible reservoirs analogous to a partially filled surgical glove, filled in the upright position and collapsed above the level. Tge blood flows up to. Blood flows in from the venous return (VR) and flows out by the pumping action of the right ventricle (RV), wherein the pressure is maintained by variation in the RV contractility as dictated by the Frank– Starling law. Failure of this hemostatic mechanism leads to excess volume and pressure and a rise in the JVP.1
EXAMINATION OF THE JUGULAR VENOUS PULSE There are two parts to the examination of the JVP:
and could be used as a guide to intensify diuretic use. This is not true in case of raised JVP in RV infarction, where diuretic use may cause hypotension.
Jugular Venous Waveforms It was Potain who first described the jugular venous waveform; however, James Mckenzie named the JVP waves and established it as an important part of the clinical examination.
External and Internal Jugular Veins Before we begin the examination and interpretation of the JVP, it is important to identify the external and internal jugular veins correctly. The external jugular vein (EJV) runs from lateral to medial side of the neck across the sternocleidomastoid muscle and can be made prominent by putting a forefinger just above the clavicle and pressing gently. Pressing at the angle of the jaw prevents filling from above and the height of the column of blood left in the vein reflects the RA pressures. The internal jugular vein (IJV) starts at the base of the neck and runs between the two heads of the sternocleidomastoid to reach the angle of the jaw (Figure 1). The IJV may not be seen until there is significant tricuspid regurgitation (TR). However, we look at its conducted pulsations on the skin.
Jugular Venous Pressure Vertical height of oscillating column of blood in the right internal jugular vein (IJV) reflects the pressure changes in the right atrium during the cardiac cycle. The IJVs being continuous with the superior vena cava (SVC) act as ‘pulsating manometers’ for right-sided pressure.2 During the ventricular systole, it provides information on right atrial (RA) pressure; while during the diastolic phase, when the tricuspid valve (TV) is open, it reflects the right ventricular (RV) diastolic pressure. The JVP may underestimate RA pressures especially when the venous pressures are high. This may be due to the valve near the termination of the internal jugular vein. All in all, in congestive heart failure, if the JVP is raised, RA pressure is at least as high as or higher than the height of the column
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Figure 1: Landmarks for identification of the external and internal jugular veins
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Three other questions need an answer: Is this pulsation due to the internal jugular or the carotid? In comparison to the carotid pulsation, jugular venous pulsations are more laterally located, soft, diffuse, undulant, and hardly palpable with two crests and two troughs (carotids have a single motion). Unlike the carotids, jugular venous pulsations are obliterated by slight pressure at the base of the neck. The height of JVP varies with change in position, increases on abdominal compression and falls during inspiration (except in Kussmaul’s physiology). While the carotids have a prominent positive pulsation, the movement of the jugular venous pulse is predominantly a descent.1 In normal subjects, the descent of the carotids is rapid while that of the jugulars, slow. Why choose the internal jugular vein (IJV) over external jugular (EJV) vein? 1. The IJV is in direct line with the superior vena cava (SVC) and thus courses directly into right atrium, while the EJV does not directly drain into the SVC taking two almost 90 degrees bends before joining it. 2. The course of EJV to the SVC passes through several facial planes and is prone to obstruction. 3. Thrombus formation in the bulb of the EJV can cause partial obstruction and rise in pressure. 4. On lateral movement of the head, the contraction of the platysma muscles can cause partial obstruction of the EJV and raise the pressure. 5. Because of the presence of valves in EJV pulsations may not be seen. 6. During conditions such as cardiogenic shock and even in congestive heart failure, because of vasoconstriction EJV may be small and barely visible. EJVs are still useful: Despite their limitations, the EJVs are paradoxically better visualized and engorged when pressure is raised versus the IJVs whose pulsations may not be easy to see on the skin except when associated with a significant TR. At such times, the EJVs may be used for assessment of RA pressure. In fact, they may even be preferred due to their better visibility.3 Also, in case of severe TR when IJV pulsations cannot be relied upon to assess RA pressure, the EJVs may be of sole help. Checking the EJV also helps in quickly establishing the JVP as normal/raised. After light pressure has distended the initially collapsed vein, release should rapidly clear it if the pressure is normal. If the rise persists or the decline is slow, the pressure is assumed to be raised.2
4
Why the right IJV? 1. The right IJV is in an almost straight line with the SVC and RA and thus better reflects the hemodynamic changes from the RA. 2. There is greater filling of the right innominate vein from the right side of the head. 3. The left innominate vein is prone to kinking or compression between the aortic arch and sternum, by a dilated aorta, or by an aneurysm.
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4. In case of persistent left SVC, the pressure in the left IJV would be higher than the right due to greater emptying resistance while draining into the coronary sinus. This may be the case especially in atrial septal defect (ASD).
INTERPRETATION OF THE JUGULAR VENOUS PULSE Interpretation of the JVP is done under the following heads: 1. Jugular venous pressure 2. Respiratory variation 3. Hepatojugular reflux/abdominal compression test 4. Waveforms. Close adherence to details of methodology are essential for reliability and reproducibility in measuring the jugular venous pressure and assessing waveforms.
Jugular Venous Pressure Positioning the Patient (Figure 2) The patient should be lying comfortably in a semireclining position with 45° angle between the trunk and the bed with the head slightly turned towards the left shoulder, so that the neck muscles are relaxed. It is helpful to place a folded pillow behind the patients head, keeping the shoulders on the mattress. Standing to the right, with a gentle pressure with the palm on the forehead turning the head away to the left, slightly raising the jaw, brings the venous meniscus into the window of visibility. Natural light is desirable for inspection; but, at times, the use of a tangential beam of light at the skin with a torch from the front or behind to casts shadows improves visibility of motion. One must keep the hand holding the torch steady by keeping it on the chest or a pillow to prevent artefacts interfering with interpretation of the JVP. 45 degrees inclination: Why? In a healthy person, the visible jugulars are fully collapsed in the sitting posture and distended to a variable degree when supine. Selecting an appropriate intermediate position permits one to see the top of the pulsating column between the clavicle and the mandible. This angle is generally between 30 and 60 degrees. A standard of 45 degrees is chosen. Sitting up may be required if the upper level goes up to the jaw. Earlobe pulsations may be looked for. While no standard exists for the height of the vertical column in the sitting posture in normal pressures, pulsations going up to the jaw at 90 degrees generally means a pressure of 25 mm Hg or more. Further, at 45 degrees inclination and a normal pressure of 8 mm blood column/water and assuming the mid-RA to be 5 cm from sternal angle and the vertical distance from here to the clavicle being 3 cm any visibility of the JVP above the clavicle at this inclination is a qualitative indication of it being raised (Figure 2). At 45 degrees inclination, the upper limit of normal is 4.5 cm of blood column: easy to remember.
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1 Jugular Venous Pulse: Elusive but Adorable
Figure 2: Positioning and method of measuring the jugular venous pulse
There is some concern that the RA pressure is underestimated by adding 5 cm to the height of the JVP. A CT study has shown that the center of the RA was 5.4 cm from the sternal angle in the supine posture, and increased to 8, 9.7 and 9.8 cm on torso rotation to 30, 45 and 60 degrees, respectively. There is also a wide range of variation from 5 to 30 cm at 30 degrees inclination. It is suggested to add 10 cm instead of 5 cm at elevations more than 45 degrees.4,5 The phlebostatic axis of Burch is a line representing the intersection of the mid-axillary line and the fourth intercostal space. It passes through the posterior RA and has been suggested by some as a reference point for the RA, but it is useful only in the supine posture and may not be relevant in the obese or those with barrel-shaped chests due to lung disease.1
Locating the Sternal Angle (Angle of Louis/Lewis/Ludwig) It is the palpable transverse prominence at the junction of the manubrium to the body of the sternum at the level of 2nd costal cartilage and is taken as the reference zero point for measuring pressures.
Measurement Two rulers are required, one placed horizontal to the upper level of pulsation and another taking the vertical distance of that ruler from the sternal angle. Measure the vertical distance (in cm) between the horizontal lines drawn from the upper level of venous pulsation and the sternal angle as shown in Figure 2.
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Some suggest use of a tongue depressor with measure markings in cm as the vertical tool and the carpenter’s spirit level as the horizontal tool for comfort and accuracy, respectively; but this is rather cumbersome.
Calculation of Right Atrial Pressure Normally, the center of RA is 5 cm below the sternal angle. Hence, 5 cm is added to the above measurement to obtain the right atrial pressure. To convert cm of H2O to mm Hg, a conversion factor as 1.36 cm of H2O or blood = 1 mm Hg is applied; another conversion is to multiply the height of the blood/water column by 0.74.6 Causes of raised central and RA pressures are obstruction at the tricuspid valve, RV systolic and/or diastolic failure such as in RV infarct, pulmonary hypertension, primary or secondary to left ventricular failure, pulmonic stenosis, Bernheim effect, pericardial disease, primary tricuspid valve incompetence, generalized volume overload either iatrogenic or due to anemia, renal disease, large atrioventricular communications and ASD.6,7
Respiratory Variation During inspiration, there is increase in visibility of JVP, especially the “a” wave (the ‘x’ and the ‘y’ descents may also become prominent), while the mean jugular venous pressure falls. However, when there is inspiratory rise or no fall in venous pressure when the heart is unable to accommodate increased volume, it is called Kussmaul’s sign. It is typically seen in constrictive pericarditis.
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Other causes of a positive Kussmaul’s sign are: right ventricular myocardial infarction (RVMI), restrictive cardiomyopathy, massive pulmonary embolism, tricuspid stenosis, right-sided tumors, and SVC obstruction. In the SVC obstruction, the elevated JVP is nonpulsatile and without any respiratory variation.
Hepatojugular Reflux Hepatojugular reflux (HJR) is also known as PasteurRondot maneuver. Jugular venous pressure is raised in congestive cardiac failure (CCF) with low output because of both increase in volume and venous tone. While this tone volume increase persists, the JVP may be high but still within the upper limits of normal and not visible. This may also occur with the use of diuretics. The use of abdominal compression will uncover this situation by causing and maintaining a rise in the upper level of venous pulsations in those with high venous, even high right atrial and right ventricular tone. 8 The greater the rise, the greater the venous pressure. This was originally called the hepatojugular reflux (not reflex: there are no neurons involved here!) being described by Pasteur in 1885 as a diagnostic test for tricuspid regurgitation; 9 and, later by Rondot in 1898 in CCF. Hence, the name. It was later realized that decompressing the congested liver was not essential to this sign and that it could be elicited even in those with no hepatomegaly. We now know that the increase in the JVP can occur with compression anywhere over the abdomen, though the best results come from pressing over the right upper quadrant.8 This should be avoided in case of tender hepatomegaly. Hence, the better term would be abdominal compression test.
Method The palm of the right hand is placed either in the center of the abdomen or in the right upper quadrant of the abdomen. Let it be warm (a garment/sheet between the patient and the palm may be a good idea if it is cold). Spreading the fingers prevents local pressure and pain. Also, explaining the procedure to the patient and asking him/her not to hold the breath (lest one lands up with a Valsalva maneuver) helps. It is preferable to start with a gentle pressure building it up gradually to approximately 20–35 mm Hg pressure of 15 seconds duration. Normally the pressure rises, but the rise is less than 3 mm Hg and this rise returns to normal within 10 seconds/a few beats. A rise of at least 3 cm for the entire duration of compression or may be even after release (more than 15 seconds) the test is considered positive.8,10,11 Mechanism of rise of venous pressure on abdominal compression are not clear but could include: (i) Increase in venous return cannot be accommodated by the already volume loaded right heart with increased tone and on
Figure 3: Normal jugular pulse waveforms in relation to the cardiac cycle and heart sounds
an upper limit of compliance; (ii) Displacement of blood from the visceral vessels to larger vessels viz. SVC with increased tone; (iii) The raised diaphragm decreases the intrathoracic and mediastinal volumes available for cardiac expansion, and (iv) Compression per se can increase the venous tone.10 A positive test in those without isolated heart failure means a capillary wedge pressure of 15 mm Hg or higher. A false-positive test can occur in those with chronic obstructive lung disease, other lung conditions with loss of vital capacity, increased blood volume, and with increased sympathetic stimulation such as nervousness, pain, acute infarct, or catecholamine infusions.10
Waveforms There are two positive waves and two descents or troughs seen in a normal JVP. Figure 3 illustrates the normal jugular venous waves and their relation to the cardiac cycle as well as heart sounds. Table 1 describes each wave and the physiological basis for each waveform. Jugular venous pulsations closely reflect transmitted changes in RA pressures with a pulsation delay of approximately 60–110 msec.6
IDENTIFICATION OF WAVES Identification of waves is easier described than is practical, but with repeated practice, the skill is bound to improve with time and experience.
Tips for the Board Examination Look more for the descents. Inward collapsing movements are easier to see. Time with radial pulse and heart sounds: If the negative wave comes with the radial pulse, it is ‘x’. If the nadir coincides with S2, it is again ‘x’.
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Table 1: Normal JVP waveforms and the genesis of production
1
Occurs during atrial systole and is due to increased pressure because of atrial contraction. It is the dominant wave occurring before carotid pulsation and S1
‘x’ descent
Primarily due to atrial relaxation but the part of ‘x’ descent after the ‘c’ wave (‘x’) is contributed by the descent of the tricuspid ring caudally during ventricular contraction
‘c’ wave
Is seen on the ‘x’ descent and it is due to carotid artefact and in the recordings during cardiac catheterization is due to the upward bulging motion of the closed tricuspid valve during isovolumetric ventricular contraction
‘v’ wave
Seen due to rise in the right atrial pressure due to passive filling from the systemic veins and the tricuspid valve closed during ventricular systole. ‘v’ peaks just after the S2 and can be timed with the downslope of the carotid pulse
‘y’ wave
It is a negative deflection with fall in right atrial pressure due to opening of the tricuspid valve and continues during the rapid filling phase of the right ventricle
‘H’ wave
Seen usually during slow rate. Occurs due to passive right heart filling during the diastole (Diastasis). It occurs just prior to the ‘a’ wave. Pre-atrial systolic squeeze from the pulmonary veins has also been quoted as a cause
If you are looking at the positive waves, then that which comes with S1 is ‘a’ and that with S2 is ‘v’.
ABNORMAL CONTOURS: WHAT THEY SAY ‘a’ Waves
Still not Sure: Correlate with Clinical Findings
Tall ‘a’ Waves
Single wave: Atrial fibrillation: Say that the wave seen is ‘v’.
It is seen when the RA contract against an appreciable resistance either at the tricuspid valve level (atresia, s t e n o s i s, m y x o m a t h ro m b u s, c a rc i n o i d , l u p u s endocarditis), intraventricular level (RV hypertrophy, subvalve stenosis) or beyond (pulmonary stenosis or pulmonary regurgitation). Prominent ‘a’ wave of tricuspid stenosis is shown in Figures 4A and B. A Berheim phenomenon due to left ventricular hypertrophy has also been described as a cause of a tall ‘a’. In the setting of congenital heart disease, large ‘a’ waves speak of intact interventricular and interatrial septa. When the ‘a’ waves are considerably large-more than 4.5 cm at 45 degrees inclination-they may be called giant
Single wave: Sinus rhythm: Tricuspid regurgitation (TR): ‘v’ again. Two waves: Rheumatic heart disease, heart failure, no TR: Say both present; ‘a’ prominent. Two waves: Congenital heart disease [pulmonary stenosis (PS), pulmonary arterial hypertension (PAH)] intact septum, no TR: Say both present; ‘a’ prominent. Two waves: Cannot decide: Say both ‘a’ and ‘v’ prominent. Constrictive pericarditis/restrictive cardiomyopathy (RCM) : Say both ‘x’ and ‘y’descents prominent.
A
Jugular Venous Pulse: Elusive but Adorable
‘a’ wave
B
Figures 4A and B: Jugular venous pulse in (A) Tricuspid stenosis: Tall ‘a’ with slow ‘y’ descent; (B) Tricuspid regurgitation: Loss of ‘x’ and prominent ‘cv’ wave
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A
B
Figures 5A and B: Cannon waves in complete heart block. (A) Differentiation between a tall ‘a’ wave (presystolic); and (B) A cannon ‘a’ wave (systolic)
‘a’ waves. Seen better on tracings, they produce a flicker in the right supraclavicular area. Giant ‘a’ wave may also produce a knocking sound in the neck during inspiration.8 Giant ‘a’ waves are presystolic, abrupt with collapsing quality, and often palpable. They measure 6–15 cm higher than the ‘v’ waves and are referred to as jugular Corrigans .11
Cannon Waves They are extreme forms of tall ‘a’ waves seen when the RA contracts against a closed tricuspid valve. Cannon waves offer diagnostic help in arrhythmias: Irregular cannon waves are seen commonly with ectopic beats, and in complete heart block (rate slow) (Figures 5A and B) and in ventricular tachycardia (fast rate). Regular cannon waves can occur in atrioventricular (AV) nodal and AV re-entrant tachycardias, slow ventricular tachycardias, 2:1 AV blocks and first-degree AV blocks with such prolonged PR that the atrial systole occurs during the preceding ventricular systole. Cannon waves with auscultation of S1 can help in the differential diagnosis of wide QRS tachycardias. The absence of cannon ‘a’ waves and constant intensity of S1 suggests a supraventricular rhythm with aberrancy.10 Cannon waves are more easily recorded (hence given this name from appearance) than seen.11 Pronounced efflux of blood during simultaneous contraction of the atria and ventricles during junctional tachycardia gives a feeling of neck pulsations as in a frog. Hence, called frog positive by Brugada.12
Figure 6: Jugular venous pulse in atrial fibrillation: Absent ‘a’ waves, attenuated ‘x’ descent
Flutter waves are occasionally visualized. A giant silent atrium as in Ebstein’s anomaly does not possess effective mechanical systole and ‘a’ waves may be absent.
‘x’ Descent Attenuated/Absent ‘x’ When it is encroached upon by increasing degrees of TR (Figure 4B) or when there is absence/reduction of the descent of the base due to poor contractility of the right ventricle as in RV infarct or because of atrial fibrillation/ flutter, the Frank–Starling effect is weakened, the descent of base is absent.
Absent ‘a’ Wave
Increased Depth of the ‘x’ Descent
Most common with atrial fibrillation (Figure 6) where an absent ‘a’ wave is accompanied by an attenuated ‘x’ and a dominant ‘y’ descent.
Increased volume in the RV as in atrial septal defect, total anomalous pulmonary venous connection, pulmonary regurgitation increases right ventricular contractility
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exaggerating the descent of base, and hence the ‘x’ descent. In cardiac tamponade, RA filling is uni-modal occurring only in systole. Hence, a prominent ‘x’ descent. The absence or limitation of RA filling during diastole flattens or eliminates the ‘y’ wave. The ‘x’ descent is prominent along with a steep ‘y’ in constrictive pericarditis and restrictive cardiomyopathy.
1 Jugular Venous Pulse: Elusive but Adorable
‘v’ Waves Large ‘v’ Waves They are usually recognized by their association with deeper ‘y’ descents. They are produced because of greater RA filling as in tricuspid regurgitation (TR) (Lancisi sign). A large ‘v’ wave fused with the ‘c’ wave is seen in severe TR and the descent is replaced by the ‘cv’ wave that is followed by a steep ‘y’ descent due to increased flow and gradient across the tricuspid valve in early diastole (Figure 4B). Due to increased influx of blood into the right IJV which in straight line with the RA through the SVC, a right to left ‘head bob’ may be seen on frontal examination.8 A large ‘v’ wave due to increased right atrial filling is also seen in ASD (which also has a deeper ‘x’ descent) (Figure 7), total anomalous pulmonary venous drainage, absent pericardium, and hyperdynamic circulatory states. Reduced or loss of compliance of the RA as in constrictive pericarditis or after surgery also gives large ‘v’ waves. In right ventricular hypertrophy of pulmonary outflow obstruction or heart failure where the end-diastolic pressure is raised, the RA pressure is already high (AV valve is open), when its filling starts, giving a more prominent ‘v’ wave.8,11
Figure 7: Jugular venous pulse in atrial septal defect: Prominent ‘a’, ‘v’, ‘x’, and ‘y’
Pericardial Disease
‘y’ Descent Slow Descent Seen typically in tricuspid stenosis due to atrial outflow obstruction (Figure 4A) and in RV hypertrophy due to outflow resistance—a steep descent rules out a significant tricuspid valve obstruction.
Rapid or Sharp Descent Prominent sharp descents occur in conditions of increased ‘v’ wave. In constrictive pericarditis, we have a very rapid sharp ‘y’ without ‘v’ prominence (Friedrich’s sign). Similar findings are found in restrictive cardiomyopathy.
Prominent and widened ‘a’ (>0.18 sec)(stronger atrial contraction: Frank–Starling law) Deep ‘x’ (Stronger RV contraction with increased descent of base) Large steep ‘v’ (increased filling of RA)
x > y: Right ventricle is compensated x = y: Beginning of right ventricular decompensation x < y: Right ventricle is decompensated.
Congenital Heart Disease
Specifics
In cardiac tamponade, ‘x’ is prominent and the ‘y’ is almost absent (atrial filling is unimodal: occurs only in systole). In constrictive pericarditis, both ‘x’ and ‘y’ are present with a dominant ‘y’ (atrial filling is bimodal but most right ventricular filling occurs in early diastole). A dominant ‘x’ with a fair almost equal ‘y’: Effusive constrictive pericarditis or milder form of constriction.
Pulmonary Artery Hypertension11
Atrial Septal Defect (Figure 7)
Deep ‘y’ (rapid emptying of a large amount of blood from RA
Tetralogy of Fallot (TOF): Usually normal unless in failure as in adult TOF or associated comorbidities. Pulmonic stenosis with intact interventricular septum: Right-to-left shunting at atrial level; raised JVP; ‘a’ prominent; tricuspid leak; prominent ‘v’ and ‘y’ waves. Tricuspid atresia : Raised JVP ; restrictive ASD; prominent ‘a’ wave. Transposition of great vessels with increased pulmonary blood flow; raised JVP; ‘a’ wave may be prominent. Eisenmenger syndrome: Small dominant ‘a’ in onefourth of all cases. 9
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A giant (6 cm or more) ‘a’ wave is seen in a small percentage of Eisenmenger ASD, rarely to never in those with ventricular septal defects or patent ductus arteriosus. If there is accompanying tricuspid leak, ‘v’ waves can become prominent.11
CONCLUSION In an age of advances in technology, neglect of physical signs referred to as hyposkillia13 is a malady plaguing the cardiologists at many levels of seniority and experience. As persons involved in dealing with a large number of patients where and to whom technology is not immediately available and as teachers who have the responsibility of taking clinical skills forward from our generation to the next, honing and stressing upon their improvement is important. The JVP assessment is not easy but continuing to focus and sharing ones findings with peers and senior colleagues who have had more experience will certainly lead to improvement in the diagnostic acumen. After all, Wenckebach first diagnosed the phenomenon, named after him, not by the ECG but by looking at the jugular venous pulsation.
REFERENCES 1. Chua Chiaco JM, Parikh NI, Fergusson DJ. The jugular venous pressure revisited. Cleve Clin J Med. 2013;80(10):638-44. 2. Constant J. Using internal jugular pulsations as a manometer for right atrial pressure measurements. Cardiology. 2000;93(1-2):26-30.
3. Vinayak AG, Levitt J, Gehlbach B, et al. Usefulness of the external jugular vein examination in detecting abnormal central venous pressure in critically ill patients. Arch Intern Med. 2006;166(19):2132-7. 4. Devine PJ, Sullenberger LE, Bellin DA, et al. Jugular venous pulse: window into the right heart. South Med J. 2007;100(10):1022-7. 5. Seth R, Magner P, Matzinger F, et al. How far is the sternal angle from the mid-right atrium. J Gen Intern Med. 2002;17(11):852-6. 6. Kanu Chatterjee. Physical exam. In: Manual of Cardiac Diagnosis. Kanu Chatterjee, Mark Anderson, Donald H Eistad, Richard E Kerber (eds). New Delhi:Jaypee Brothers Medical Publishers, 2014. 7. Willems J, Roelandt J, Kesteloot H. The jugular venous pulse tracing. Proc Vth European Cong Cardiol, 1968. pp. 433. 8. Constant J. Jugular pressure and pulsations. Essentials of Bedside Cardiology. Humana Press, 2003. pp. 63-88. 9. Pasteur W. Note on a new physical sign of tricuspid regurgitation. Lancet. 1885;2:524-5. 10. Theo E Meyer, Mark H Drazner, Susan B Yeon. Examination of the jugular venous pulse, 2018. 11. Oomen K George, Bobby John. Jugular venous pulse. In: Cardiology Clinical Methods. V JacobJose, S Ramakrishnan (eds). New Delhi:Jaypee Brothers Medical Publishers, 2017. pp. 23-40. 12. V Jacob Jose, S Ramakrishnan. History taking. Cardiology Clinical Methods. New Delhi:Jaypee Brothers Medical Publishers, 2017. pp. 11. 13. Herbert L Fred. Hyposkillia: Deficiency of clinical skills. Tex Heart Inst J. 2005;32(3):255–7.
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How to Measure Blood Pressure CHAPTER 2 in Children and Adults? A Guide Justin Paul G, Sandeep S, Kumaran S
INTRODUCTION Hypertension is a cause of significant morbidity and mortality in the population. The patients have to bear costs for their treatment and the pill burden adds on to their difficulty. The overall crude prevalence of hypertension in India was 25.3% with significant differences noted between rural and urban parts. Globally, however, the overall prevalence of hypertension in adults aged 25 and more was 40% in 2008. The concept of hypertension has undergone several changes over the years. Revolutionary changes with respect to our understanding of the pathophysiology, diagnosis and therapeutics have taken place relatively recently over the past hundred years. The discovery of thiazide diuretics in the late 1950s made some progress towards management of hypertension. The Veterans Affairs Cooperative trial started in 1964 demonstrated that treatment of diastolic blood pressure (BP) to less than 90 mm Hg reduced cardiovascular (CV) events significantly. Numerous trials on hypertension after that have consistently demonstrated the benefit of lowering BP. The diagnosis of hypertension relies heavily on accurate measurement. This article gives an outline on measurement of BP in adults and children and highlights the associated practical challenges.
HISTORY OF BLOOD PRESSURE MEASUREMENT The path-breaking concept of pressure within the cardiovascular system (CVS) was demonstrated by the pioneering work of Stephen Hales. He tied a mare down alive and after opening its left crural artery, inserted a brass pipe whose bore was one-sixth an inch of a diameter (Figure 1). He fixed a glass pipe of the same diameter nearly nine meters in length. He noticed that after untying the ligature, the blood column rose to 8 feet and 3 inches and at its maximum height would rise and fall after each pulse 2 to ever 4 inches. Thus, it was in 1733 that the first measurement of BP was made.
Use of Mercury in Measuring Blood Pressure Mercury is a stable fluid at room temperature, with a specific gravity of 13.6. This means that compared to water
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Figure 1: An artist’s impression of Hales’ experiments to determine blood pressure of a horse
if mercury is used for measuring BP, the height of the column required will be 13.6 times less and measurement can be done with greater ease. Further, the silvery appearance of mercury imparts greater visibility. The height, to which the mercury column rises, is reported as unit of pressure in mm of Hg. It was Poiseuille who first innovated the use of mercury for measuring arterial BP. This earned him a gold medal at the Royal Academy of Medicine. Later, Ludwig, in 1847, developed the kymograph which gave a primitive graphical representation of the arterial pulse. Initial equipment used in measuring BP although conceptually great was invasive and cumbersome for clinical use. This provoked a search for development of noninvasive techniques of BP measurement. Simultaneous developments in physics, science and technology have led to further innovations and we now have the measuring devices which are non-invasive and comfortable for use.
NONINVASIVE TECHNIQUES The First Sphygmomanometer In 1855, Lord Vierordt postulated that BP can be estimated by applying counter-pressure causing the pulsation in an artery to cease. He developed a device which could estimate the BP using this principle (Figure 2).
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Figure 2: Vierordt’s sphygmograph. The pad is applied over the radial artery. Weights are placed in the large cup until a pulse wave is traced out, then weights are placed in the smaller cup which acts as a fine adjuster
Figure 3: Marey’s modification. A direct sphygmograph attributed to Marey, was a modification of Vierordt’s syphgmograph
However, this device was cumbersome and the process was tedious and difficult. This device was subsequently modified by Marey in 1860 (Figure 3). Potain added to the design. Thus, there was a gradual improvement in the style of measuring BP with new methods slowly being accepted (Figure 3). Riva Rocci Cuff: It was in 1896, that Riva Rocci reported a method which involved compression of the arm around its whole circumference by a rubber bag (tube of a bicycle wheel) which was surrounded by some inexpansible material. The pressure in the cuff was measured using a mercury manometer, and was steadily increased until the radial pulse could no longer be palpated. Subsequently, the pressure was slowly released watching the mercury level in the manometer fall. The reading at which pulse reappeared was taken as the systolic BP. The present-day technique uses this same principle (Figure 4).
PRESENT-DAY METHODS The currently used sphygmomanometers are in fact a progressive modification of previous primitive models. There are three main methods of BP measurements in adults which are widely practiced in clinical use. These include mercury sphygmomanometer, aneroid manometer, and oscillometric manometers. These methods have their own advantages and disadvantages.
Mercury Sphygmomanometer This is the most widely used method in most developing countries. However, it is losing its charm due to rising environmental concerns. The appropriate use of mercury sphygmomanometer and its practical challenges are discussed later in this chapter.
Aneroid Manometers These have the advantage of being portable but have the disadvantage of losing its calibration over time which
Figure 4: Riva Rocci’s demonstration of measurement of blood pressure. Riva Rocci used a narrow cuff which rendered readings inaccurate. It was later modified by Von Recklinghausen who used a wider cuff to obtain accurate readings
makes them less dependable. The pressure is registered by a system of metal bellows that expands as the cuff pressure increases and a series of levers that register pressure on a circular scale. They can lose their stability over time.
Oscillometric Methods This is currently the recommended method for BP measurement. The oscillometric devices work on the principle that blood flowing through an artery causes vibrations in the arterial wall which can be detected and transduced to electric signals that can be presented as a digital readout. The cuff in oscillometric method is placed on the arm. It uses fuzzy logic to decide how much cuff should be inflated to reach a pressure almost 20 mm Hg over the systolic BP for any individual. When the cuff is inflated to reach this pressure, no blood flow occurs through the artery. As the cuff is deflated below the systolic BP, blood flow is re-established and sets up a detectable vibration
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Digital Sphygmomanometer This is a hybrid device using features of both electronic and auscultatory method. The mercury column is replaced by an electronic pressure gauge as is used in oscillometric devices. BP is measured using the standard auscultatory technique. The cuff pressure is usually displayed as a simulated mercury column, as a digital readout or as a simulated aneroid display. The other newer techniques of measurement includes finger cuff method of Penaz, ultrasound techniques and tonometry, which are not in wide clinical use.
PRACTICAL POINTS IN BLOOD PRESSURE MEASUREMENT Patient Factors Site of Measurement The standard location for BP measurement is the upper arm although measurements at the wrist, finger, thigh and leg are possible. However, it is important to know that systolic and diastolic BPs vary according to the site of the arterial tree but variations in mean arterial BP are generally minimal.
Effects of Body Posture There is no consensus as to whether measurement has to be made in supine or seated position, although most guidelines recommend sitting.
Effects of Arm Position There is progressive increase in the pressure of about 5-6 mm Hg as the arm is moved from horizontal to vertical position (due to increase in hydrostatic pressure).
Other Factors The patient must be seated comfortably with the back and arm supported. The patient should refrain from talking or doing any physical activity. Fist should be open and not clenched. Caffeine, nicotine, and exercise should be avoided 30 minutes before BP measurement. Ideally, BP is measured after short period of rest of about 5 minutes.
Apparatus Factors
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An ideal BP apparatus should be easy to carry, free from repeated calibration and should reproduce the same results when repeatedly tested. Before checking the BP of a patient it should be ensured that the rubber tubing, cuff, and connections are all intact. It should be ensured that the initial displayed reading starts at zero. The size of the cuff is different for adults and children. Ideally, the cuff bladder should encircle at least 80% of the patient’s arm circumference and the ideal width is at least 40% of the patient’s arm circumference. The cuff size in children depends upon the age group. The cuff should be wrapped around the bare arm snugly; approximately two finger breadth above the cubital fossa with the center of the cuff placed over the brachial artery.
How to Measure Blood Pressure in Children and Adults? A Guide
in the arterial wall, which is sensed by the transducer and this marks the systolic BP. When the cuff pressure falls below the patients’ diastolic pressure, blood flow becomes smooth through the artery, and the vibrations cease, which marks the diastolic BP. These digital devices deflate at about 4 mm Hg per second making them sometimes seem slower to use than the auscultatory aneroid devices, but they are more accurate.
PROCEDURE OF MEASURING BLOOD PRESSURE Both palpatory and auscultatory methods are used for measuring the BP. First, the approximate systolic BP should be identified using palpatory method. The cuff is initially inflated up to a point when the radial pulse disappears. It is then slowly deflated until radial pulse reappears. This point is taken as approximate systolic BP. Subsequently, the auscultatory method is used to accurately measure the systolic and diastolic BPs. The cuff is inflated to about 30 mm Hg above the estimated systolic BP and then deflated at the rate of 2 mm Hg per second. The diaphragm of the stethoscope is placed over the brachial artery just under the lower margin of the cuff to auscultate for Korotkoff sounds. The Korotkoff sounds originate from a combination of turbulent blood flow and oscillations set up in the arterial wall. These sounds have been classified into five phases: Phase 1: Appearance of clear tapping sounds which corresponds to the appearance of a palpable pulse Phase 2: Sounds become softer and longer Phase 3: Sounds become crisper and louder Phase 4: Sounds become softer and muffled Phase 5: Disappearance of sounds. Systolic BP corresponds to appearance of the first Korotkoff sound. This is slightly lower than the direct intra-arterial BP. Phase 5 is taken as the diastolic BP. This is slightly higher than the direct intra-arterial BP value. Phase 4 of Korotkoff, which marks the onset of muffling of sounds, is taken as the diastolic BP in pregnant women, in patients with arteriovenous fistulas, and in aortic regurgitation as the Korotkoff sounds are audible even after complete deflation of the cuff. The above-said conditions are characterized by widened pulse pressure. 13
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Auscultatory Gap
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During the measurement of BP, the Korotkoff sounds may become inaudible between systolic and diastolic BPs and then reappear as cuff deflation continues. This phenomenon is known as auscultatory gap (gap in auscultation of Korotkoff sounds). This can lead to false overestimation of the diastolic BP. If only auscultatory method is used, without using the palpatory method, auscultatory gap can lead to underestimation of systolic pressure also. This is often observed in older patients who have a wide pulse pressure due to the stiffening of arterioles. Auscultatory gap can be prevented by raising the arm overhead for about 30 seconds before checking the BP in the usual position. This maneuver decreases the vascular volume in the limb and increases inflow enhancing the Korotkoff sounds.
Sources of Error in Measurement of Blood Pressure
Inadequate cuff size: It is the most common cause of error in BP measurement. White coat effect: In some patients, the BP is found to be elevated only in the presence of a physician. When measured in other places including at work or at home, the BP is found to be lower. Recent ingestion of pressor substances can increase BP. Terminal digit preference: This is due to a difference in the actual BP value measured by the clinician and the reported value, related to subconscious preference to include certain terminal digits in the value. Zero is often the preferred terminal digit (measured value may be 142 or 138, but the clinician may report a value of 140). Smoking: It can lead to transient increase in systolic BP. Cuff inflation hypertension: In occasional patients, there may be a transient but substantial increase of up to 40 mm Hg coinciding with cuff inflation. Therefore, it is required that cuff be inflated gradually and deflated gradually at 2 mm Hg/sec. Lower rates diminishes Korotkoff sounds, resulting in slightly higher diastolic BPs. Masked hypertension: This is characterized by lower BP readings in the office and higher readings when measures elsewhere like at work or at home and this is usually lifestyle that can be attributed to it such as alcohol consumption , smoking, physical activity away from clinic, etc. Pseudohypertension: This entity seen is seen when peripheral vessels become rigid as a result of advanced arteriosclerosis. The cuff has to be inflated at higher pressures to compress them resulting in overtly high BP measurements. The distal radial pulse may be palpable even after the cuff is fully inflated.
Conditions where BP measurement could be difficult: Atrial fibrillation Cardiogenic shock Burns Absent limbs Heart failure Skin diseases Aortoarteritis Embolism to peripheral vessels.
Self-Blood Pressure Monitoring Home-based monitoring of BP has been practiced for several years. Initially, aneroid sphygmomanometers were used which is now replaced by devices which use oscillometric technique. Home-based BP measurement has advantages in that it is relatively cheap and provides an opportunity to monitor BP over prolonged periods. It is noted that home-based measurements are usually lower than clinic measurements and when accurately measured can improve both therapeutic compliance and BP control.
AMBULATORY BLOOD PRESSURE MONITORING It is a noninvasive, fully automated technique in which BP is recorded over an extended period of time typically over 24 hours. Typically, ambulatory blood pressure (ABP) devices use oscillometric method for determination of BP. The standard equipment includes a cuff which is usually tied to the nondominant upper arm, a small monitor attached to a belt and a tube connecting the monitor to the cuff. A typical session involves recording BP once every 15 to 30 minutes (which is programmable) over 24 hours preferably on a workday. The data are stored in the monitor and then transferred to system. The software analyzes the data and gives the report by an hour and period—daytime, night time, and 24-hour BP. The systolic and diastolic BPs are recorded. The ABP monitoring has the following advantages. First, it helps to identify the usual level of BP outside the clinic setting and, therefore, helps to specifically identify people with white coat hypertension. Second, it helps to identify the individual’s BP variations (spontaneous BP variations, dippers and nondippers, etc.) which help in risk stratification. Lastly, it helps to identify patients with gross discrepancy between home- and clinic-based measurements.
BLOOD PRESSURE MEASUREMENT IN SPECIAL POPULATIONS Children The BP in children is measured using the standard auscultatory method. Oscillometric method is generally
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Elderly Elderly often have isolated systolic hypertension due to hardening of blood vessels, due to arteriosclerosis. The other factors, such as BP variability, presence of comorbidities, intercurrent illness, polypharmacy, and defective autoregulation, complicate BP measurement in the elderly. In elderly, the BP should be measured in both sitting and standing positions to look for orthostatic hypotension which is common in these individuals. The
ABP measurements in adults will help elucidate symptoms such as episodic faintness and nocturnal dyspnea.
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How to Measure Blood Pressure in Children and Adults? A Guide
used in newborn and young infants as well as in the intensive care setting. The right arm is generally preferred as it can be used to compare with reference tables. Correct sized cuff should be used in children. Using regular cuffs in children can lead to underestimation of BP. The prerequisites for measuring BP in children are similar to that for adults. Children preferably can have the BP measurements taken when supine; however, the feet of the child be on the floor rather than dangling from the bedside. Repeated measurements are necessary before terming a child as a hypertensive. Infants should have the measurements taken when supine. It is recommended that an average of multiple BP measurements be taken for weeks or months. Role of ambulatory and home-based BP monitoring is not clear in children. The BP in children is measured using the standard auscultatory method. Oscillometric method is generally used in newborn and young infants as well as in the intensive care setting. The right arm is generally preferred as it can be used to compare with reference tables. Correct sized cuff should be used in children. Using regular cuffs in children can lead to underestimation of BP. The prerequisites for measuring BP in children are similar to that for adults. Children preferably can have the BP measurements taken when supine; however, the feet of the child be on the floor rather than dangling from the bedside. Repeated measurements are necessary before terming a child as a hypertensive. Infants should have the measurements taken when supine. It is recommended that an average of multiple BP measurements be taken for weeks or months. Role of ambulatory and home-based BP monitoring is not clear in children. “Flush technique of measurement of blood pressure can be used in infants. The sphygmomanometer cuff is applied to the wrist or ankle. An elastic bandage is wrapped around the wrist [or ankle] beginning from the digits up to the proximal edge of the cuff. The sphygmomanometer is then inflated rapidly to about 300 mm Hg and the elastic wrapping is removed. The manometer pressure is then gradually released at the rate of 5 mm Hg. With gradual release there is a distinct blush of the blanched portion of the extremity. The reading at this point approximates mean blood pressure. This method is considered to be a reliable method for blood pressure measurement in infants”.
Measurement of BP in obese individuals has greater practical challenges. The cuff size should be of adequate size to give an accurate estimate. However, it is often difficult to get the appropriate cuffs for these persons. This can lead to overestimation of BP in these individuals.
Arrhythmias Arrhythmias set up vibrations in vessel wall which interfere with BP measurement. The variability in cardiac output induced by arrhythmia can lead to beat-to-beat and temporal variations in the BP.
Pregnancy In pregnancy, the presence of hyperdynamic circulation necessitates that the fourth stage of Korotkoff sounds be used as cutoff for determining diastolic BP. The BP measured does not vary much between sitting and left lateral positions.
Chronic Kidney Disease In patients with chronic kidney disease (CKD), there is calcification of vessel wall which can affect BP measurement.
Diabetes Mellitus The presence of autonomic dysfunction and the coexistence of other comorbid illnesses in diabetic patients can influence BP measurement.
CONCLUSION The BP is a ver y impor tant deter minant of the cardiovascular risk of a patient. It is very important to know not only the techniques of its measurement but also to know the methodology underlying these techniques and the difficulties and errors that could arise. Accurate measurement of the technique is important to risk stratify, prognosticate, and advise appropriate steps in management.
SUGGESTED READING 1. Arthur J Moss, Wilbert Leibling, Wallace O Austin, Forrest H Adams. Determination of blood pressure in infants – use of the flush technique. Los Angeles – California Medicine. 1957;87(3):166-7. 2. Bilo G, Sala O, Perego C, et al. Impact of cuff positioning on blood pressure measurement accuracy: may a specially designed cuff make a difference? Hypertension Res. 2017;40:573-80.
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3. Booth J. A short history of blood pressure measurement. Proc R Soc Med. 1977;70(11):793-9. 4. Geldsetzer P, Manne-Goehler J, Theilmann M, et al. Diabetes and hypertension in India: A nationally representative study of 1.3 million adults. JAMA Intern Med. 2018;178(3):363 -72. 5. Kotchen TA . Histor ical trends and milestones in hypertension research: a model of the process of translational research. 2011;58(4):522-38.
6. Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45(1):142-61. 7. Saklayen MG, Deshpande NV. Timeline of history of hypertension treatment. Front Cardiovasc Med. 2016;3:3.
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Peripheral Signs of Aortic CHAPTER 3 Regurgitation: Revisited S Shanmugasundaram, B Vinodkumar, U Ilayaraja
INTRODUCTION Clinical examination of the heart is a rewarding exercise, capable of offering a gratifying experience. Most of the structural cardiac diseases can be diagnosed at the bedside and the diagnostic tools, however sophisticated they are, offer a marginal incremental benefit. Laboratory techniques are, however, required to precisely quantify the disease, identify associated lesions that are clinically silent and to establish the etiopathology. It is appropriate here to recall one of our mentors who used to tell us that: “Properly elicited history establishes the hemodynamic situation, inspection and palpation at the bedside would evince the exact lesion(s) and the severity and auscultation merely helps the clinician to confirm the diagnosis made already, and to identify associated lesions”. Look, feel and listen are the three cardinal aspects of a comprehensive physical examination and application of this principle forms the basis of diagnosis of aortic run-off situations causing the typical peripheral signs in the arterial tree. Though aortic regurgitation (AR) can be diagnosed with confidence, when a typical early diastolic murmur is present along the left sternal edge, simple observation of the behavior of the arterial pulse might offer an easy way of identifying AR and the other ‘aortic runoff’ situations. Aortic regurgitation and certain other diseases, such as large patent ductus arteriosus (PDA), and ruptured aneurysm of sinus of Valsalva (RSOV), have the common hemodynamic hallmarks of larger stroke volume of left ventricle (LV) causing an increase in systolic blood pressure (BP) and lowered peripheral arterial resistance causing a decrease in diastolic pressure. The net result is wide pulse pressure, which may produce an array of interesting clinical findings, generally grouped together as peripheral signs. More than the wider pulse pressure, it is the rapid ejection of blood into a dilated more compliant arterial system with subsequent rapid emptying into the dilated distal arterial bed that is responsible for the behavior of the arterial pulse. One should remember that the run-off into the periphery occurs both during systole and diastole. Reflected waves from the distal bed are often unimpressive in AR, because of highly compliant arterial system. Obviously, such peripheral signs of AR manifest when the regurgitation is moderate to severe in nature
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and chronic in duration with preserved left ventricular function. In chronic AR with significant LV dysfunction, the peripheral signs may not manifest well because the stroke volume is less and the LV ejection is less forceful. In acute AR, the peripheral signs are again absent despite the regurgitation being severe. It is because the LV is unprepared to meet the additional load of regurgitation, LVEDP rapidly increases to very high levels and mitral valve closes prematurely thereby resulting in reduction of stroke volume and cardiac output with compensatory increase in heart rate and peripheral arterial resistance. With diminished stroke volume and ejectile force of LV and increased peripheral arterial resistance, the pulse will be of smaller volume with narrow pulse pressure; and hence, the peripheral signs are conspicuous by their absence. Coexisting stenotic lesions, such as mitral stenosis and aortic stenosis, may also mask the peripheral signs.
TYPICAL ARTERIAL PULSE OF SIGNIFICANT AORTIC REGURGITATION The pulse volume is larger because of wide pulse pressure, the upstroke is steep due to rapid ejection, the peak is illsustained and the downstroke is steep due to peripheral run-off. This results in the characteristic ‘Waterhammer’ quality (an abrupt thud imparted to the palpating finger due to rapid upstroke) and the collapsing nature (a feeling of pulse quickly fading away from the palpating finger, due to rapid downstroke which in turn is caused by runoff into the periphery). The collapsing nature of the pulse is mainly due to the rapid downstroke in midlate systole, rather than that happens in diastole. One may recall that the dicrotic notch in AR occurs lower down in the descending limb and thus the collapsing quality is mainly felt in systole rather than in diastole. Waterhammer refers to the toy of Victorian era in which a glass tube with vacuum is filled with water or mercury partially. The vacuum causes the liquid in the tube to abruptly shift to the other end when the glass tube is inverted giving rise to the abrupt thud to the holding hand. Similar feeling is imparted to the palpating finger in AR, because of rapid ejection of larger volume of blood into the arterial system with an ill-sustained (sharp)
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peak. Both the waterhammer quality (rapid upstroke) and the collapsing quality (rapid downstroke) are better felt when the examiner encircles the patient’s wrist with his hand in such a way that the distal palm (the most sensitive part of the palm) is on the radial pulse and the arm of the patient is quickly raised above the head. In the past, it was commonly taught that the typical features of the pulse are better felt by this maneuver because the arteries in the upper limb are brought in vertical line to the aorta that allows greater degree of regurgitation into LV. In true sense, the phenomenon is likely to be due to reduction of volume of blood which results in increase in compliance of the distal arteries when the upper limb is elevated. The increase in compliance is responsible for the exaggeration of rapid upstroke and rapid downstroke.1
Wide Pulse Pressure Pulse pressure, the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP), is considered to be wide if it is >50 mm Hg or when the ratio of pulse pressure/systolic BP is > 0.5. Wide pulse pressure is a characteristic finding in aortic run-off situations and is the hemodynamic abnormality that is responsible for most of the peripheral signs. However, age-related loss of elasticity of large conduit vessels may also result in wide pulse pressure.
Bisferiens Pulse It is a form of twice beating pulse, characterized by a large volume pulse with two peaks, both being present in systole. In Latin, ‘bis’ means twice and ‘ferire’ means beat. The bisferiens character is better felt in carotids and when marked aortic run-off occurs, distal pulses such as brachial may also exhibit this feature. Apart from manually feeling the two peaks, one would also be able to hear double Korotkow sounds with each pulse during BP recording. The mechanism of bisferiens pulse is attributed to the Venturi forces that are created at the root of aorta, when a large volume of blood is ejected rapidly. The suction that is induced by the Venturi forces causes a dip in forward flow into the arterial tree. The two peaks of bisferiens pulse should not be called as percussion and tidal waves, as the reflection of incident wave does not occur in conditions such as AR, in which condition the systemic arterial resistance is low.
PERIPHERAL SIGNS OF AORTIC RUNOFF Wide pulse pressure, rapid upstroke and downstroke of the pulse seen in aortic run-off conditions may be accompanied by many signs known by eponyms, called peripheral signs of aortic runoff. Most of them are now antiques of clinical medicine because of no added value in diagnosis.
Corrigan sign is dancing of carotids caused by abrupt distension and rapid collapse. Corrigan pulse refers to the tactile qualities of the pulse of aortic runoff. Sir Dominic Corrigan wrote a seminal paper on AR in 1832, when he was at Jervis Street Hospital, Dublin, Ireland. Locomotor brachii is rhythmical pulsation of a serpentine brachial artery. This sign may at times be present in thin built elderly individuals, due to atherosclerotic changes causing tortuosity and wide pulse pressure due to increased stiffness of arteries. Duroziez sign refers to the double intermittent murmur heard over femoral arteries. Paul Duroziez, a French physician, described this in 1861. Proximal compression either by a finger or by tilting the edge of the diaphragm upwards causes a systolic bruit; and, distal compression by a finger or by caudal tilting of the edge of stethoscope diaphragm causes a diastolic bruit. This was originally attributed to systolic turbulence created by partial proximal pressure of femoral artery and retrograde flow towards aorta with distal compression. But the diastolic component is probably a local phenomenon of accentuating the brief reversal of flow as observed by Doppler study and electromagnetic flow recordings.2 It was shown by Luisada that the optimal compressive force would be required to evoke this sign—about three quarters of the pulse pressure above the diastolic pressure.3 Pistol shot sound is a sharp sound heard over the femoral artery during rapid ejection of large volume of blood into the arterial tree. Sometimes, two sounds will be heard with each heart beat—Traube’s double tone. Quincke’s pulse is the capillary pulsation (normally capillary flow is nonpulsatile) detected at the nail bed as intermittent blanching of skin when illuminated from the palmar aspect of finger with gentle compression of nail. If a glass slide is kept over the lips, alternate blanching and filling can be identified. By hooking the patient’s fingertips, the examiner can identify the accentuated pulsation of digital arteries. Hill’s sign: In 1909, Hill described disproportionate elevation of lower limb blood pressures when compared to upper limb blood pressure, in patients with AR.4 This sign is also known as popliteal–brachial gradient. When popliteal BP is recorded by cuff method, the systolic pressure is 0–20 mm Hg higher than the brachial systolic pressure in normals. In those with AR, this discrepancy is exaggerated and Hill’s sign is considered to be present when the difference exceeds 20 mm Hg. Arbitrarily, the severity of AR was determined by clinicians at the bedside based on the magnitude of difference—20–40 mm Hg in moderate AR, 40–60 mm Hg in moderately severe AR and >60 mm Hg in severe AR. Frank et al. did find a
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pulsations tend to become obvious. In normals, only the retinal veins pulsate and the retinal arteries do not. It was initially believed that the transmitted pressure from the arteries to the veins across the vitreous is responsible for venous pulsations—decrease in size in systole and increase in size in diastole by passive compression. But the important determinant of venous pulsation is now believed to be the gradient of pressure across the venous wall inside the globe and outside it. Intraocular pressure increases by 1.5 mm Hg in systole and the retinal venous pressure also increases by the same magnitude because of the transmitted pressure to the thin-walled veins across the intraocular fluid. Outside the eyeball, it travels in the subarachnoid space and the cerebrospinal fluid (CSF) pressure increases only by 0.5 mm Hg in systole and falls by 0.5 mm Hg in diastole. This creates a gradient of 1 mm Hg between the intraocular veins and the extraocular vein in systole, which results in emptying (collapse) of retinal veins in systole and filling (expansion) in diastole. Retinal vein pulsation is present in nearly 90% of normals, better seen in the vessels close to the disc and better elicited by gentle pressure on eyeball through the eyelids. If CSF pressure increases, retinal vein pulsation may cease to occur; and, in glaucoma too, the venous pulsations may disappear.8 Landolfi sign is pulsatile iris causing rhythmical alteration of pupil size. Ashrafian sign: It denotes pulsatile pseudoproptosis, a rhythmical anterior propulsion of both eyes in systole. Bozzolo sign is pulsatile nasal mucosa. Dennison sign (Shelly sign) is pulsatile cervix. Drummond sign is pulsatile systolic expulsion of air from nostrils when mouth is closed. Lincoln sign refers to the rhythmic movement of leg crossed over the other. This was diagnosed in hindsight on Abraham Lincoln, the 16th US President, who had Marfan’s syndrome with AR. A blurred photograph was believed to be caused by the leg movement because of bounding pulse. Palmar click refers to the pulsating palms—palpable systolic flushing of palms. Morton and Mahon sign refers to facial flushing and blanching. Lighthouse sign refers to blanching and flushing of forehead. Muller sign is pulsating uvula. Minervini’s sign refers to pulsation of tongue. Penny sign is pulsation seen on an urticarial rash. Sherman sign is a prominent and easily palpable dorsalis pedis in elderly, in whom the dorsalis pedis is often unimpressive due to commonly occurring peripheral arterial disease. Watson pulse refers to the waterhammer pulse.
CHAPTER
3 Peripheral Signs of Aortic Regurgitation: Revisited
similar rough correlation between the severity of AR in angiography and the magnitude of BP difference.5 However, studies done later have confirmed that the intra-arterial pressures recorded directly by catheterization, did not differ between upper and lower limb arteries, with both systolic and diastolic pressures being identical. 6 Hence, this sign is now considered to be an artifact possibly caused by the BP recording technique. It is well understood that when arm BP cuff is used on the thigh, it will obviously show higher readings, as the smaller cuff used on larger sized limb is expected to give higher readings. But the exaggerated difference between lower limb BP and upper limb BP is noticeable even when the appropriately sized thigh cuff is used. It is then possibly due to the fact that higher than the usual cuff pressures are needed to obliterate popliteal pulse, because the thigh is conical, it is more muscular than the arm and the femoral artery cannot be compressed effectively against the bone because of anatomical relationships. Because of similar anatomical reasons, the lower limb pressures are found to be higher than the upper limb pressures, even when the ankle pressures are recorded. Leg muscle bulk is only slightly more than that of arm, but the conical shape and inability to effectively compress the tibial arteries against the bone would be the reasons for a higher reading obtained at ankle. In a study done on 83 patients with significant AR, cardio ankle vascular index (CAVI) was measured using parameters such as pulse wave velocity, pulse pressure in the brachial and ankle arterial pressure readings, ankle brachial blood pressure difference (ABD), ankle brachial index (ABI), ejection time, and upstroke time. Ankle brachial blood pressure difference was 38.0 ± 16.4 mm Hg in patients with AR, while it was 18.9 ± 13.2 mm Hg in normal controls. ABI was 1.30 ± 0.14 in AR and 1.12 ± 0.09 in normals. Ejection time was longer and upstroke time was shorter in AR.7 Alfred de Musset sign is anteroposterior bobbing of the head. Bobbing of the head may be present in severe tricuspid regurgitation (TR) also. But in TR, the head bobbing is sideways. Mayne sign refers to >15 mm Hg diastolic pressure reduction with arm elevation. Rosenbach sign is the systolic pulsation of enlarged liver. Gerhardt sign (Sailer’s sign) is systolic pulsation of enlarged spleen Becker sign: It refers to the presence of retinal arterial pulsations. Normally, the retinal arteries do not pulsate because they are small end arteries and their pulsations are dampened when the central retinal artery passes through the tight compartment of optic nerve sheath. When there is wide pulse pressure with increased systolic and decreased diastolic pressure, the arterial
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Nwosu, from Nigeria, has added a few more signs detectable at bedside in patients with aortic regurgitation: (a) Pistolshot sounds over carotids; (b) Pulsation of eyelids due to pulsatile zygomaticofacial artery; (c) Visible pulsation (bobbing) of abdomen and legs; (d) Visible pulsation of superficial temporal arteries; (e) Visible and palpable pulsation of digital and metacarpal arteries, and (f ) Bobbing of hands synchronous with the bobbing of head.9 Our teachers have noticed another sign encountered in severe aortic regurgitation—pulsation of the entire bed/cot synchronous with hyperkinetic arterial pulse. The eponyms de Musset sign and Lincoln sign were named after patients in whom the sign was detected. Alfred de Musset was a French poet who suffered from syphilitic AR and the bobbing head was noted and described by his brother. The other eponyms refer to the physicians who have described the finding.
INVESTIGATIONS Investigations have yielded widely varying sensitivity and specificity of some of these peripheral signs. Sensitivity and specificity of Corrigan sign ranged from 38–95% and 16%, respectively; Duroziez sign 33–81% and 35–100%, and Hill sign 0–100% and 71–100%. Obviously, the sensitivity was close to 100%, whenever the aortic regurgitation was severe.10
CONCLUSION While most of the peripheral signs are of historic importance, the presence of wide pulse pressure with rapid upstroke, ill-sustained peak and collapsing quality with or without bisferiens quality should be recognized by the examining physician. Such findings not only imply
aortic runoff situation but also indicate that the lesion is of hemodynamic significance. Such bedside signs come to help when the investigation findings provide overlapping values.
REFERENCES 1. Warnes CA, Harris PC, Fritts HW. Effect of elevating the wrist on the radial pulse in aortic regurgitation: Corrigan revisited. Am J Cardiol. 1983;51(9):1551-3. 2. Folts JD, Young WP, Rowe GG. A study of Duroziez’s murmur of aortic insufficiency in man utilizing an electromagnetic flowmeter. Circulation. 1968;38(2):426-31. 3. Luisada AA. On the pathogenesis of the signs of Traube and Duroziez in aortic insufficiency. A graphic study. Am Heart J. 1943;26:721-36. 4. Hill I, Flack M, Holtzmann W. The measurement of systolic pressure in man. Heart. 1909;1:73-82. 5. Frank MJ, Casanegra P, Migliori AJ, Levinson GE. The clinical evaluationof aortic regurgitation. Arch Intern Med. 1965;116:357-65. 6. Kutryk M, Fitchett D. Hill’s sign in aortic regurgitation: enhanced pressure wave transmission or artefact? Can J Cardiol. 1997;13(3):237-40. 7. Shiraishi H, Shirayama T, Maruyama N, et al. Usefulness of peripheral arterial signs in the evaluation of aortic regurgitation. J Cardiol. 2017;69(5):769-73. 8. Jacks A S, Miller N R. Spontaneous retinal venous pulsation: aetiology and significance. J Neurol Neurosurg Psychiatry. 2003;74(1):7-9. 9. Nwosu PU. New peripheral signs of chronic aortic regurgitation seen in five patients in the north of Nigeria and literature review. Intl J Multidisc Curr Res. 2017;5:86572. 10. Babu AN, Kymes SM, Carpenter Fryer SM. Eponyms and the diagnosis of aortic regurgitation: What says the evidence? Ann Intern Med. 2003;138(9):736-42.
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Clinical Examination in CHAPTER 4 Atrial Fibrillation Ganesh Kumar Kasinadhuni, Parag Barwad
INTRODUCTION Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. 1 It is responsible for approximately one-third of hospital admissions. It is associated with increased risk of stroke and all-cause mortality.2 One-fourth of the patients may be asymptomatic, especially elderly. In recent years, there was increase in burden of AF, incidence, prevalence, and mortality associated with AF.3 So, a thorough knowledge about this arrhythmia is necessary to increase its detection and correct the reversible causes, to avoid complications of treatment and to reduce morbidity and mortality associated with it. Clinical presentation may be due to arrhythmia itself or as a part of another disease leading to AF. Dyspnea, effort intolerance, angina, palpitations, and presyncope/ syncope are common presenting symptoms.4 Almost onefourth of the patients may be asymptomatic in-spite of arrhythmia being detected on electrocardiogram during routine hospital visits.5 Patients may also present with thromboembolic phenomena or signs and symptoms of heart failure due to tachycardia-induced cardiomyopathy.6 Initial evaluation of patients who present with AF should include assessment of hemodynamic stability for further management. Assessment of patients who are hemodynamically stable begins with history taking to characterize the type and duration of arrhythmia, precipitating factors, history of any pharmacological or previous direct current (DC) cardioversion or ablation done to terminate the arrhythmia. History of any structural heart disease or systemic disease responsible of the arrhythmia should be sought. As already mentioned, its incidence increases with age, but AF can also present in young population with predisposing conditions. In elderly, it may be related to age-related changes in the atria or due to associated diseases. In young, it may be associated with rheumatic heart disease, cardiomyopathies, structural heart disease, pericardial disease, and other causes of multivalvular heart disease. Isolated AF in young individuals suggest supraventricular tachycardia (SVT), like atrioventricular node re-entrant tachycardia (AVNRT) or atrioventricular re-entry tachycardia (AVRT), with accessory pathways are responsible, and ablation of re-
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entry circuits may prevent its recurrence.7 Familial history should also be considered. History of precipitating factors, such as alcohol and caffeine, and substance abuse, such as cocaine, should be sought. History of dermatological disorders, such as psoriasis, and history of snoring and excessive daytime somnolence, heat intolerance, alopecia, and tremors should be noted.
PHYSICAL EXAMINATION Physical examination always begins with circulation, airway, breathing, and vital signs which help in deciding the urgency with which treatment or intervention should be given. In a patient, who is hemodynamically unstable, intervention precedes everything. Hemodynamic instability attributed to arrhythmia can occur at very rapid ventricular rates, aortic stenosis, hypertrophic and restrictive cardiomyopathy, and in patients with diastolic dysfunction. Treatment includes DC cardioversion if the onset of AF is less than 48 hours. Otherwise, transesophageal echocardiography (TEE) to look for left atrial (LA)/left atrial appendage (LAA) clot and proceed with cardioversion if it is not showing any clot. In case of nonavailability of TEE, intravenous (IV) heparinization followed by DC cardioversion can be done. 8 Physical examination also helps in revealing the underlying causes and squeal of AF.
Pulse Assessing heart rate gives a clue about hemodynamic status and adequacy of rate control. Irregularly irregular pulse (chaotic) is characteristic. It describes unpredictable irregular radial or ventricular beats. The volume of pulse is variable. Observation of irregular pulse for just 20 seconds, remarkably increases the probability of detecting AF [late recurrence (LR = 24.1)].9 Chaotic pulse can also be found in cases with multiple multifocal premature complexes which can be differentiated at bedside from AF by examining jugular venous pulse and rhythm of ventricular pulse. The difference between apical/ventricular pulse and radial pulse is called pulse deficit. Traditionally, it has been associated with AF, but it can also occur in patients with premature complexes and rapid heart rates. Pulse
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deficit >10/min suggestive of AF, whereas 110/min (AF with fast ventricular rate). Bradycardia may indicate drug toxicity or electrolyte abnormalities, and sick sinus syndrome and tachycardia may indicate poor drug compliance or any other precipitating events. High-volume pulse may give clue to the presence of aortic valvular disease (may be a part of rheumatic and other multivalvular diseases or isolated to aortic valve), and other hyperdynamic states such as hyperthyroidism, etc. All peripheral pulses to be palpated which may indicate peripheral vascular disease increasing the likelihood of coronary artery disease or an embolic phenomenon in patients with acute presentation.
Blood Pressure
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Hypertension is an important risk factor for AF and both diseases are associated with increasing age. Hypertension with left ventricular hypertrophy (LVH) causing diastolic dysfunction with raised filling pressures, increases incidence of AF [similar to aortic stenosis (AS) with LVH and diastolic dysfunction]. Hypertension in AF also increases the risk for stroke and contributes to increased mortality and morbidity. Hypertension is associated with left atrial stasis, thrombi10 and aortic atherosclerosis which increases risk for thromboembolism. Blood pressure (BP) should be taken in both the upper and lower limbs along with ankle brachial index giving a clue to peripheral arterial disease (PAD) which may be associated with coronary artery disease (CAD). Wide pulse pressure may again give clues to aortic valvular disease or other hyperdynamic states, decreased vessel wall compliance, and narrow pulse pressure, may give clue to left ventricular dysfunction. In AF variations, filling times, stroke volumes, and contractility lead to increased beat-to-beat BP variability which affects both auscultatory and oscillometric methods.11 Pulse palpation while measuring BP during auscultatory method is recommended for diagnosis of AF in patients with age 65 years and above. 12 Current guidelines recommend repeated BP measurements with auscultatory method in AF. Using this method, there may be difficulty in interpretation of muffled sounds leading to intra- and interobserver variability of BP. The deflation
rate should be less than the heart rate as too rapid deflation may underestimate systolic BP and overestimate diastolic BP.13 Automated oscillometry may be inaccurate in AF14 and not recommended. Beat-to-beat variations in mean and pulse pressure may distort relationship between cuff pressure and oscillometric wave amplitude in AF affecting its accuracy. Automated techniques may be reasonably accurate for systolic BP but overestimates diastolic BP. Recently, automated BP monitors are used to detect AF in asymptomatic elderly hypertensive patients. Sensitivity for detecting AF was 100% and specificity was 94% for Omron M6 device compared with 92% and 97% respectively, for Microlife BPA 200 plus device.15
Jugular Venous Pulse Examination of jugular venous pulse (JVP) is invaluable to diagnosis along with irregular pulse in AF. Normal JVP has two peaks A and V waves (C wave cannot be recognized on clinical examination) along with two troughs X and Y descents. In AF, there is loss of A wave (no atrial contraction) and X descent.16 Only V and Y waves are prominent (single crest and trough). Onset of AF alters JVP in some clinical conditions, such as constrictive pericarditis and restrictive cardiomyopathy, which otherwise is a clue to diagnosis at bedside. Also, examination of JVP gives a clue to differentiate AF from multiple premature complexes, both of which can have pulse deficit on clinical examination (two troughs present). Elevation of JVP suggests a primary cardiac pathology that may be the cause of atrial fibrillation.
Neck Examination Neck examination may also show pretracheal swelling, exophthalmos, heat intolerance, and alopecia along with other symptoms gives a clue to hyperthyroidism. Carotid bruits may suggest PAD, and may be associated with CAD. The presence of ecchymosis and racoon eyes may suggest amyloidosis as the etiology. Marfanoid habitus may give clue to valvular etiology for the arrhythmia. Skin examination may show plaque sign of psoriasis which is an established risk factor for AF. Morbid obesity along with history of snoring and daytime somnolence gives clue to obstructive sleep apnea. Cachexia and signs of peripheral congestion may suggest congestive cardiac failure (CCF) or liver disease or renal disease. The presence of recent surgical scars may suggest postoperative arrhythmia. Family history along with lentigines may suggest association between cardiac tumor and arrhythmia.
SYSTEMIC EXAMINATION In patients with rheumatic heart disease, AF is more common with mitral valve disease. In mitral stenosis (MS), the onset of AF depends both on severity and age of the patient, consistent with the natural history of AF
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and systemic hypertension. The S4 is absent with the onset of AF in these conditions. THe AF can occur in one-third of patients of constrictive pericarditis. Raised JVP with rapid X and Y descents,22 pericardial knock, and ascites precox suggests constrictive pericarditis. But with the onset of AF, JVP has single Y descent. The presence tumor plop suggests atrial myxoma. Loud P2 component of the second heart sound with signs of peripheral congestion suggests pulmonary hypertension and right heart failure. Large pretricuspid shunts can have right atrium (RA) enlargement and predisposition for AF. Wide fixed split is suggestive of atrial septal defect (ASD). Post-tricuspid shunts can have AF with CCF or after Eisenmenger disease. Cyanotic heart disease with multiple arrhythmic episodes on history and multiple clicks on examination gives clue to Ebstein’s anomaly. The presence of fine crepitation on lung auscultation may suggest congestive failure. Wheeze and ronchi may suggest lung disease in appropriate clinical scenario. Absent breath sounds can occur in pleural effusions which may be due to failure or due to primary lung disease. Ascites, jaundice, gynecomastia, spider nevi, and palmer erythema may suggest alcoholic liver disease and cardiomyopathy. Ascites precox (early onset of ascites) along with elevated JVP and other symptoms of right heart failure gives clue to constrictive pericarditis rather than liver disease. Pain in the left hypochondrium may suggest splenic infarct due to systemic embolization and pain in the right hypochondrium may be due to congestive hepatopathy. Unilateral weakness or sensory loss, aphasia, history of dizziness, and swaying, all may suggest embolic phenomena due to arrhythmia. Examination findings of exaggerated reflexes may suggest old cerebrovascular events, or may be due to hyperthyroidism.
CHAPTER
4 Clinical Examination in Atrial Fibrillation
in general population. 17 In mitral regurgitation (MR), its incidence depends on the age of the patient and left atrium (LA) dimension. In a set of patients with MR, left atrial compliance is high and enlarged LA predisposes to AF. The AF incidence further increases with combined MS with MR due to massively enlarged LA. The onset of AF marks progression of the disease in both the conditions. Tapping apex without any shift, loud S1, opening snap (OS) followed by mid-diastolic murmur with presystolic accentuation suggests MS. In AF, S1 becomes variable in intensity (although loud) and there is no presystolic accentuation of diastolic murmur. However, sometimes, presystolic component can be heard during short R-R intervals. A holo-diastolic murmur following OS in AF is consistent with significant MS. Soft S1, displaced illsustained apex with pansystolic murmur radiating to axilla or base is suggestive of MR. Rheumatic heart disease (RHD) patients with chronic MR have compliant enlarged LA predisposing to AF. The AF in patients with chronic MR is clue to its severity. Pansystolic murmur of MR does not vary in intensity with cycle lengths in AF.18 The AS is suggested by pulsus parvus tardus, heaving and sustained apex, ejection systolic murmur radiating to carotids, and presence of S4. The AF occurs late in the course of aortic valve disease. Increased left ventricular end-diastolic pressure (LVEDP) secondary to severe AS and LV dysfunction in aortic regurgitation (AR) causes left atrial enlargement and AF. The onset of AF suggests poor prognosis in conditions with raised LVEDP and diastolic dysfunction such as the AS, HCM, RCM, and diastolic heart failure. All these have to depend on atrial booster pump action which is lost in AF. With AF, S4 is absent. In patients with calcified valves, selective transmission of highfrequency sounds to apex (Gallavardin phenomenon), can confuse with MR. In patients of AS with AF, beat-to-beat variation in the ejection systolic murmur (ESM)19 intensity differentiates it from pansystolic murmur (PSM) of MR which remains constant. The AF generally occurs with LV dysfunction in AR which leads to systolic decapitation of BP and attenuation of peripheral signs. The CCF can cause AF by increasing LA size and filling pressures. The AF can cause CCF due to tachycardiarelated cardiomyopathy. Coexistence of AF and CCF occurs in approximately 40% of patients.20 On clinical examination, the presence of displaced, sustained apex with apical systolic murmur and S3 can give clue to left ventricular dysfunction. Double apical impulse (spike and dome) with S4 and apical systolic murmur is suggestive of hypertrophic cardiomyopathy. The systolic murmur of hypertrophic cardiomyopathy (HCM) responds unpredictably to changing cycle lengths in AF. Long pause may make the murmur louder or softer or may not change it.21 The S4 can also be seen in other conditions with diastolic dysfunction such as restrictive cardiomyopathy, diastolic heart failure,
REFERENCES 1. Chugh SS, Blackshear JL, Shen WK, et al. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol. 2001;37(2):371-8. 2. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2-220. 3. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837-47. 4. Lip GY, Beevers DG. ABC of atrial fibrillation. History, epidemiology, and importance of atrial fibrillation. BMJ. 1995;311(7016):1361-3. 5. Furberg CD, Psaty BM, Manolio TA, et al. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol. 1994;74(3):236-41. 6. Gopinathannair R, Etheridge SP, Marchlinski FE, et al. Arrhythmia-induced cardiomyopathies: mechanisms,
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8.
9.
10.
11.
12.
13.
recognition, and management. J Am Coll Cardiol. 2015;66(15):1714-28. Wutzler A, von Ulmenstein S, Attanasio P, et al. Where there’s smoke, there’s fire? Significance of atrial fibrillation in young patients. Clin Cardiol. 2016;39(4):229-33. King DE, Dickerson LM, Sack JL. Acute management of atrial fibrillation: Part II. Prevention of thromboembolic complications. Am Fam Physician. 2002;66(2):261-4. Morgan S, Mant D. Randomised trial of two approaches to screening for atrial fibrillation in UK general practice. Br J Gen Pract. 2002;52(478):373-80. Zabalgoitia M, Halperin JL , Pearce L A , et al. Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators. J Am Coll Cardiol. 1998;31(7):1622-6. Kollias A, Stergiou GS. Automated measurement of office, home and ambulatory blood pressure in atrial fibrillation. Clin Exp Pharmacol Physiol. 2014;41(1):9-15. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):2071-104. Manolis AJ, Rosei EA, Coca A, et al. Hypertension and atrial fibrillation: diagnostic approach, prevention and treatment. Position paper of the Working Group ‘Hypertension Arrhythmias and Thrombosis’ of the European Society of Hypertension. J Hypertens. 2012;30(2):239-52.
14. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ ESC Practice Guidelines for the management of arterial hypertension. Blood Press. 2014;23(1):3-16. 15. Marazzi G, Iellamo F, Volterrani M, et al. Comparison of Microlife BP A200 Plus and Omron M6 blood pressure monitors to detect atrial fibrillation in hypertensive patients. Adv Ther. 2012;29(1):64-70. 16. Hartman H. The jugular venous tracing. Am Heart J. 1960;59:698-717. 17. Acar J, Michel PL, Cormier B, et al. Features of patients with severe mitral stenosis with respect to atrial rhythm. Atrial fibrillation in predominant and tight mitral stenosis. Acta Cardiol. 1992;47(2):115-24. 18. Karliner JS, O’Rourke RA, Kearney DJ, et al. Haemodynamic explanation of why the murmur of mitral regurgitation in independent of cycle length. Br Heart J. 1973;35(4):397-401. 19. Henke RP, March HW, Hultgren HN. An aid to identification of the murmur of aortic stenosis with atypical localization. Am Heart J. 1960;60:354-63. 20. Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107(23):2920-5. 21. Kramer DS, French WJ, Criley JM. The postextrasystolic murmur respons e to gradient in hyper tro phic cardiomyopathy. Ann Intern Med. 1986;104(6):772-6. 22. el-Sherif A, el-Said G. Jugular, hepatic, and precordial pulsations in constrictive pericarditis. Br Heart J. 1971;33(2):305-12.
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CHAPTER 5
Continuous Murmur Ranjit Kumar Nath
INTRODUCTION Continuous murmur is defined as a murmur that begins in systole and continues uninterrupted through the second heart sound into all or part of diastole.1 It has to be remembered that when the murmur crosses over from systole to diastole, the following criteria have to be fulfilled: There is no change in the character of the murmur from systole to diastole. The second heart sound (S ) or its components are 2 enveloped or masked by the murmur. Murmurs do not follow the boundary of the systole and diastole of the cardiac cycle, hence no break in between the systolic and diastolic components. Murmurs may not occupy the whole length of systole (holosystolic) or diastole (holodiastolic); rather, they start in systole and continue to occupy part or whole of diastole. The basic mechanism of the murmur is the presence of a continuous significant pressure gradient producing turbulent flow between two vessels or chambers during both systole and diastole. Intracardiac murmurs can seldom be true continuous murmurs as there is hardly a continuous pressure gradient. Pathological continuous murmurs are mostly produced due to a communication between high pressure arterial vascular beds to low pressure structures, either to venous system or right-sided cardiac chambers, including pulmonary circulation. A continuous murmur is often helpful in diagnosing a disease or abnormality comprehensively if we meticulously listen to the murmur in relation to its site, pattern, associated clinical signs, along with a meticulous history.
PHYSIOLOGIC CLASSIFICATION Continuous murmurs can be grouped based on the type of communication that is causing the turbulent flow producing the murmur. The following are the different conditions that can produce a continuous murmur according to different physiological mechanisms:2
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Abnormal communications between systemic and pulmonary arteries: — Patent ductus arteriosus (PDA) — Aortopulmonary window (AP window) — Truncus arteriosus with pulmonary stenosis — Anomalous origin of left coronary artery from pulmonary artery (ALCAPA) — Bronchial collaterals in pulmonary atresia or tetralogy of Fallot (TOF) physiology — Different surgical shunt created as palliation in TOF physiology such as Blalock-Taussig shunt (BT shunt), Waterston-Cooley shunt, and Pott’s shunt. Abnormal communications between systemic arteries to right heart: — Ruptured sinus of Valsalva aneurysm (RSOV) — Coronary cameral fistula. Critical narrowing of an artery leading to turbulent flow: — Proximal coronary stenosis — Coarctation of aorta (CoA) — Peripheral pulmonary stenosis. Change or increase in venous flow leading to turbulence: — Venous hum — Anomalous pulmonary venous connection — Portosystemic shunts. Arteriovenous fistulas: — Systemic: Congenital, hemodialysis, posttraumatic, femoral artery puncture site — Pulmonary: Diffuse small, localized large (solitary or multiple). Excessive flow through an area or organ due to physiological or pathological changes: — Mammary soufflé — Mitral stenosis or atresia with a restrictive atrial septal defect (ASD) — Hemangioma — Hyperthyroidism — Hyperemia of neoplasm: Hepatoma, Paget’s disease, renal cell carcinoma.
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DIFFERENTIAL DIAGNOSIS
Clinical Cardiology
Long cardiac murmurs may sometimes mimic continuous murmurs and they need to be looked carefully to differentiate from true continuous murmurs. Two such conditions are to-and-fro murmurs and combined systolic and diastolic murmurs. To-and-fro murmurs are due to flow in one direction during systole and flow in the reverse direction during diastole through the same orifice or valve.3 Typical examples are murmurs of aortic stenosis (AS) and aortic regurgitation (AR) or pulmonary stenosis (PS) and pulmonary regurgitation (PR). But they are not true continuous murmurs as the murmurs of stenosis are rough, medium pitched, diamond shaped, and gets tapered towards the end of the systole, ending in or before the aortic component of the second heart sound (A 2) or the pulmonary component of the second heart sound (P2). The diastolic murmur is high pitched, blowing character starting after the A2 or P2. So, there is change in character of murmur at the boundary of systole and diastole of the cardiac cycle and has a gap at this point with two different picking of the murmurs during systole and diastole. Moreover, the second heart sound is well audible in these conditions unless the valves are grossly deformed or damaged. The combined systolic and diastolic murmurs are not due to flow through the same orifice or valve, rather they are combinations of systolic murmur of one pathology and diastolic murmur of another. Typical example is the presence of a ventricular septal defect (VSD) with AR, or combined mitral regurgitation (MR) with AR. They occupy varying lengths of systole or diastole and different character of murmurs in systole and diastole. For example, the VSD murmur is high pitch pansystolic at left sternal border and the AR murmur is early diastolic at left second or third parasternal area, but when the murmurs are traced to the infraclavicular area, there is a gap heard in between the two murmurs loosing the continuity. Also, the S2 and its components are well heard and the peaking of the murmurs are different and do not peak around S2. Figures 1A to C depicts different types of murmurs that need differentiation from a continuous
murmur. Table 1 shows different characteristic points in differentiating them.
Patent Ductus Arteriosus Patent ductus arteriosus (PDA) produces the classical continuous murmur due to the persistent flow from aorta to pulmonary artery through the patent duct during both systole and diastole. The murmur is of mixed frequency and harsh, crescendo during systole, peaks just before or after the S2, and tapers off during late diastole, when the murmur is decrescendo and smooth. The murmur is commonly associated with a thrill and best heard in the left second intercostal space or just below the left clavicle. The typical murmur is also called the machinery murmur because of its rough, crescendo-decrescendo nature or Gibson’s murmur after the classical description by George Alexander Gibson in the year 1900. Multiple clicks are heard at the peak of the murmur, called Eddy
A
B
C Figures 1A to C: Different types of murmurs. (A) Continuous murmur that peaks near S2 with A2 and P2 enveloped by the murmur; (B) To-and-fro murmur that indicates combination of two murmurs; (C) Combined systolic and diastolic murmur Abbreviations: S1: first heart sound, A2: aortic component of second heart sound, P2: pulmonary component of second heart sound, ec: ejection click
Table 1: Clinical characteristics to differentiate between a continuous murmur, to-and-fro murmur, and combined systemic and diastolic murmur
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Characteristics
Continuous murmur
To-and-fro murmur
Combined systolic and diastolic murmur
Direction of flow
Unidirectional, single murmur
Systolic in one direction and diastolic in reverse direction. Two separate murmurs from same valve
Not through same orifice or valve. Combination of different orifices or valves producing two murmurs
Classic example
PDA
AS + AR
VSD + AR
S2
Masked in the murmur
Separate
Separate
Peaking of murmur
One peak, either systolic or diastolic or at S2
Separate peak in systole and diastole
Separate peak in systole and diastole
Source of murmur
Extracardiac or extracardiac to cardiac shunt mostly
Intracardiac
Intracardiac
Gap at S2
Absent
Present
Present
Abbreviations: PDA: patent ductus arteriosus; AS: aortic stenosis; AR: aortic regurgitation; VSD: ventricular septal defect; S2: second heart sound
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A
B
Figures 2A and B: (A) PDA in the short axis view with color Doppler imaging; (B) Continuous-wave Doppler interrogation showing a persistent gradient during systole and diastole that peaks around S2
sounds, signifying stretching of a large ductus with high flow and increased pulmonary artery (PA) pressure, which originate both in the pulmonary artery and the aorta. The pulmonary ejection clicks originate in maximally dilated pulmonary arteries and at the peak of systolic stretching, which become more intense and occur later with expiration. Additional sounds in midsystole correspond to the reaching of the aortic pressure peak at the ductus.4 The murmur intensity and duration increases with isometric hand grip, sometimes bringing out the silent diastolic component and disappear or decrease in intensity and duration with Valsalva maneuver. With increasing grades of pulmonary artery hypertension (PAH), the murmur shortens, first to disappear is the diastolic component and with severe PAH, the PDA may be silent. The S2 is normally split with a small shunt and normal pulmonary artery pressure. Large shunt flowing across the PDA (Qp/ Qs >2) can be associated with left ventricular (LV) type of apex, LV third heart sound (S3), mid-diastolic murmur (MDM) across the mitral valve, single or paradoxically split S2, and a high volume pulse with wide pulse pressure producing a collapsing pulse. 5 S 2 is mostly masked in the murmur but the P2 gets loud due to PAH, which can be well heard as described by Gibson in his description of both the cases.6 With the development of severe PAH and reversal of the shunt (Eisenmenger physiology), the murmur disappears and differential cyanosis appears in which desaturated pulmonary artery blood crossing the PDA to the lower extremities, producing cyanosis and clubbing of the toes. Figures 2A and B show 2D and color Doppler echocardiography of a PDA with continuouswave Doppler showing persistent gradient from aorta to PA which produces a continuous murmur.
Ruptured Sinus of Valsalva Aneurysm The sinus of Valsalva aneurysm may be congenital or acquired due to trauma or post-endocarditis and can rupture to any cardiac chamber. Major site of origin is
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reported to be from the right coronary sinus (76.9%) followed by non-coronary sinus (18.3%) and common cardiac chamber of rupture is right ventricle (58.65%) followed by right atrium (24%) producing a continuous murmur.7 When ruptures to right atrium (RA), it produces a true continuous murmur with louder systolic component as the gradient during systole is very high. The jet of blood coming from posterior located aorta to anterior RA produces a thrill that feels very superficial and classical feeling of ‘purring of a cat’. The murmur is best heard in the lower left and right sternal border and over the xiphoid process. When ruptures to right ventricle (RV), the diastolic component of the murmur is more pronounced as the intensity of the systolic component can be reduced due to: (1) elevated RV systolic pressure due to PAH, (2) narrowing of the tract due to contraction of the ventricle during systole, or (3) Venturi effect of the LV to aortic forward flow beyond the origin of the fistula. The murmur is best heard in the mid-to-lower left parasternal area. RSOV may be associated with a VSD in 44% of cases and AR in 43.3%,7 which is difficult to hear separately and the presence of a VSD murmur will make systolic component of the RSOV murmur more intense and the presence of AR will make diastolic component of the continuous murmur more prominent. Large RSOV is associated with a dynamic precordium and congestive heart failure. Associated clinical findings may help in determining the site of rupture of an aneurysm and they are summarized in Table 2.
Coronary Cameral Fistula Coronary cameral fistulas represent a communication between coronary artery and any chamber of the heart, coronary sinus (CS), vena cava, or PA. Most commonly they involve the left coronary artery and drain into the right-sided cardiac chambers, CS or PA producing continuous murmurs. They may also originate from two coronary arteries and can have multiple drainage sites.8
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Table 2: Clinical signs that may help in differentiating the site of rupture of a sinus of Valsalva aneurysm into RA or RV Clinical findings
RSOV to RA
RSOV to RV
Site of murmur
Left and right lower sterna border and over xiphoid
Mid-to-lower left sterna border
Intensity of the continuous murmur
More in systole
More in diastole
Thrill
Very superficial, typical ‘purring of cat’
Diffuse
JVP
Prominent a wave
Prominent v/cv wave depending upon the severity of TR
S3
Both RV and LV
Mostly LV
MDM
Both in tricuspid and mitral area
In mitral area
Hepatic pulsation
Diastolic
Systolic
Abbreviations: RSOV: ruptured sinus of Valsalva; RA: right atrium; RV: right ventricle; JVP: jugular venous pressure; TR: tricuspid regurgitation; S3: third heart sound; LV: left ventricle; MDM: mid-diastolic murmur
Figure 3: Best audible sites of murmurs of coronary cameral fistulas A. RCA to RA; B. RCA to CS; C. RCA to RV; D. LCA to PA; E. LCA to CS or RCA to PA, or LCX to CS; F. LCA to PA or apex of RV, or LCX to CS; G. LCA to RV Abbreviations: RCA: right coronary artery; RV: right ventricle; RA: right atrium; CS: coronary sinus; LCA: left coronary artery; LCX: left circumflex artery; PA: pulmonary artery.
The site of best audibility of the murmur is different and depends upon the origin of the fistula and the site of draining that is depicted in Figure 3.3 These fistulas produce a continuous murmur with increased intensity during systole with a systolic peak and both the systolic and diastolic components of the murmur are smooth. Since the coronary cameral fistulas are not associated with a large left-to-right shunt, there is hardly any sign of aortic runoff like wide pulse pressure or very low diastolic blood pressure.
Aortopulmonary Window A continuous murmur is most unlikely in patients with aortopulmonary (AP) window since they are large and
mostly have identical aortic and pulmonary artery pressure. In isolated patients with small AP window, there can be a loud continuous murmur that peaks in systole and has louder systolic component. They are best heard in the left third intercostal space and are not associated with multiple clicks or Eddy sounds of PDA. Associated features of PAH are mostly present in majority of patients with AP window.
Coarctation of Aorta A continuous murmur can be heard in very tight coarctation of aorta (CoA), due to a continuous gradient across the coarctation, and the murmur is best heard over the back in the interscapular region or over the vertebrae. But the
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5 Continuous Murmur
A
B Figures 4A and B: (A) Mild coarctation producing only systolic gradient; (B) Very tight coarctation gives continuous high gradient, producing a continuous murmur
common source of a continuous murmur in coarctation is the collateral vessels including intercostal collaterals and the murmur is diffuse over the precordium and the back. Figures 4A and B show continuous-wave Doppler echocardiography of two different patients with CoA, one with mild CoA with only systolic gradient but the other is with tight CoA giving continuous systolic and diastolic gradient which can produce a continuous murmur.
Venous Hum The venous hum was first described by Pontain in 1867, and is the most common physiological continuous murmur. It is commonly found in young children and adolescents, best heard in the supraclavicular region either medial to or in-between the two heads of sternocleidomastoid muscle. It is more commonly heard in the right side and becomes prominent with head rotated to the opposite side and chin lifted up in sitting position. Murmur disappears with manual compression over the neck above the site of murmur, when head is rotated toward the same side, and changing posture from sitting to supine position. The murmur is often harsh and when heard below the clavicle, it causes confusion with a PDA murmur. The murmur is louder during diastolic phase and during inspiration. The theory behind the origin of the murmur is not clear. It may be because of: (1) the convergence of the venous flow from left, right, and the internal jugular vein (IJV) at this point producing the turbulence, (2) rapid descent of the jugular blood column to the superior vena cava, (3) relatively small thoracic inlet in children up to age six or seven years producing turbulent flow in jugular veins,5 or (4) the angulation of the IJV by the transverse process of the atlas while sitting and rotating the head, disturbing the laminar venous flow.
Mammary Soufflé Continuous murmur can be heard in 10 to 15% of women in late pregnancy and early postpartum period. The murmur is audible over the precordium in second to fourth intercostal space, over the breast, having maximum intensity during systole. The murmur starts after the origin of the systole with a delay because of the time required for the blood to reach the mammary artery, which is thought to be the origin of the murmur. Light pressure with the diaphragm of the stethoscope increases the intensity of the murmur and firm pressure causes reduction or disappearance of the murmur.
Pulmonary Arteriovenous Fistula Diffuse, small, capillary level pulmonary arteriovenous fistulas (AVF) cause central cyanosis, clubbing with normal electrocardiogram, normal chest X-ray, normal cardiac examination, and structurally normal heart in 2D echocardiography. They can hardly produce any murmur. Large AVF, which can be solitary or multiple, can produce continuous murmur over localized part of chest wall overlying the fistula. They can be diagnosed by performing contrast echocardiography with agitated saline during echocardiographic examination. The small bubbles of the agitated saline after reaching the right cardiac chambers from brachial vein should disappear in the pulmonary circulation; but if they reappear in the left chambers after a gap of 5 to 7 cardiac cycles, the diagnosis of pulmonary AVM is confirmed. The bubbles cross from the pulmonary artery, through the fistula, to the pulmonary venous side and travel to the left atrium. Figure 5 is an angiographic picture of a localized pulmonary AVF in the lower lobe of left lung. 29
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Figure 5: Selective pulmonary angiography showing a large pulmonary arteriovenous fistula producing a localized continuous murmur
Extracardiac Arteriovenous Fistula They can be congenital, spontaneous, or acquired secondary to trauma, iatrogenic after catheterization, surgically created for hemodialysis. They produce a continuous murmur localized to the area over the fistula and the systolic component of the murmur having increased intensity. These murmurs disappear with the compression of the fistula. Compression of the artery proximal to the fistula produces bradycardia by stimulation of baroreceptors, named Nicoladoni-Branham sign, and sudden release of the pressure leads to reflex tachycardia.
Continuous Murmurs in Cyanotic Congenital Heart Disease
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Continuous murmur is a very common clinical finding in patients with continuous murmurs in cyanotic congenital heart disease (CCHD). Though the PDA can be the source of such murmur, there are other causes of continuous murmurs in this group of patients. Campbell and Deuchar9 reported their incidence of 91% in a series and the murmurs were loud, heard best on the right side in nearly one-third, on the left side in half, and equally heard in both sides in the remaining. The murmurs were also heard in the back. In another series of patients with large VSD and pulmonary atresia, Zutter and Somerville10 reported that the presence of a continuous murmur below the left clavicle is always associated with a PDA; and, if the murmur is heard in another site along with left infraclavicular area, large aortopulmonary collateral arteries were the cause of the murmur. Hypertrophied bronchial arteries or branches of thoracic aorta or its branches to the pulmonary artery branches are the
common source of pulmonary blood flow in pulmonary atresia or TOF physiology, especially in the adult TOF. Some of them may be very large, causing increased pulmonary blood flow and no murmur. But normally they develop stenosis at their origin and cause continuous flow from the arterial bed to the pulmonary bed producing a continuous murmur. The source of continuous murmurs in CCHD can be:11 Patent ductus arteriosus (PDA) Aortopulmonary collaterals (bronchial collaterals, origin of left or right pulmonary artery from aorta with stenosis, coronary to pulmonary artery fistula) Total anomalous pulmonary venous connection (TAPVC) Pulmonary arteriovenous fistula Stenosis of pulmonary artery (right, left, or both pulmonary artery) Persistent truncus arteriosus Surgically created shunts.
Surgically Created Shunts They are the communications surgically created between arterial bed (aorta or its branches) and the pulmonary artery branches for maintaining pulmonary circulation when there is significant reduction in pulmonary blood flow due to severe PS or pulmonary atresia. Continuous gradient across the shunt produces a continuous murmur localized to the chest wall overlying the shunt. The murmur is helpful in clinically following-up a child as absence of a murmur with worsening cyanosis indicates acute thrombotic occlusion of a shunt. History of a surgery in the past and its location in the chest wall gives the clue of presence of a shunt. Color Doppler echocardiography
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5 Continuous Murmur
A
B
Figures 6A and B: (A) Color Doppler image of a modified Blalock-Taussig shunt (BT shunt) in a patient of tetralogy of Fallot; (B) The continuouswave Doppler interrogation showing a continuous gradient during both systole and diastole being the source of a continuous murmur
of a modified Blalock-Taussig shunt (BT shunt) with continuous-wave Doppler showing persistent gradient across the shunt produces a continuous murmur is given in Figures 6A and B.
REFERENCES 1. Perloff JK, Braunwald E. Physical examination of the heart and circulation. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine.5th ed. Philadelphia: WB Saunders Company;1997. pp. 43-5. 2. Ginghina C, Nastase OA, Ghiorghiu I, et al. Continuous murmur – the auscultatory expression of a variety of pathological conditions. J Med Life. 2012;5(1):39-46. 3. Jules Constant. Essentials of Bedside Cardiology. New Jersey: Humana Press Inc. Totowa, First Indian reprint 2003:234-41. 4. Hubbard TF, Neis DD. The sounds at the base of the heart in cases of patent ductus arteriosus. Am Heart J. 1960;59:807-15.
5. Tandon R. Bedside Approach in the Diagnosis of Congenital Heart Diseases.2nd edn. New Delhi: Sitaram Bhartia Institute of Science & Research, 2011. 6. George Alexander Gibson. Diseases of the Heart and Aorta. Young J Pentland, New York: The Macmillan Company. 1898, pp. 310-2. 7. Choudhary SK, Bhan A, Sharma R, et al. Sinus of valsalva aneurysms: 20 years’ experience. J Card Surg. 1997;12(5): 300-8. 8. Armsby LR, Keane JF, Sherwood MC, et al. Management of coronary artery fistulae. J Am Coll Cardiol. 2002;39(6): 1026-32. 9. Campbell M, Deuchar DC. Continuous murmur in cyanotic congenital heart disease. Br Heart J. 1961;23(2):173-93. 10. Zutter W, Somerville J. Continuous murmur in pulmonary atresia with reference to aortography. Br Heart J. 1971; 33(6):905-9. 11. Ongley PA, Rahimtoola SH, Kincaid OW, et al. Continuous murmurs in tetralogy of Fallot and pulmonary atresia with ventricular septal defect. Am J Cardiol. 1966;18(6):821-6.
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CHAPTER 6
Dynamic Auscultation Rishi Sethi, Akshyaya Pradhan, Snigdha Boddu
INTRODUCTION Dynamic auscultation is the technique of altering circulatory dynamics by physiological and pharma cological maneuvers and observing the effects of these maneuvers on heart sounds/murmurs. With the advent of echocardiography and other widely available modes of noninvasive diagnosis, the fine art of clinical examination is losing its importance. However, despite all the new age tools, the technique of performing methodical clinical examination is the fundamental backbone of any training in cardiology and forms the basis of all further diagnostic tests. Before performing and speaking about it in clinical examination, the following fundamental philosophical points of dynamic auscultation should be kept in mind:13 Dynamic auscultation should only be performed when we have faintly heard heart sounds or murmurs that we want to accentuate by performing some special augmentation tests. Or, we have confusion in similar sounding heart sounds or murmurs and we want to differentiate between them. So, it is the really not judicious for us to perform or to speak about dynamic auscultation when we have clearly heard and well defined murmurs/heart sounds. Dynamic auscultation should be taken as part of the entire clinical picture and should not be taken as a standalone gold standard tool for making a dogmatic clinical diagnosis. The techniques of dynamic auscultation can be broadly classified into physiological maneuvers, pharmacological maneuvers, and maneuvers that relate to simple change in posture of the body (Table 1).
PHYSIOLOGICAL MANEUVERS Valsalva Maneuver4 Method The maneuver is performed by asking patient to exhale forcefully into mercury manometer to generate and maintain a pressure of 40 mm Hg for 20 seconds.
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Table 1: Classification techniques of dynamic auscultation Physiological maneuvers
Pharmacological maneuvers
Simple postural changes
Valsalva maneuver
Amyl nitrite inhalation
Left lateral-MS
Sudden standing from squatting or lying down
Methoxamine/ phenylephrine
Sitting up and leaning forward
Muller maneuver
Stretching of neck
Passive leg elevation Sudden squatting Isometric exercise Abbreviations: MS, mitral stenosis; AR, aortic regurgitation.
Practically, this can be done by asking the patient to take a deep inspiration, followed by forced expiration against a closed glottis for 20 seconds. (Examiner may place flat of hand on the abdomen to provide the patient the force, against which to strain). There are four stages of Valsalva maneuver (Table 2 and Figure 1).
Clinical Implications Pressure and Heart Rate Response (Figure 1) Square-wave response: This is seen in conditions like left heart failure, mitral stenosis (MS), and atrial septal defect (ASD). During Valsalva maneuver, blood pressure increases in stage I (normally), but remains elevated in all subsequent stages due to abolished stage II and loss of overshoot in stage IV. This is seen when lungs are overloaded with fluid and this excessive volume continues to empty in the LV even during straining. So, there is little effect of fall in systemic vascular return on LV volume and hence, blood pressure (Figures 2A to C).
Physiological Changes Stage II (Figure 3).
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Table 2: Stages of Valsalva maneuver Blood pressure
1. Onset of straining (1st 10 sec)
↑ Aortic compression due to raised intrathoracic pressure
↓
2. Continued expiration (10–20 sec)
↓ Due to venous compression and decreased venous return
↑
3. End of expiration
↓↓ Due to increased capacitance of pulmonary bed
4. Recovery 5–10 sec after stopping expiration
↑ Overshoot due to sympathetic activation
6
Heart rate
Dynamic Auscultation
Stages
↑↑ ↓
Note: Normally changes in intensity of murmur are only recorded in stage 2. Caution: Valsalva maneuver should not be performed in ischemic heart disease patients and patients of severe left ventricular (LV) outflow obstruction.
the mitral valve to prolapse early in the systole. This makes the click move closer to S1 and the murmur to become longer.
Rapid Standing from Squatting or Lying Posture Method
Figure 1: Pressure and heart rate response during normal and Valsalva maneuver
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Physiologically, effects of rapid standing from squatting or lying down posture are similar to Valsalva stage II. The patient must be in squatting position for at least 30 seconds. The patient is asked to stand rapidly from squatting position and changes in heart sound and murmur are seen at 15–20 seconds.
Response in Specific Diseases
Clinical Implications
Hypertrophic obstructive cardiomyopathy: Murmur of hypertrophic obstructive cardiomyopathy (HOCM) starts well after S1 and it has a crescendodecrescendo pattern. Basic pathology is the dynamic obstruction of LVOT by combined effect of systolic increase in thickness bulge in LV cavity of already hypertrophied septum and systolic anterior motion (SAM) of anterior mitral leaflet (AML). Any factor which decreases LV size [left ventricle end diastolic volume (LVEDV)], such as decreased preload, decreased afterload, and increased contractility, will increase murmur of HOCM (Figure 3).
Similar to stage II Valsalva, this maneuver leads to decreased venous return, decreased LVEDV, and decreased stroke volume. These physiological changes result in narrow splitting of A2P2, soft S3, S4, softer murmur of pulmonary stenosis (PS), aortic stenosis (AS), tricuspid regurgitation (TR), mitral regurgitation (MR), tricuspid stenosis (TS), mitral stenosis (MS), louder HOCM murmur, click of MVP moves closer to S1 and the murmur becomes longer.
Mitral valve prolapse: Basic pathology in mitral valve prolapse (MVP) is the prolapse of mitral leaflet above annulus during ventricular systole. It is said that mitral valve leaflet and chordae are too big for left ventricle; so, they prolapse into left atrium during ventricular systole when a critical LV volume is reached (midtolate systole). Click in MVP occurs in midlate systole because of billowing of mitral valve (MV) leaflets and tensing of chordae and is synchronous with maximum prolapse of involved leaflet. Murmur usually begins with the click and then fans out up to A2. Any maneuver which decreases LV size (LVEDP) leads to early attainment of critical volume of LV which causes
This maneuver is commonly known as opposite of Valsalva maneuver.
Müller Maneuver
Method It is done as the patient’s nares are held closed and then patient has to suck forcibly into a manometer to generate a negative pressure of 40–50 mm Hg for 10 seconds and changes are seen in the intensity of murmur at the end of 10 seconds. Practically, this is done by asking the patient to inspire forcefully for 10 seconds while the patient’s nares are pinched and mouth firmly sealed.
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A
B
C
Figures 2A to C: (A) Normal: sinusoidal response with sounds intermittent during strain and release; (B) Briefly audible sounds during initial strain phase and absence overshoot suggests only impaired systolic function in the absence of fluid overload; (C) Persistence of Korotkoff sounds throughout strain phase suggests elevated left ventricular filling pressures known as square root pattern
Figure 3: Physiological changes during stage II Valsalva maneuver and its effect on heart sounds and murmurs Abbreviations: LVEDV, left ventricle end-diastolic volume; AS, aortic stenosis; PS, pulmonary stenosis; AR, aortic regurgitation; PR, pulmonary regurgitation; MR, mitral regurgitation; TR, tricuspid regurgitation; MS, mitral stenosis; TS, tricuspid stenosis; HOCM, hypertrophic obstructive cardiomyopathy; MVP, mitral valve prolapse
Clinical Implications This maneuver leads to increased venous return which leads to increase in rightsided murmurs, increase in A2 P2 gap, and increase in right ventricle (RV) S3 and S4.
lie down from the standing posture. The changes in murmur or heart sound are noticed after 15–20 seconds. Physiology and effects are almost similar to Muller’s maneuver, but are more pronounced (Figure 4).
Passive Leg Elevation or Sudden Lying Down
Clinical Implications
Method In this maneuver, the patient is asked to lie in supine position and passive elevation of both the legs is done straightly for 15–20 seconds or the patient is asked to
Physiologically, this maneuver leads to increased venous return, which leads to increased RV stroke volume; and after a few beats, this leads to increased LVEDV and increased LV stroke volume. The increased RV stroke
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6 Dynamic Auscultation
Figure 4: Physiological changes during passive leg elevation or sudden standing Abbreviations: RV, right ventricle; LV, left ventricle; SV, stoke volume; PS, pulmonary stenosis; TS, tricuspid stenosis; TR, tricuspid regurgitation; AS, aortic stenosis; MS, mitral stenosis; MR, mitral regurgitation; MVP, mitral valve prolapse; HOCM, hypertrophic obstructive cardiomyopathy
Figure 5: Physiological effects of sudden squatting and effects on heart sounds and murmurs Abbreviations: BP, blood pressure; LV, left ventricle; LVEDP, left ventricle end-diastolic pressure; SV, stoke volume; PS, pulmonary stenosis; AS, aortic stenosis; TS, tricuspid stenosis; MS, mitral stenosis; AR, aortic regurgitation; MR, mitral regurgitation; VSD, ventricular septal defect; TOF, tetralogy of Fallot; PDA, patent ductus arteriosus; HOCM, hypertrophic obstructive cardiomyopathy; MVP, mitral valve prolapse
volume leads to widely split A2P2, louder RV S3, S4, louder rightsided murmurs like PS, TS, and TR. The increase in LVEDV leads to softer HOCM murmur and the click of MVP moves later in systole with a shorter murmur. The increase in stroke volume leads to louder LV S3, S4 and louder leftsided murmurs such as MS, MR, and AS.
Sudden Squatting Method The patient is asked to squat suddenly from standing position (Valsalva maneuver to be avoided) and changes in murmur or heart sounds are heard just after squatting (Figure 5).
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tetralogy of Fallot (TOF), ventral septal defect (VSD), and patent ductus arteriosus (PDA). Due to combination of increased preload and afterload, there is increase in murmur intensity of HOCM, click of MVP is delayed, and the murmur of MVP shortens.
Isometric Exercise Method To perform this maneuver, the patient is asked to tightly grip a calibrated hand grip device or handball with both the hands simultaneously and sustain it for at least 20–30 seconds (care should be taken not to perform Valsalva maneuver). This maneuver is most useful for leftsided lesions and it should not be done in patients with coronary artery disease (CAD) and ventricular arrhythmia.
Clinical Implications
Clinical Implications
Physiological effect of this maneuver is simultaneous increase in venous return and systemic vascular resistance. This leads to increased stroke volume, increased blood pressure, and increased LV size (LVEDV). Increased stroke volume leads to increased S3, S4 sounds, louder murmurs of PS, AS, TS, and MS. Increased systemic vascular resistance leads to increased louder murmurs of AR, MR,
Physiologically, there is transient but significant increase in systemic vascular resistance, increase in heart rate, increase in stroke volume, increase in cardiac size, and increase in LV filing pressures. Clinical effects on heart sounds and murmurs are as follows: Murmur of AS is diminished due to reduction of pressure gradient across aortic valve
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Murmur of AR, rheumatic MR and VSD increases due to increase in SVR LVS3 and LVS4 accentuated due to increase in LV filling pressures Murmur of MS becomes louder due to increase in flow across valve Murmur of HOCM decreases due to increase in LV volume Click and murmur of MVP delayed due to increase in LV volume, but the murmur of MVP becomes louder.
PHARMACOLOGICAL MANEUVERS Amyl Nitrite Method An ampoule of amyl nitrite (0.3 mL) is crushed into a gauze piece and the patient is asked to take 3–4 deep breaths with the gauze piece near the patient’s nostril. Changes in the murmur are noticed in the first 15–30 seconds. Physiologically, in the first 30 seconds, there is intense vasodilation leading to decreased arterial pressure. In the next 30–60 seconds, there is reflex tachycardia and, therefore, increased cardiac output.
Clinical Implications Due to decreased aortic pressure, amyl nitrite accentuates the murmurs of AS (increased gradient across aortic valve), HOCM (decreased afterload), MS (reflex tachycardia) and diminishes the murmurs of AR, MR, VSD, PDA, and TOF. Amyl nitrite is very useful in differentiating: Middiastolic murmur (MDM) of MS vs. Austin flint murmur of AR (MS murmur is accentuated and Austin flint is diminished) TOF vs. isolated PS (TOF murmur is diminished and PS murmur is accentuated) MR vs. TR (MR murmur is diminished and TR murmur is accentuated) AR vs. PR (AR murmur diminishes and there is no change in PR murmur).
Methoxamine and Phenylephrine Method Methoxamine is administered at 3–5 mg IV (intravenous) to increase arterial pressure by 20–40 mm Hg for 10– 20 min. Phenylephrine is administered at 0.5 mg IV to elevate systolic pressure around 30 mm Hg for 3–5 min. Phenylephrine is preferred due to shorter duration action.
Clinical Implications Physiologically, there is increased systemic arterial pressure that causes reflex bradycardia and decreased
contractility and thus decreased cardiac output. They are contraindicated in chronic heart failure (CHF) and hypertension (HTN). The effects of methoxamine and phenylephrine on heart sounds are reduced S1, louder A2, prolonged A2OS interval and variable response of S3 and S4. Methoxamine and phenylephrine accentuate the electrolytedriven mobilization (EDM) (EDM) of AR, paradoxical septal motion (PSM) of MR, murmur of VSD, TOF, and continuous murmurs of PDA and arteriovenous fistula (AVF). Also, the systolic murmur of HOCM softens (increased LV size), click and murmur of MVP delayed (increased LV size). Due to decrease in cardiac output, ejection systolic murmur (ESM) of AS, functional systolic murmurs, and MDM of MS are diminished.
Clinically Dynamic Auscultation Helps to Differentiate AS and HOCM Squatting (AS murmur increases, HOCM murmur diminishes) Valsalva/standing (AS murmur diminishes, HOCM murmur accentuates). AS and MR Handgrip (AS murmur diminishes, MR murmur accentuates) Phenylephrine (AS murmur diminishes, MR murmur accentuates) Postventricular premature contractions (VPC) (AS murmur accentuates and MR murmur diminishes) Amyl nitrate (AS murmur accentuates and MR murmur diminishes). MS and Austin flint Amyl nitrite (MS murmur accentuates and Austin flint murmur diminishes). PS and small VSD Amyl nitrite (PS murmur accentuates and VSD murmur diminishes) Phenylephrine (PS murmur diminishes and VSD murmur accentuates).
REFERENCES 1. Lembo NJ, Dell’ Italia LJ, Crawford MH, O’Rourke RA. Bedside diagnosis of systolic murmur. N Engl J Med. 1988;318:15728. 2. Grewe K, Crawford MH, O’Rourke RA. Differentiation of cardiac murmurs by dynamic auscultation. Curr Probl Cardiol. 1988;13:669721. 3. Braunwald E, Perloff JK. Physical examination of the heart and circulation. In: Braunwald E, Zips DP. Libby P (Eds): Heart disease, 6th edn Philadelphia,WB Saunders; 2001. 4. Nishamura RA, Tajik AJ. The valsalvsa maneuver and response revisited. Mayo Clin Proc. 1986;61(3):2117.
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Valvular Heart Disease—Rheumatic Heart Disease Challenges in the Diagnosis and Management of Acute Rheumatic Fever
Anita Saxena Pathogenesis of Rheumatic Fever and Rheumatic Heart Disease:
What have we Learned?
Santhosh Satheesh, Sasinthar Rangasamy Decline of Rheumatic Heart Disease: Is it Real?
Prakash C Negi, Sanjeev Asotra, Sachin Sondhi Clinical Assessment of Severity of Valvular Heart Disease
Ajith Ananthakrishna Pillai, Devendra Kanshilal Sharma, Balachander Jayaraman Subclinical Rheumatic Heart Disease
RK Gokhroo, Kailash Chandra Natural History of Mitral and Aortic Valve Regurgitation
Sudhir S Shetkar, Sivasubramanian Ramakrishnan, Kewal C Goswami Natural History of Rheumatic Mitral Stenosis
Vivek Chaturvedi Percutaneous Transvenous Mitral Commissurotomy: Tips and Tricks
CN Manjunath, Vijaykumar JR, BC Srinivas Clinical Diagnosis of Tricuspid Valve Disease
S E C T I O N
Sudeep Kumar, Pramod Sagar BK Atrial Fibrillation in Rheumatic Heart Disease
Krishnakumar S, Harkrishnan S Prevention of Rheumatic Fever/Rheumatic Heart Disease
Anil Bharani, Anjali Bharani
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Challenges in the Diagnosis and Management of Acute CHAPTER 7 Rheumatic Fever Anita Saxena
INTRODUCTION Rheumatic fever is an acute, diffuse, and nonsuppurative inflammatory disease that occurs as a delayed complication after an untreated or partially treated pharyngotonsillitis, the infection itself sometimes being asymptomatic. It is caused by group A β-hemolytic Streptococcus, specifically, Streptococcus pyogenes. The process is triggered by an inappropriate immunological response, both humoral and cellular, and results from a complex interaction among individual susceptibility, environment and the bacteria. The exact nature of this response is incompletely understood. The disease is characterized by four distinct phases. The initial streptococcal pharyngotonsillitis is followed by a latent period and then by the acute and chronic phases. The chronic phase is also known as rheumatic heart disease (RHD), when the cardiac lesions remain as sequela of the acute phase. Rheumatic fever (RF) has the potential to involve multiple organs systems including the heart, joints, brain, and subcutaneous and cutaneous tissues. Cardiac injury is the most important manifestation, and it is the damage to the heart that produces its clinical, social, and economic impact. Although RF has declined in Europe and North America over the past 4 to 6 decades, this preventable disease continues to be both socially and clinically devastating in low- and middle-income countries, with significant rates of morbidity and mortality. 1, 2 Acute episodes of RF are still a cause of death in childhood and its sequela are the major causes of cardiovascular death in children and young adults. The RF is more frequent among children and adolescents between the ages 5 and 15, and has a peak of incidence around the ages of 8 to 9 years. These ages coincide with the peak of streptococcal pharyngotonsillitis in school-aged children, this infection being less common in late adolescence and in adults. Likewise, RF is uncommon in children under 4 years of age, and exceedingly rare under the age of 2.3-5 In recent years, epidemiological studies, including surveys using portable echocardiographic screening, have described RHD burden in Africa, Asia, and Oceania, with prevalence varying between 2% and 6% and around 90% of
KG-7 (Sec-2).indd 39
cases detected by echocardiography being asymptomatic and subclinical.6-8
DIAGNOSIS OF RHEUMATIC FEVER There is no single confirmatory clinical sign or laboratory test. Diagnosis is based on the Jones criteria, which have recently been updated for the first time since 1992. A single set of diagnostic criteria has become insufficient to encompass the variability in the clinical profile of acute episodes related to different populations in diverse geographic settings. Additionally, the concept of cardiac involvement in the absence of auscultatory findings, the so-called subclinical carditis, has emerged from the widespread use of Doppler echocardiography. Taking into account the technological advances and new evidence from epidemiological data, the Jones criteria were last reviewed and updated9 in the year 2015 (Table 1). Firstly, subclinical carditis was incorporated as a major manifestation for all patient populations. Secondly, with the introduction of two different sets of diagnostic criteria based on population risk, monoarthritis, or polyarthralgia were considered a major criterion for arthritis, and lowgrade fever was included as a minor manifestation, both conditions applied only for moderate- and high- risk populations. Moderate–high risk is defined as coming from a population with an RF incidence of ≥2 per 100,000 school-aged children (usually 5–14 years old) per year or an all age RHD prevalence of >1 per 1,000 people per year. The five most characteristic clinical features constitute the major manifestations, namely carditis, arthritis, chorea, subcutaneous nodules, and erythema marginatum, independent of their severity. Classically, arthritis and carditis, isolated or combined are seen most frequently. Chorea is less common, and the other major manifestations are rare. The minor manifestations are frequent and mostly related to the underlying systemic inflammation. These clinical and laboratorial findings are nonspecific but supportive of the diagnosis when accompanying a major manifestation. In addition to the Jones criteria, other non-specific clinical findings may also be present during the course of the acute episodes.
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2
Table 1: Revised Jones criteria 2015 update For all patient populations with evidence of preceding GAS infection
Valvular Heart Disease—Rheumatic Heart Disease
Diagnosis: Initial acute rheumatic fever:
Diagnosis: Recurrent acute rheumatic fever:
2 major manifestations or 1 major plus 2 minor manifestations 2 major or one major plus 2 minor or 3 minor
Low-risk populations* Major manifestations
Minor manifestations
Carditis z Clinical or subclinical
Fever (>38.5º)
Arthritis z Polyarthritis only
Polyarthralgia
Chorea
Prolonged PR
Subcutaneous nodules
ESR ≥ 60 mm in the first hour
Erythema marginatum
and/or CPR ≥ 3.0 mg/dL
Moderate- and high-risk populations* Carditis z Clinical or subclinical
Fever (>38º)
Arthritis z Monoarthritis or polyarthritis z Polyarthralgia
Monoarthralgia
Chorea
Prolonged PR
Subcutaneous nodules
ESR ≥ 30 mm in the first hour
Erythema marginatum
and/or CPR ≥ 3.0 mg/dL
Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate * See text for complementary information. Source: Gewitz MH, Baltimore RS, Tani, Sable CA, Shulman ST, Carapetis J, et al. On behalf of the American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young. Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131(20):1806-18.
The diagnosis of a first episode of RF includes the combination of two major, or one major and two minor manifestations, supported by evidence of a preceding infection with the group A Streptococcus. When clinical or subclinical carditis is considered as a major manifestation, a prolonged P-R interval cannot be included as minor manifestation in the same patient. Similarly, in the presence of arthritis, mono- or polyarthralgia cannot be considered as a minor manifestation. Once other diagnoses are excluded, Sydenham’s chorea and indolent carditis are exceptions to the strict adherence to the Jones criteria. Since Sydenham’s chorea usually occurs as a late manifestation of the disease, evidences of the inflammatory process and of the preceding streptococcal infection could have already subsided when the major manifestation becomes evident. Similarly, the evidence of a streptococcal infection is not required for patients
with indolent carditis. This subacute condition is more frequently seen in young children and shows insidious onset and slow progression over several weeks or months. By the time of evaluation, the acute phase reactants and levels of antistreptococcal antibodies may be normal. 9 For the diagnosis of a recurrent attack, the complete set of Jones criteria is not needed when faced with a reliable history of a previous episode of RF, or an established chronic RHD. The diagnostic requirements are two major or one major and two minor or at least three minor manifestations, along with supporting evidence of a recent streptococcal infection. Diagnostic categories described as ‘possible’ and ‘probable’ RF have been used to include patients, who did not meet the Jones criteria for a definitive diagnosis of an acute episode although RF is the most likely diagnosis.10-12
MAJOR CRITERIA Carditis The cardiac involvement is variable ranging from subclinical to severe presentation with heart failure and fulminating evolution. The severity of carditis is the most important prognostic factor. Rheumatic carditis is characterized by pancarditis. The determinants of morbidity and mortality, nonetheless, are the degree and extent of endocarditis, represented by the damage in the cardiac valves. The cardiac involvement tends to appear early, and is usually diagnosed within the first 3 weeks of the acute episode. Carditis is reported to be seen in up to three-fifths of first attacks although more recent series of patients have shown higher rates when echocardiography is included in the evaluation.13, 14 Pericarditis may rarely occur as a part of pancarditis. It produces pericardial effusion, mostly mild, and does not cause constriction. Similarly, myocarditis is rare. Congestive heart failure (CHF) in RF is not due to primary myocarditis but results from significant valvular dysfunction secondary to valvulitis. Endocarditis is the diagnostic hallmark of rheumatic carditis, being expressed by valvitis. The inflammatory process affects the mitral and aortic valves. Mitral regurgitation is the dominant valvar lesion in over 90% of patients; it may be associated aortic regurgitation. Isolated aortic regurgitation is seen in less than 5% of cases. Subclinical carditis: Silent carditis, diagnosed by Doppler echocardiography has been accepted as part of the spectrum of rheumatic carditis. It is found in patients with isolated arthritis and/or pure chorea, without auscultatory findings of valvar dysfunction, but with a pathological pattern of valvar regurgitation revealed by Doppler echocardiographic interrogation. As trivial valvar leaks are commonly identified by Doppler echocardiographic investigation in normal subjects at all ages, it is essential to use strict criterions to differentiate
40
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pathological from physiological regurgitation. The finding of a subclinical carditis has been included in the most recent revision of Jones criteria for diagnosis of RF.
Polyarthritis is the most frequent major manifestation seen in older children, adolescents and adults, but is the least specific clinical finding of RF. Polyarthritis is nonsuppurative, asymmetric, migratory, and self-limited. There is a marked preference to involve the peripheral large joints, particularly of the legs. The small joints of the hands and feet, the shoulders and hips are less commonly affected. The spine is rarely involved. Tenderness and severe pain, out of proportion to the findings of the physical examination, are the most prominent features. Redness, swelling, and heat are usually less marked. Salicylates and nonsteroidal anti-inflammatory agents produce a marked and prompt relief of the symptoms and signs. Usually, the arthritis heals without anatomical deformities or functional abnormalities. Monoarthritis is less common, but has been included as a major criterion in recent revision for moderate- and high-risk populations.
Sydenham’s Chorea Sydenham’s chorea, chorea minor, or St. Vitus’ dance, affects children and adolescents, more commonly in prepubertal females. The latent period, after the streptococcal infection, is longer than for arthritis and carditis, varying from 1 to 7 months. Chorea may occur as an isolated manifestation, the so-called pure chorea, or less frequently in association with carditis or arthritis.15 It is usually a self-limited disorder, characterized by muscular weakness, hypotonia, and emotional instability, besides involuntary and purposeless but conscious movements of the skeletal muscles. One-fifth of patients have hemichorea, with the manifestations limited to one side of the body.
Subcutaneous Nodules and Erythema Marginatum Subcutaneous nodules are one of the most characteristic major criteria, but are rarely seen. They have a diagnostic value as are invariably associated with severe carditis. The nodules are seen over the extensor surface of joints and bony prominences, are small, firm, painless, and freely movable under the skin. Er y t h e ma ma rg i nat u m i s a v e r y u n c o m m o n manifestation; it is seen as a macular rash over trunk; blanches on pressure, has a serpiginous or circular form, is painless and nonpruritic. The rash is characteristically evanescent or transient, may last minutes, more usually days. The lesions are more easily seen in fair-skinned patients, and may become more apparent with the application of heat.
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CHAPTER
7
The minor manifestations are nonspecific, providing support for diagnosis when associated with a major manifestation. Arthralgia is the most common minor criteria; joint pain shows the characteristics of polyarthritis without features of inflammation. Fever is usually present in the early stage of the disease, commonly of low-grade, and can persist for 2 to 3 weeks.9 There is no characteristic pattern, and it is rare for the temperature to rise higher than 39°C. The laboratory data included among the minor manifestations, as with the clinical findings, are also nonspecific. A prolonged P-R interval can be found in healthy people. Regarding the patterns of the acute phase reactants, both the rise and fall of the serum concentration of C-reactive protein occurs earlier than the erythrocyte sedimentation rate, which may remain elevated for 3-6 months, more frequently for more than 4 weeks.
Challenges in the Diagnosis and Management of Acute Rheumatic Fever
Polyarthritis
MINOR MANIFESTATIONS
Clinical Features not included in Jones Criteria Epistaxis is an uncommon presentation, and abdominal pain, mainly around the navel, may precede the major manifestations. Rheumatic pneumonia is rarely seen. Manifestations, such as anorexia, listlessness, fatigue, anemia, weight loss, and pallor, are described, but are related to systemic inflammation and to the severity of the clinical presentations, mainly carditis.
Challenges in Diagnosis of Rheumatic Fever An early diagnosis is important as it may prevent progression of damage to the cardiac valves. As no laboratory finding is specific, the history and physical examination remain the basis for the diagnosis. The established guidelines, although very useful, cannot substitute the physician’s experience and common sense. As a systemic disease, with a wide spectrum of manifestations and multiple associations, diagnostic problems can be present, since several other conditions can fulfill the Jones criteria. On the other hand, not all patients with an acute episode meet these diagnostic requirements. Even in areas where RF is still prevalent, its frequency and severity have decreased, resulting in less characteristic presentations. Carditis: Significant cardiac involvement is easy to diagnose but clinical characterization of mild, subclinical, or smoldering cardiac involvement is difficult. These circumstances have potential implications in prognosis, when the risks of recurrences and worsening of the valvar lesions are taken into account. Considering that almost 50% of adults presenting with an established rheumatic valvar disease do not give any preceding history of RF, underdiagnosis is very common. Similarly, children with innocent murmurs or murmurs caused by congenital cardiac defects may be wrongly diagnosed as having RF.
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Valvular Heart Disease—Rheumatic Heart Disease
2
Polyarthritis/polyarthralgia: A number of illnesses in children can give rise to symptom of polyarthritis, particularly when the articular involvement is the sole manifestation of the acute phase. The difficulties increase with the presence of atypical presentations of arthritis. Also, premature use of aspirin or other anti-inflammatory agents may mask the diagnosis. Usually, the joint involvement is an early and self-limited manifestation. Milder forms of arthritis/arthralgia may contribute to misdiagnosis, mainly when the symptoms and signs have already subsided at the clinical examination. Furthermore, the differential diagnosis between polyarthritis and polyarthralgia is difficult, if based exclusively on clinical history. There are many diseases that may currently fulfill the Jones criteria in their early stage, or mimic the acute rheumatic process very closely. The differential diagnosis includes rheumatoid arthritis, serum sickness, other arthropathies, infective endocarditis, Henoch–Schönlein purpura, acute leukemia, poliomyelitis, and acute appendicitis. Viral myocarditis, viral pericarditis, systemic lupus erythematosus, and other collagen disorders may affect both the joints and the heart. Recurrence of rheumatic fever: The diagnosis of recurrences can also be challenging. In patients with cardiac murmurs from a previous attack, a more precise diagnosis of recurrence can only be established if pericarditis is found, or if a different valve is damaged producing new murmur. Recent worsening of cardiac status could also represent a recurrence, although it can also result from the evolution of severe RHD. In many instances, a given presentation may not fulfill the updated Jones criteria, but the clinician with a vast experience of dealing with cases with RF may still suspect that RF is the diagnosis. This is more likely to happen in high prevalence settings. In such situations, clinicians should use their discretion and clinical acumen to make the diagnosis and manage patients accordingly. In genuinely uncertain cases, it is reasonable to consider the diagnosis of RF and offer secondary prophylaxis for 12 months followed by re-evaluation to include a careful history, physical examination and a repeat echocardiogram.9 The supporting evidence of recent streptococcal infection and rise in acute phase reactants are not specific for the disease, but are useful to characterize the presence of the inflammatory process. Besides the minor manifestations, other clinical features, such as fatigue and anorexia, contribute to the diagnostic approach when they are not part of the cardiac failure. As the clinical features are crucial for a better understanding of the course of the disease, a period of closer observation sometimes is needed to clarify the diagnosis.
MANAGEMENT Apart from mild cases, most individuals with suspected RF are hospitalized for diagnostic work-up and to initiate treatment. Management of the acute episode includes eradication of tonsillar and pharyngeal group A Streptococcus, treatment of the acute inflammatory phase, which is supportive and focuses on providing symptomatic relief of arthritis, supportive care for carditis, and education for the patient and family, especially for emphasizing the importance of secondary prophylaxis. After obtaining a throat swab, penicillin is commenced to eradicate group A Streptococcus from the pharynx. Either oral phenoxymethylpenicillin (penicillin V), 250 mg twice daily in children or 500 mg twice daily in adolescents for 10 days, or a single dose of intramuscular benzathine penicillin (benzathine benzylpenicillin) can be given until the patient is established on long-term secondary antibiotic prophylaxis. For patients with penicillin allergy, erythromycin is the recommended alternative antibiotic.
Management of Clinical Manifestations Bedrest: The recommended duration and strictness of bedrest is variable depending on the manifestations and severity of the clinical presentation. The recommendation of prolonged bedrest is based primarily on reducing cardiac work in those with carditis, and avoiding as much as possible the use of the involved joints in those with arthritis. Strict bedrest is no longer recommended for most patients with rheumatic carditis, it should be limited to patients with a more significant involvement of the heart with CHF, and to those with arthritis of the legs. The rest need not be strict, and it should be followed by supervised activities for the following weeks. Patients with cardiomegaly, and congestive failure, should be made to rest over the first 3–4 weeks, and then gradually allowed activities. Carditis: Anti-inflammatory drugs have been extensively employed in the treatment of carditis, showing a prompt effect in terms of cardiac symptoms. Salicylates are used for those with no or mild forms of carditis, corticosteroids are used for patients with moderate or severe carditis, especially for those with CHF. Prednisone is usually preferred, initial dose of 1–2 mg/kg, given for 2–3 weeks followed by a gradual tapering, total duration of the treatment should be 8–12 weeks. Some authors have recommended an overlapping therapy with the aim to prevent rebounds, with the introduction of salicylates as the dose of corticosteroids is reduced. In addition, supportive measures include the treatment of CHF and arrhythmias. Diuretics, angiotensin-converting enzyme (ACE) inhibitors should be used in patients with significant valvular regurgitation and/or left ventricular dysfunction.
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CHAPTER
Table 2: Treatment of major manifestations of carditis Treatment schedule
Severe carditis
Prednisone 2 mg/kg/day once daily
Moderate carditis
Prednisone 1–2 mg/kg/day once daily or Aspirin 75–100 mg/day divided into 4 doses
Mild carditis
Aspirin 75–100 mg/day divided into 4 doses
Polyarthritis
Aspirin 75–100 mg/day divided into 4 doses or Naproxen 10–20 mg/kg/day
Chorea
Carbamazepine 4–10 mg/kg/day or Valproic acid 20–30 mg/kg/day or Haloperidol 2–6 mg/day
Cardiac surgery is best deferred in the acute stage as the valve repair is difficult and less durable. However, urgent surgery may be required due to very severe mitral and/ or aortic regurgitation with heart failure or in those with a flail leaflet due to chordae tendinae rupture. Repair of the valve is to be preferred over valve replacement in young patients.16 Arthritis: Salicylates are the first-line treatment; these agents usually have a dramatic effect on the inflammatory process, with prompt improvement. However, paracetamol should be used till confirmation of diagnosis. The full dose is given for the first 2 weeks and subsequently is gradually reduced to up to 60 mg/kg over the next 2–3 weeks (Table 2). A smaller or a larger dose can be used, depending on the clinical response to treatment, and may be maximized for those failing to respond to lower doses. A higher dose, such as 100 mg/kg, is required by few patients. Naproxen is an alternative therapy for patients who are allergic to or intolerant of aspirin. It has similar analgesic potency as salicylate but does not have the risk of Reye’s syndrome, a rare complication of salicylate. Sy d e n h a m’s c h o re a : Is o l at e d c h o re a i s t re at e d symptomatically. The patients should be kept in a quiet environment to protect them from external stimulation and stress. As most drugs used for chorea are not without side effects, treatment should be considered, if symptoms affect the normal activities significantly or patient has risk of injury. Valproic acid and carbamazepine are preferred over haloperidol as haloperidol has significant side effects. Carbamazepine should be used initially and valproic acid given for refractory cases (Table 2). Anti-inflammatory agents are usually not indicated, because chorea often occurs after the resolution of the systemic inflammatory process. A short course of corticosteroids may be considered for severe refractory cases.
7 Challenges in the Diagnosis and Management of Acute Rheumatic Fever
Clinical manifestation
Challenges in Management of Rheumatic Fever For many people with mild-to-moderate carditis, the degree of valvular regurgitation stabilizes or improves within 12 months after diagnosis. Individuals who experience severe carditis during the initial episode, or recurrences of RF, are at greatest risk of severe chronic RHD,4 which is associated with an increased risk of heart failure, infective endocarditis, pregnancy complications, stroke, arrhythmias, and premature death. As mentioned earlier, the treatment of RF is largely supportive and does not alter the natural history of the disease in most cases. However, these medicines including drugs for control of heart failure, arrhythmias need to be taken regularly in advanced level of rheumatic carditis. The most important aspect of treatment is preventing the recurrence of RF, as each recurrence tends to worsen the damage to valves increasing its severity. The recurrences are prevented by means of continuous use of antibiotics, independently from the type of clinical manifestation in the acute phase or the presence of sequela. This is called secondary prevention. Effective secondary prevention results in reduction in hospitalization, disability, intervention, and mortality rates. Therefore, careful attention to ensure good adherence to secondary prophylaxis (mostly by benzathine penicillin) is required. The regimes for secondary prevention are shown in Table 3.17,18 Benzathine penicillin remains the drug of choice and the most effective to prevent recurrences. The use of four-weekly benzathine penicillin has been considered the standard regimen; however, in populations with a high prevalence of RF, shorter intervals have been recommended. This measure is supported by observations of higher rates of recurrent episodes related to monthly prophylactic regimens when compared to three-weekly intervals. The use of the long-acting intramuscular penicillin is more effective than oral penicillin. Adequate 43
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Valvular Heart Disease—Rheumatic Heart Disease
2
Table 3: Drugs and regimes for secondary prophylaxis Drug
Dose
Interval of doses
Benzathine Penicillin G (deep IM injection) To be given after sensitivity test. Contraindicated if Penicillin allergy present
If body weight > 27 kg: 12 lakh unit If body weight ≤ 27 Kg: 6 lakh unit
Every 21 days’ Every 14 days’
Penicillin V (oral) To be given one hour before or two hours after meals. Contraindicated if Penicillin allergy present
250 mg
Two times a day
Erythromycin ethyl succinate (oral) Contraindicated in liver disease
250 mg
Two times a day
levels are less predictable with the use of oral medication, contributing to higher risks of recurrences.
Challenges to Secondary Prophylaxis Patient-related challenges: These include low levels of education of patients and families and poor level of understanding of the disease and importance of secondary prophylaxis. Since RF primarily affects poor patients, the inability to afford the medicine and cost of travel to a health facility for injection is also responsible for lack of compliance. Some communities tend to have distrust with health services and would rather go for alternate therapy and indigenous medicines for their symptoms. Health system-related challenges: Limited knowledge amongst physicians practicing in metro cities, where poor patients are unable to access health care, has given an impression that RF is declining. A number of private health facilities refuse to administer penicillin injections for fear of allergic reaction, which is very rare in children. Since there is no national policy for prevention and control of RF and RHD, the health systems do not maintain any register nor do they track patients with RF. Penicillin-related challenges: Penicillin is the cornerstone of any prevention program for RF, it is required for treatment of bacterial sore throat as well as for long-term secondary prophylaxis. Unfortunately, neither long-acting benzathine penicillin nor oral penicillin is available on a regular basis. In fact, some of the states in India have banned the use of penicillin in private hospitals. The quality of some of the available brands is also suspected. As the margin of cost benefit is very low, most pharmaceutical companies are not interested in producing this drug. Pain during injection of long-acting penicillin further deters patients from taking it on a regular basis.
Measures to Improve Secondary Prophylaxis Rates
44
These include: Dedicated staff to supervise secondary prophylaxis coordination. Development of registries at hospital/state/national levels to track patients. Strong staff-patient relationship, community-based service delivery.
KG-7 (Sec-2).indd 44
Identifying local health facility for each patient. Education of affected patients and their families about importance of regular prophylaxis. Reliable supply of safe, good quality penicillin. Training of manpower for safe penicillin injection. Encouraging staff to use pain-reducing mechanisms.
CONCLUSION The RF continues in developing countries including India. The recent updated Jones criteria for moderateand high-risk population assist in diagnosis of RF, but clinicians should use their clinical acumen in cases where these criteria are not fully satisfied so as not to miss cases with RF. The management of acute episode is largely symptomatic. The main thrust should be on prevention of recurrences by instituting secondary prophylaxis. Adherence with prophylaxis can be improved by various means; perhaps, the most important is educating the patients and their families.
REFERENCES 1. Carapetis JR, Steer AC, Mulholland EK, et al. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5(11):685–94. 2. Seckeler MD, Hoke TR. The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol. 2011;3:67–84. 3. Tani LY, Veasy LG, Minich LLA, et al. Rheumatic fever in children younger than 5 years: Is the presentation different? Pediatrics.20 07;112(5):1065-8. 4. Canter B, Olguntürk R, Tunaoglu FS. Rheumatic fever in children under 5 years old. Pediatrics. 2007;114(1):329-30. 5. Chockalingam A, Gnanavelu G, Elangovan S, et al. Clinical spectrum of chronic rheumatic heart disease in India. J Heart Valve Dis. 2003;12(5):577-81. 6. Beaton A, Okello E, Lwabi P, et al. Echocardiography screening for rheumatic heart disease in Ugandan schoolchildren. Circulation. 2012;125(25):3127-32. 7. Roberts K, Maguire G, Brown A, Atkinson D, Reményi B, Wheaton G, et al. Echocardiographic screening for rheumatic heart disease in high and low risk Australian children. Circulation. 2014;129(19):1953-61. 8. Saxena A, Desai A, Narvencar K, et al. Echocardiographic prevalence of rheumatic heart disease in Indian school children using World Heart Federation criteria - A multi
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and Secondary Prevention of Acute Rheumatic Fever and Rheumatic Heart Disease: 2014 Update. Juneja R, Tandon R. Rheumatic carditis: a reappraisal. Indian Heart J. 2004;56(3):252-5. Kassem AS, el-Walili TM, Zaher SR, et al. Reversibility of mitral regurgitation following rheumatic fever: clinical profile and echocardiographic evaluation. Indian J Pediatr. 1995;62(6):717-23. Mota CC, Meira ZM. Rheumatic fever. Cardiol Young. 1999;9(3):239-48. Finucane K, Wilson N. Priorities in cardiac surgery for rheumatic heart disease. Glob Heart. 2013;8(3):213-20. World Health Organization. Rheumatic fever and rheumatic heart disease. World Health Organ Tech Rep Ser. 2004;923:1-122. Dajani A, Taubert K, Ferrieri P, Peter G, Shulman S. Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: a statement for health professionals. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, the American Heart Association. Pediatrics 1995;96:758-64.
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7 Challenges in the Diagnosis and Management of Acute Rheumatic Fever
10.
site extension of RHEUMATIC study (the e-RHEUMATIC study). Int J Cardiol. 2017;249:438-42. Gewitz MH, Baltimore RS, Tani LY, et al. On behalf of the American Heart Association Committee (on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young): Revision of the Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131(20):1806-18. Ralph A, Jacups S, Kay McGough K, et al. The challenge of acute rheumatic fever diagnosis in a high-incidence population: a prospective study and proposed guidelines for diagnosis in Australia’s Northern Territory. Heart Lung Circ. 2006;15(2):113-8. RHD Australia (ARF/RHD writing group), National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. Australian guidelines for prevention, diagnosis and management of acute rheumatic fever and rheumatic heart disease (2nd edition). 2012. Heart Foundation of New Zealand. New Zealand Guidelines for Rheumatic Fever. Diagnosis, Management
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CHAPTER 8
Pathogenesis of Rheumatic Fever and Rheumatic Heart Disease: What have we Learned? Santhosh Satheesh, Sasinthar Rangasamy
INTRODUCTION Acute rheumatic fever (ARF) is a nonsuppurative inflammatory sequelae of group A Streptococcus (GAS) pharyngitis occurring after a 2 to 3-week latent period in children aged 5–15 years presenting as fever, polyarthritis, pancarditis, chorea, and skin manifestations. Rheumatic heart disease (RHD) is a delayed sequelae of initial or recurrent ARF characterized by chronic progressive valvopathy which occurs in 60% of patients with ARF.1 The exact pathogenesis leading to the occurrence of ARF remains elusive and is continually evolving. It seems clear that pharyngeal infection by GAS is essential although the cause is multifactorial.2 Genetic susceptibility and environmental issues play an important role. Autoimmune response called ‘molecular mimicry’ is considered to exert a pivotal role in the commencement of the disease.
THREE COMPONENTS OF RHEUMATIC FEVER PATHOGENESIS Pathogen The link between GAS and autoimmunity has evolved since the early reports of ARF and RHD.3-5 ARF is the result of autoimmune response to pharyngitis caused by Streptococcus pyogenes, the sole member of GAS. There is a strong epidemiological association between GAS throat infection and ARF suggesting ‘causation’ as evidenced by the following: ARF outbreaks closely follow epidemics of streptococcal pharyngitis or scarlet fever.6 Optimal antibiotic treatment of a documented streptococcal sore throat significantly decreases ARF incidence.2 Appropriate antibiotic prophylaxis prevents ARF recurrence.7 Antistreptococcal antibodies, such as antistreptolysin O (ASO), hyaluronidase, and streptokinase, are seen in most patients with ARF irrespective of preceding sore throat.8
Link between the Pharynx and the Heart Why ARF is associated with only pharyngitis and not with any other disease caused by GAS, remains poorly
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understood. The pharyngeal lymphoid tissue is considered important in the initiation of abnormal immune response. GAS can be broadly divided into two classes based upon the C repeat regions of the M protein. One is associated with pharyngitis and the other, impetigo.9 The presence of impetigo is associated with acute glomerulonephritis (AGN) but not with ARF. The M types 1, 5, 6, 14, 18, and 24 are considered to be ‘rheumatogenic’.10 So, the particular strain of GAS may be crucial in determining disease process. In addition, bacterial genetic patterns determine the site of infection. The strains with patterns A, B and C of emm genes which code for M protein are associated with pharyngitis, whereas strains with D and E patterns are associated with impetigo.11
Host Susceptibility There is equal incidence of ARF in males and females, but RHD is more common among females. This paradox could be explained by: Increased susceptibility to develop autoimmune diseases in females. Social factors, such as involvement in child-raising, increase the likelihood of streptococcal infection. Decreased access to medical care due to sociocultural issues. The genetic component for determining susceptibility is supported by the following: Only 0.3–3% of people with GAS pharyngitis develops ARF.12 High concordance among twins (risk 44% in monozygotic and 12% in dizygotic twins).13 It is likely that the susceptibility to RHD is polygenic following a nonmendelian pattern of inheritance with variable and incomplete penetrance. 14 Several major histocompatibility complex (MHC)-related, and nonMHC-related candidate genes and loci are identified to be associated with RHD, the most consistent of which is the MHC class II allele, human leukocyte antigen (HLA) DR-7. Other MHC class II alleles, such as HLA DR-2, DR-4, DR-1, DRw6, and DRw53 were shown to be associated with ARF in people from different countries.15 The presence of a non-MHC-related marker in B cell known as ‘D8/17+’ might identify a population at risk of ARF.16 Polymorphisms
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Environmental and Social Factors Environmental risk factors, such as household crowding and poor living conditions, can facilitate spread of GAS and increase the risk of ARF. In fact, one of the most important factors contributing to the decline of ARF incidence in developed countries is reduced overcrowding.19 ARF and RHD relate to poverty and are described as classic diseases of ‘social injustice’.20 ARF and RHD became rare in wealthy nations. At present, these are common in low- and middleincome nations and in some indigenous populations in wealthy nations where GAS may not be treated. Whenever there is social disruption and war, resurgence of RHD occurs through displacement, overcrowding and poor living conditions.21 Low socioeconomic status and limited access to health care lead to increased incidences of ARF and RHD in rural areas and urban slums. There is insufficient evidence whether malnutrition is directly associated with ARF and RHD.
IMMUNOLOGICAL MECHANISMS IN ACUTE RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE RHD is considered as an autoimmune disease with a component of active inflammation both acutely and chronically. Inflammatory markers, such as C-reactive protein (CRP), fibrinogen, interleukin 6 (IL-6), IL-8, and tumor necrosis factor alpha (TNF-α), are found to be expressed.22 High levels of high sensitivity-CRP (hs-CRP) levels are shown to correlate with more rapid progression of mitral stenosis.23 Pharyngeal infection with GAS leads to activation of innate immune system leading to antigen presentation to B and T cells (Figure 1). CD4+ T cells are activated, and B cells produce specific immunoglobulin G (IgG) and IgM antibodies.24
Molecular Mimicry ‘Molecular mimicry’ is a process by which immune tolerance is breached through immune stimulation by foreign antigens, which then results in immune activity against structurally similar self-antigens. In fact, ARF/ RHD is regarded as the best example of molecular mimicry in human pathological autoimmunity. Antibodies to the GAS antigens, alpha helical coiled coil structures in streptococcal ‘M protein’ and group A carbohydrate
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antigen: N-acetyl-β-d-glucosamine (NABG) were shown to exhibit cross reactivity to antigenic epitopes in the host tissues, such as cardiac myosin, producing tissue injury in ARF.25 Particularly, M protein shares structural homology with cardiac myosin, tropomyosin, actin, keratin, laminin, and vimentin.26 Both humoral and cell-mediated crossreactive immune responses play contributory role in pathogenesis. The strongest evidence for the role of molecular mimicry comes from ‘Lewis rat model’ where passive transfer of GAS-specific T cell lines to naïve rats resulted in valvulitis.27 Immunization with GAS antigens in Lewis rat models led to formation of autoantibodies and valvulitis28 or behavior similar to those in Sydenham’s chorea.29 Also, cross-reactive antibodies, which could recognize several types of epitopes, were defined in human studies of molecular mimicry between the Streptococcus and heart.25,30-32
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8 Pathogenesis of Rheumatic Fever and Rheumatic Heart Disease: What have we Learned?
involving several genes that code for proteins involved both in the innate and adaptive immune pathways confer susceptibility to ARF/RHD. Several proteins, such as toll-like receptor 2, ficolin 2, mannose-binding lectin 2, HLA class II alleles, interleukin-1 receptor antagonist, tumor necrosis factor α, and transforming growth factor β-1, were identified to determine susceptibility in recent genome-wide association studies.17,18
Humoral Immune Response and Endothelial Injury: Primary Event in Rheumatic Heart Disease Antibody-mediated response initiates rheumatic carditis followed by cellular infiltration resulting in further damage. Antistreptococcal antibodies were shown to be cytotoxic to human valvular endothelium and basement membrane. 25 Direct anti-endothelial antibodies were demonstrated in 40% of RHD patients. 33 Activation of endothelium occurs by autoantibodies which target ‘laminin’ and other glycosylated proteins on the surface valvular endothelium that cross-react with group A carbohydrate.25 Endothelial overexpression of vascular cell adhesion molecule-1 (VCAM-1) occurs which facilitates infiltration of CD4+ and CD8+ lymphocytes into the subendothelium.34 Once endothelium is damaged, Type IV collagen is exposed, and continuous damage of the valve occurs by non-cross-reactive anti-collagen antibodies (Figure 1).35 Cross-reactive autoantibodies target intracellular antigens but for disease pathogenesis, the antibodies must target the endothelial surface.
Cellular Immune Response in Rheumatic Heart Disease The characteristic histological finding in myocardium and endocardium of a rheumatic heart is the granulomatous ‘Aschoff body’ made up of T-cells, B-cells, macrophages, large mononuclear cells and neutrophils (Figure 1). Rheumatic mitral valve predominantly contains CD4+ T-cells, macrophages, and IL-17 and IL-23 producing cells. 36 Further, the presence of cross-reactive and autoreactive T-cells against GAS M-protein and cardiac proteins such as myosin, human light meromyosin, tropomyosin, and the valvular protein laminin strongly support cellular pathogenicity in ongoing RHD.
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Valvular Heart Disease—Rheumatic Heart Disease
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Figure 1: Pathogenesis of rheumatic fever. 1. GAS pharyngitis leads to antigenic presentation of pathogenic peptides to T-cells. 2. In immunologically susceptible individuals, the innate and adaptive (both humoral and cellular) immune responses gets activated leading to the development of cross-reactive antibodies and cross-reactive T-cells which incites immune response in the joints, heart, skin, and brain leading to different manifestations of ARF. 3. In the heart, valve damage is initiated by ‘endothelial activation’ by cross-reactive antibodies which trigger increased expression of vascular cell adhesion molecule-1 (VCAM-1). This facilitates T-cell infiltration leading to cytokinemediated immune damage. Exposure of Type-IV collagen can lead to production of collagen-specific antibodies which can cause further damage. 4. In the brain, autoantibodies can target dopamine receptors and lysoganglioside leading to increased release of dopamine by the neurons thereby causing rheumatic chorea Abbreviations: ARF, acute rheumatic fever; GAS, group A Streptococcus; IL, interleukin; IFN, interferon; NABG, N-acetyl-β-d-glucosamine; PARF, peptide associated with rheumatic fever; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule-1
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Many researchers have suggested a ‘two-hit hypothesis’ operating in the damage to the valve. 34,37,38 The valve endothelium becomes activated by group A carbohydrate
antibody allowing M protein-specific T cells to enter the valve and produce disease. Valve inflammation leads to edema, cellular infiltration, neovascularization of
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Epitope Spreading An ‘epitope’ is the part of an antigen molecule to which an antibody attaches itself. Reactivity is induced to epitopes that are distinct from the original disease-inducing epitope, with the result that these epitopes now become the target of the immune response leading to recognition of several self-antigens after the initial response. In RHD, repeated GAS pharyngitis due to rheumatogenic strains containing cardiac myosin-like sequences in the M protein may be crucial in mimicry and breaching immunological tolerance, inducing epitope spreading and initiating disease in susceptible patients.39
Pathogenesis of Noncardiac Manifestations in Acute Rheumatic Fever Disease pathogenesis in Sydenham’s chorea is antibody mediated and molecular mimicry has been demonstrated between group A carbohydrate epitope, NABG and several antigens found in basal ganglia of the brain such as Dopamine receptors D1 and D2, 40 lysoganglioside,32 and tubulin. 41 Binding of cross-reactive antibodies to these receptors lead to activation of calcium/calmodulindependent protein kinase II (CAMK2) which in turn increases tyrosine hydroxylase and release of excess dopamine resulting in chorea and neuropsychiatric symptoms of ARF (Figure 1).40,42 Arthritis in ARF may be due to the deposition of immune complexes in synovium and collagen in joints leading to inflammatory cell recruitment. Erythema marginatum may be due to antibodies against group A carbohydrate which cross-react with ‘keratin’ and subcutaneous nodules may be a delayed hypersensitivity against GAS antigens (Figure 1).43
Collagen Autoimmunity Hypothesis: Emerging Concept The molecular mimicry hypothesis fails to deliver a single common mechanism explaining the multisystem nature of ARF. Also, how specific damage to cardiac valvular tissue occurs and why myocardium is spared is unexplained by this theory. Further, involvement of several crossreactive antibodies and multiple streptococcal antigens in the pathogenesis indicates a gross failure of a highly evolved human immune system which is unlikely. So, an alternative hypothesis44 without molecular mimicry has been proposed which gives some insights to some unanswered questions. It involves direct interaction of streptococcal M protein with CB3 region of type IV collagen in the subendothelial extracellular matrix (ECM)
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through an octapeptide motif in M protein called ‘PARF (peptide associated with rheumatic fever)’ inciting an anticollagen antibody response (Figure 1). There are multiple evidences supporting the collagen autoimmunity hypothesis. Several surface components of GAS strains, such as M type 3 and 18, were suggested to form a complex with human collagen type IV in subendothelial basement membranes through PARF which binds to CB3 region of type IV collagen with high affinity.45 Mice immunized with M proteins containing PARF develop non-cross-reactive anticollagen antibodies. Sera from Indian patients with ARF have elevated anticollagen antibodies.46 Previous description of collagen autoimmune diseases, such as Goodpasture syndrome and Alport syndrome, exists which acts through similar mechanisms. Antibodies against collagen, however, do not induce valvulitis in animal models. Therefore, molecular mimicry is still regarded as the probable mechanism leading to induction of autoimmunity and initiation of valve damage.
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8 Pathogenesis of Rheumatic Fever and Rheumatic Heart Disease: What have we Learned?
the previously avascular valve, fibrinous vegetations especially in the rough zone of anterior mitral leaflet, and chordal elongation eventually leading to scarring of valves with repeated attacks of ARF.
CONTROVERSIES IN PATHOGENESIS OF ACUTE RHEUMATIC FEVER/RHEUMATIC HEART DISEASE In spite of multiple available evidences, several questions remain unanswered with regard to the pathogenesis of ARF/RHD.
Why Only the Valves Get Scarred? One of the unsolved mysteries of ARF/RHD is why the disease has a propensity to scar only the cardiac valves with all other involved tissues healing without residual damage. The possible explanations are: Endothelial heterogeneity: The endothelium lining the cardiac valves differs considerably in their behavior compared to endothelium in other parts of the circulatory system. In fact, even within a valve, cells at different parts show heterogeneity.47 Healing ability: The endothelium in other affected areas (joints, basal ganglia and skin) exhibits an immense capacity to heal quickly. But ‘the unique anatomy’ of the valve—an avascular structure with a small core of connective tissue covered by endothelium on both sides without any muscle tissue—explains the residual damage which occurs selectively in a rheumatic valve. ‘A vicious inflammatory cycle’ ensues due to the abundant expression of adhesion molecules, such as VCAM-1 and P-selectin, on the surface of a rheumatic valve and involvement of connective tissue leading to neovascularization and healing with progressive scarring.48 Inflammation in multiple systems, such as joints, skin, and brain including the valves, eventually heals completely in ARF, but the valves become permanently dysfunctional
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due to scarring. Even though ARF is characterized by involvement of all three layers of the heart, valvular lesions most likely lead to chronic disease and heart failure.
Why Left-sided Heart Valves are more Commonly involved in Rheumatic Heart Disease? Histopathology of heart valves in patients dying of ARF indicates that microscopic involvement of tricuspid and pulmonary valves occurs in 100% cases.49 But, clinically mitral valve involvement is the most common followed by aortic valve. Tricuspid valve involvement is less frequent and pulmonary valve involvement is rare. The probable explanation to this is that equivalent damage occurs in all the valves with improved healing in the lower pressure system of the right compared with the left.
mitral regurgitation (MR) or mixed mitral valve disease, is not understood clearly. It is proposed that all patients start with MR of variable severity depending upon the severity of carditis. Those with severe MR most likely remain with this lesion or may develop associated MS due to commissural fusion, leaflet thickening, and subvalvular disease. Whereas development of pure MS may be due to recurrent carditis of milder degree, a slower evolution of the disease or greater predisposition for commissural fusion.53
RECENT CONFLICTING EVIDENCES IN RHEUMATIC HEART DISEASE PATHOGENESIS
Does Myocardial Damage Occur in Acute Rheumatic Fever? Multiple clinical, echocardiographic and pathological studies have found that myocardial damage does not occur in ARF. Endomyocardial biopsy in ARF hardly shows any myocardial necrosis thereby not satisfying the ‘Dallas criteria’ for the definition of myocarditis. Instead, Aschoff nodules were found in up to 40% of cases.50 Even in patients with cardiac failure, myocardial damage does not occur. Instead, the pathology suggests an ‘interstitial carditis’ picture.51 Markers of myocardial damage, such as creatinine kinase and troponins, does not seem to elevate significantly in cases of ARF even in patients with dilated heart or cardiac failure.46 Cardiac failure resolves completely after surgical mitral valve replacement suggesting that it was due to acute volume overload secondary to MR and not due to myocarditis.52 Even though rheumatic carditis was classically described as ‘pancarditis’ involving all three layers of the heart—the endocardium, the myocardium and the pericardium, the term ‘myocarditis’ does not appear to be an apt description.
KNOWING THE PATHOGENESIS OF RHD: HOW DOES IT HELP IN TACKLING THE DISEASE?
EVOLUTION INTO CHRONIC RHEUMATIC HEART DISEASE Most of the valvular lesions reduce in severity as the acute illness resolves, but it can be perpetuated by repeated attacks of ARF and by hemodynamic factors leading to chronic RHD. In addition to this, the magnitude of host immune response and the severity of the first episode of carditis also determine whether the valve remains permanently damaged. Why some patients develop predominant mitral stenosis (MS) and some develop pure
New genetic and epidemiological data support skin infection as the trigger for ARF. 54,55 In Australian aboriginal communities, where incidences of ARF and RHD are amongst the highest in the world, GAS throat colonization and symptomatic GAS pharyngitis are rare.56 Instead, pyoderma is the most common manifestation of GAS. Further, group C and G streptococci were more commonly isolated from the pharynx and they seem to exchange key virulence determinants with GAS. These evidences suggest that GAS pyoderma or non-GAS infections may be involved in the pathogenesis of ARF and the epidemiology of ARF appears to vary from region to region.57 Though there is enough evidence that demonstrate cross-reactive antibodies and T cells involved in pathogenesis, it does not confirm that ‘molecular mimicry’ is the ‘triggering event’ in RHD. Humoral and cellular autoreactivity in RHD could just be an ‘epiphenomenon’.57 Evidence of active viral coinfections, such as coxsackie B, was found in ARF and has been suggested as an immunological trigger for RHD.
The World Heart Federation (WHF) aims to decrease RHD deaths in patients below 25 years by 25% by 2025. An improved understanding of the disease might help in directing the resources effectively. Effective methods for primary prevention or specific medical therapy can be made available. Identifying various characteristics of ‘rheumatogenic’ versus ‘nonrheumatogenic’ GAS strains by bacterial genome-wide association studies facilitates the production of an effective vaccine to induce a protective mucosal or systemic immune response. Knowledge about molecular pathogenesis opens new possibilities for immunotherapy such as T-cell vaccination. Identification of predisposing or protective genetic variations for RHD by large genome-wide human
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studies will help in guiding prospective pathogenesis studies. Treatment can be targeted to prevent a coinfection.
The ARF and RHD are established as a disease of ‘microbialinduced autoimmunity’. Though the existing hypothesis of ‘molecular mimicry’ is established to play the key role in pathogenesis, the exact trigger for the disease is unknown and needs to be clarified by additional research. Large genome-wide association studies, prospective studies of bacteriological surveillance in high-risk group, and studies involving molecular typing methods and DNA microarray are needed to unravel the immunopathogenesis of RHD.
REFERENCES 1. Carapetis JR, Steer AC, Mulholland EK, et al. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5(11):685–94. 2. Denny FW, Wannamaker LW, Brink WR, et al. Prevention of rheumatic fever; treatment of the preceding streptococcic infection. J Am Med Assoc. 1950;143(2):151–3. 3. Stollerman GH. Rheumatic and heritable connective tissue diseases of the cardiovascular system. In: Braunwald E, editor. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders. 1988. p. 1706-34. 4. Wannamaker LW. The chain that links the heart to the throat. Circulation. 1973;48(1):9–18. 5. Jones TD. The diagnosis of rheumatic fever. JAMA. 1944;126:481–4. 6. Kaplan EL, Bisno AL. Antecedent streptococcal infection in acute rheumatic fever. Clin Infect Dis. 2006;43(6):690–2. 7. Shulman ST, Gerber MA, Tanz RR, et al. Streptococcal pharyngitis: the case for penicillin therapy. Pediatr Infect Dis J. 1994;13(1):1–7. 8. Stollerman GH, Lewis AJ, Schultz I, et al. Relationship of immune response to group A streptococci to the course of acute, chronic and recurrent rheumatic fever. Am J Med. 1956;20(2):163–9. 9. Bessen D, Jones KF, Fischetti VA. Evidence for two distinct classes of streptococcal M protein and their relationship to rheumatic fever. J Exp Med. 1989;169(1):269–83. 10. Fischetti VA, Vashishta A, Pancholi V. Streptococcal M Protein: Structure, function and immunology. In: Narula J, Virmani R, Reddy KS, Tandon R, editors. Rheumatic fever. Washington DC: Amer Reg Path AFIP. 1999. pp. 113–34. 11. Bessen DE, Sotir CM, Readdy TL, et al. Genetic correlates of throat and skin isolates of group A streptococci. J Infect Dis. 1996;173(4):896–900. 12. Siegel AC, Johnson EF, Stollerman GH. Controlled studies of streptococcal pharyngitis in a pediatric population: Factors related to the attack rate of rheumatic fever. New Engl J Med. 1961;265:559-65. 13. Engel ME, Stander R, Vogel J, et al. Genetic susceptibility to acute rheumatic fever: a systematic review and metaanalysis of twin studies. PLoS One. 2011;6(9):e25326.
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CONCLUSION
14. Bryant PA, Robins-Browne R, Carapetis JR, et al . Some of the people, some of the time: susceptibility to acute rheumatic fever. Circulation. 2009;119(5):742−53. 15. Ayoub EM, Barrett DJ, Maclaren NK, et a l. Association of class II human histocompatibility leukocyte antigens with rheumatic fever. J Clin Invest. 1986;77(6):2019–26. 16. Khanna AK, Buskirk DR, Williams RC, et al. Presence of a non-HLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody. J Clin Invest. 1989;83(5):1710–6. 17. Gray LA, D’Antoine HA, Tong SYC, et al. Genome-wide analysis of genetic risk factors for rheumatic heart disease in Aboriginal Australians provides support for pathogenic molecular mimicry. J Infect Dis. 2017;216(11):1460–70. 18. Parks T, Mirabel MM, Kado J, et al. Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania. Nat Commun. 2017;8:14946. 19. Quinn RW. Epidemiology of group A streptococcal infections—their changing frequency and severity. Yale J Biol Med. 1982;55(3-4):265–70. 20. Brown A, McDonald MI, Calma T. Rheumatic fever and social justice. Med J Aust. 2007;186(11):557-8. 21. Omurzakova NA, Yamano Y, Saatova GM, et al. High incidence of rheumatic fever and rheumatic heart disease in the republics of Central Asia. Int J Rheum Dis. 2009;12(2):79-83. 22. Guilherme L, Cury P, Demarchi LM, et al. Rheumatic heart disease: pro inflammatory cytokines play a role in the progression and maintenance of valvular lesions. Am J Pathol. 2004;165(5):1583–91. 23. Alyan O, Metin F, Kacmaz F, et al. High levels of high sensitivity C-reactive protein predict the progression of chronic rheumatic mitral stenosis. J Thromb Thrombolysis. 2009;28(1):63–9. 24. Cunningham MW. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev. 2000;13(3):470–511. 25. Galvin JE, Hemric ME, Ward K, et al. Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin. J Clin Invest. 2000;106(2):217–24. 26. Guilherme L, Dulphy N, Douay C, et al. Molecular evidence for antigen-driven immune responses in cardiac lesions of rheumatic heart disease patients. Int Immunol. 2000;12(7):1063–74. 27. Kirvan CA, Galvin JE, Hilt S, et al. Identification of streptococcal M-protein cardiopathogenic epitopes in experimental autoimmune valvulitis. J Cardiovasc Transl Res. 2014;7(2):172–81. 28. Quinn A, Kosanke S, Fischetti VA, et al. Induction of autoimmune valvular heart disease by recombinant streptococcal M protein. Infect Immun. 2001;69(6):4072–8. 29. Brimberg L, Benhar I, Mascaro-Blanco A, et al. Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders. Neuropsychopharmacology. 2012;37(9):2076–87. 30. Cunningham MW. Autoimmunity and molecular mimicry in the pathogenesis of post-streptococcal heart disease. Front Biosci. 2003;8:s533–43.
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31. Cunningham MW. Rheumatic fever revisited. Nat Rev Cardiol. 2014;11(2):123. 32. Kirvan CA, Swedo SE, Heuser JS, et al. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med. 2003;9(7):914-20. 33. Scalzi V, Hadi HA, Alessandri C, et al. Antiendothelial cell antibodies in rheumatic heart disease. Clin Exp Immunol. 2010;161(3):570–5. 34. Roberts S, Kosanke S, Terrence Dunn S, et al. Pathogenic mechanisms in rheumatic carditis: focus on valevnudloatrh elium. J Infect Dis. 2001;183:507–11. 35. Martins TB, Hoffman JL, Augustine NH, et al. Comprehensive analysis of antibody responses to streptococcal and tissue antigens in patients with acute rheumatic fever. Int Immunol. 2008;20(3):445–52. 36. Kemeny E, Grieve T, Marcus R, et al. Identification of mononuclear cells and T cell subsets in rheumatic valvulitis. Clin Immunol Immunopathol. 1989;52(2):225– 37. 37. Ellis NMJ, Li Y, Hildebrand W, et al. T cell mimicry and epitope specificity of cross-reactive T cell clones from rheumatic heart disease. J Immunol. 2005;175(8):5448–56. 38. Faé KC, da Silva DD, Oshiro SE, et al. Mimicry in recognition of cardiac myosin peptides by heartintralesional T cell clones from rheumatic heart disease. J Immunol. 2006;176(9):5662–70. 39. Guilherme L, Faé K, Oshiro SE, et al. Molecular pathogenesis of rheumatic fever and rheumatic heart disease. Expert Rev Mol Immunol. 2005;7(28):1–15. 40. Cox CJ, Sharma M, Leckman JF, et al. Brain human monoclonal autoantibody f rom Sydenham chorea targ ets dopaminergi c neurons in transgenic mice and signals dopamine D2 receptor: implications in human disease. J Immunol. 2013;191(11):5524–41. 41. Kirvan CA, Cox CJ, Swedo SE, et al. Tubulin is a neuronal target of autoantibodies in Sydenham’s chorea. J Immunol. 2007;178(11):7412–21. 42. Kirvan CA, Swedo SE, Kurahara D, et al. Streptococcal mimicry and antibody-mediated cell signaling in the pathogenesis of Sydenham’s chorea. Autoimmunity. 2006;39(1):21–9. 43. Carapetis JR, Beaton A, Cunningham MW,et al. Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers. 2016;2:15084.
44. Tandon R, Sharma M, Chandrashekhar Y, et al. Revisiting the pathogenesis of rheumatic fever and carditis. Nat Rev Cardiol. 2013;10(3):171–7. 45. Dinkla K, Talay SR, Mörgelin M, et al. Crucial role of the CB3-region of collagen IV in PARF-induced acute rheumatic fever. PLoS One. 2009;4(3):e4666. 46. Gupta M, Lent RW, Kaplan EL, et al. Serum cardiac troponinI in acute rheumatic fever. Am J Cardiol. 2002;89(6):779–82. 47. Butcher JT, Simmons CA, Warnock JN. Mechanobiology of the aortic heart valve. J Heart Valve Dis. 2008;17(1):62–73. 48. Gulizia JM, McManus BM. Immunopathologic studies of rheumatic fever. In: Narula J, Virmani R, Reddy KS, Tandon R, (ed). Rheumatic fever. Washington DC: Amer Reg Path AFIP. 1999. pp. 235–44. 49. Gross L, Friedberg CK. Lesions of the cardiac valves in rheumatic fever. Am J Pathol. 1936;12(4):469–94. 50. Narula J, Chopra P, Talwar KK, et al. Does endomyocardial biopsy aid in the diagnosis of active rheumatic carditis? Circulation. 1993;88(5 Pt 1):2198-205. 51. Narula J, Narula N, Southern JF, et al. Endomyocardial biopsy in rheumatic carditis. In: Narula J, Virmani R, Reddy KS, Tandon R, ed. Rheumatic fever. Washington DC: Amer Reg Path AFIP. 1999. pp. 319–28. 52. Kinsley RH, Girdwood RW, Milner S. Surgical treatment during the acute phase of rheumatic carditis. In: Nyhus LM, editor. Surgery Annual Vol 13. New York: AppletonCentury-Crofts. 1981;13:299–323. 53. Essop MR, Peters F. Contemporary issues in rheumatic fever and chronic rheumatic heart disease. Circulation. 2014;130(24):2181–8. 54. Williamson DA, Smeesters PR, Steer AC, et al. M-protein analysis of Streptococcus pyogenes isolates associated with acute rheumatic fever in New Zealand. J Clin Microbiol. 2015;53(11):3618−20. 55. Parks T, Smeesters PR, Steer AC. Streptococcal skin infection and rheumatic heart disease. Curr Opin Infect Dis. 2012;25(2):145−53. 56. McDonald MI, Towers RJ, Andrews RM,et al. Low rates of streptococcal pharyngitis and high rates of pyoderma in Australian aboriginal communities where acute rheumatic fever is hyperendemic. Clin Infect Dis. 2006;43(6):683–9. 57. McDonald M, Currie BJ, Carapetis JR. Acute rheumatic fever: a chink in the chain that links the heart to the throat? Lancet Infect Dis. 2004;4(4):240–5.
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CHAPTER 9
Decline of Rheumatic Heart Disease: Is it Real? Prakash C Negi, Sanjeev Asotra, Sachin Sondhi
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INTRODUCTION
METHODS OF DETECTION
Rheumatic fever (RF)/rheumatic heart disease (RHD) is the result of autoimmune response triggered by group A beta-hemolytic streptococcal pharyngitis leading to immune-inflammatory injury to cardiac valves. The inflammatory injury of pericardium and myocardium is transient and self-limiting without leaving any squeal. The valvular injury is the main cause of acute and longterm morbidity and mortality in patients with acute RF and RHD, respectively.1,2 The risk of RF/RHD is primarily determined by the host, agent, and environmental factors.3 The RF/RHD is considered to be a physical manifestation of poverty. The distribution of the burden of RF/RHD mirrors the distribution of human development index in given geographical region, state, nation, and globally. The socioeconomic state, access, and quality of healthcare services are important determinants of the burden of RF/RHD. The incidence of RF/RHD has practically disappeared in developing countries. 4 However, RF/ RHD continues to be a major cause of disease burden among children, adolescents, and young adults in lowincome countries and even in high-income countries with socioeconomic inequalities. The burden of RF/RHD is likely to be variable between countries, within the country, within states depending upon the socioeconomic status, and state of health systems.5-8 The major determinant of the persistent burden of RF/RHD in developing countries are due to poor standards of living conditions, overcrowding, lack of strong population-based surveillance system for pharyngitis, RF and RHD for effective implementation of primary and secondary preventive interventions. 9 The Indian Council of Medical Research (ICMR) initiated community control and prevention of RF/RHD through hospital-based passive surveillance and implementation of secondary prophylaxis under Jai Vigyan mission mode project from 2000 to 2010.10 There is no structured program at a national level for prevention and control of RF/RHD. However, changing socioeconomic state, improved living conditions, and improving connectivity and access to health care centers after adopting a policy of economic liberalization and globalization since 2000 is expected to have translated into a decline in the burden of RF/RHD in India.
The detection of RF/RHD in the population is challenging. The RF/RHD are detected based on symptoms, audible murmurs, and echocardiography evidence of structural and functional abnormalities of the affected valves. The ability to detect murmurs, differentiating functional from pathological murmurs depends upon clinical skills of the physician, settings of auscultation, etc. Thus, auscultation-based methods of screening RF/RHD has its limited sensitivity and specificity. The morphological and Doppler-based detection of RHD in echocardiography study has high sensitivity and specificity in detection being more objective and subject to validation. The echocardiography detects RHD in patients without being clinically evident called subclinical RHD. The prevalence of subclinical RHD is about 7 to 10 times higher than clinically evident RHD. However, the clinical significance of subclinical RHD needs to be validated in future longterm follow-up studies. The severity and nature of valvular dysfunction in RHD is variable from patient to patient. The hemodynamically insignificant valvular dysfunctions may be asymptomatic, may not be evident on clinical examination thus escapes detection. Thus, the variable prevalence of RHD reported may be partly related to differences in the methodology adopted for screening.
DATA SOURCES FOR ESTIMATION OF BURDEN OF RF/RHD Hospital admission data, hospital- and population-based registry data, and population-based active surveillance studies are databases that could be used to estimate the burden and their trends in a population. The hospital admission and hospital-based registries data may provide a rough estimation of the burden of clinically symptomatic patients from the population that is served by the hospital. In hospital admission data, the relative proportion of RF/ RHD is subject to vary with changes in the incidence of other diseases and admission policy followed by a given hospital, thus affecting the reliable estimate of the trends of the burden of RF/RHD. Population-based registry data provide more reliable estimates of burden and
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their trends of symptomatic patients. The prospective active surveillance of the population is the only method to determine the burden of any given disease and their trends. In India, there are no hospital- and populationbased registries or systematically done periodic active surveillance studies on the country representative sample to estimate the burden and trends of RF/RHD. The data available are individual investigator-led survey studies done mostly in school children of urban and some rural areas. The registry studies and population-based survey studies reveal the prevalence of RHD peaks around 30–40 years or so. Thus, the prevalence reported in school age group may be an underestimation of disease burden.
EPIDEMIOLOGICAL TRENDS OF BURDEN OF RHD IN INDIA The burden of RF/RHD has been estimated and reported since 1960s from hospital-based data (Table 1), population-based [(Table 2) and school-based (Table 3) survey studies using different case definition, and screening methods. There are no survey studies estimating the burden of RF/RHD based on national and state representative samples using uniform screening method at different timeline to evaluate the trends of the burden of RF/RHD in India.
Hospital Admission Data Hospital admission data (Table 1) shows a decline in admission rates of RF/RHD overtime period. The RF/RHD accounted for 30–50% of total admissions till the early 80s and it declined to 5–26% in the late 1990s.11-19 Whether the declining trends in admission rate truly reflects the decreasing incidence is much to be debated. Inadequacy of hospital statistics, varied hospital admission policies, and a large number of corporate hospitals coming up can cause significant bias in hospital-based data. The emergence of an epidemic of CAD and lack of interest among cardiologists in RHD has further compounded the problem. The only useful forgone conclusion can be
derived from hospital statistics if the data is derived from the same hospital over a different time period. But data of this kind is scaring. A study from territory care center in Odisha showed no change in admission rate over a decade and still there was admission rate of 50% in 2013.19
Population-based Survey Studies Data from population-based surveys (Table 2) are likely to give us reliable estimates of the prevalence of RF/RHD. There is no data available about the prevalence of RF/RHD based on active surveillance studies in a representative sample of the country or the state. The available data are based on estimation done in cities or rural areas of certain regions of the states in different points of time using either clinical screening method alone or confirmed by echocardiography. The prevalence of RF/RHD reported from cities of Agra, Chandigarh and Delhi based on clinical examination alone in the late 1960s and the early 1970s ranged from 1.8 /1000 to 4.58/1000.20-24
School-based Surveys Survey studies with clinical screening method (period 60s to 90s ): The estimation of prevalence of RF/RHD among school children done in the period from 70s till 90s was based on clinical screening method alone (Table 3A). Thus, reported figures of prevalence have the limitation of sensitivity and specificity of the cases reported. The reported prevalence from different regions of the country in urban and rural school children varied from 1 to 11 per 1000.25-32 Survey studies with clinical screening confirmed by e c h o c a rd i o g ra p h y ( p e r i o d 1 9 9 0 s t o 2 0 0 0 ) : T h e epidemiological studies with clinical screening followed by confirmation of suspected cases with echocardiography using Doppler-based WHO criteria in urban and rural school children in different regions of the country from the early 1990s to the early 2000s reported prevalence ranging from 1.3/1000 to 6.4/1000 (Table 3B). The reported variation in the prevalence of RF/RHD may be an
Table 1: Hospital-based RHD studies done in India Author
Study area
Year
Percentage
Kutumbiah
Madras
1941
39.5%
Sanjeevi 12
Bombay
1946
46.8%
Bombay
1954
24.7%
Delhi
1958
39.1%
Shimla
1959
50.6%
11
Vakil
13
Padamavati14 15
Devichand 16
Mathur
Agra
1960
35.1%
Punjab
1963
27.6%
Banerjea
Calcutta
1965
44.6%
Routray19
Orissa
2003
45%
Malhotra17 18
54
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Table 2: Population-based RHD surveys in India (clinical screening) Author Roy
Number
Study area
Year of survey
Prevalence per 1000
5–30
4847
Ballabhgarh
1969
2.2
5–30
7953
Agra
1971
1.8
5–30
19768
Chandigarh
1972
1.87
5–15
31200
Rural area of Ambala, Haryana
1988–91
0.9
7–15
3963
Rural area of Kanpur
2000
4.58
Mathur21 Berry
22
Grover et al.
23
Lalchandani et al.24
9 Decline of Rheumatic Heart Disease: Is it Real?
Age group
20
Table 3: School surveys on prevalence of rheumatic heart disease Author
Period
Area
Population
Age group
Prevalence
(A) Clinical screening only: ICMR25
1972–75
Agra, Alleppy, Delhi, Hyderabad
133000
–
6–11
Koshi et al.26
1975–78
Vellore
3890
4–16
4.4
27
1982–90
Delhi
13509
5–15
2.9
28
1984–87
Delhi, Varanasi, Vellore
52793
–
1.0–5.7
Patel et al.29
1986
Anand
11346
8–18
2.03
ICMR
ICMR
30
Avasthi
Padamavati31 32
Kumar et al.
1987
Ludhiana
6005
6–16
1.3
1984–94
Delhi
40000
5–10
3.9
1992
Churu
10168
5–15
3.34
31200
5–15
2.1
(B) Clinical screening followed by echocardiographic confirmation: Grover et al.23
1988–9123 34
Ambala
Agarwal et al.
1991
Aligarh
3760
5–15
6.4
Gupta et al.35
199235
Jammu
10263
6–16
1.3
1992–93
Shimla
10805
5–16
2.98
1993
Agra
8449
5–15
1.42
1999–2000
Srinagar
4125
5–15
5.09
2001–02
Vellore
229829
6–18
0.68
2002–05
Kochi, Vellore, Chandigarh, Indore, Shimla, Dibrugarh, Waynard, Jodhpur, Jammu, Mumbai
100269
5–15
0.43–1.47
2003–06
Gorakhpur
118212
4–18
0.5
2006
Bikaner
3292
5–14
0.67
2007–08
Shimla
15145
5–15
0.59
2011
Prakasam AP
4213
5–16
0.7
2007–09
Bikaner
1059
6–15
51
2008–10
Ballabgarh
6270
5–15
20.4
Thakur et al.
36 37
Vashistha et al. Kaul et al.39 Jose et al.
38
ICMR10 Misra et al.40 Periwal et al. Negi et al.
41
42
Rama et al.33
(C) Echocardiographic screening: Bhaya et al.43 44
Saxena et al. Rama et al.
33
2011
Prakasam AP
4213
5–16
7.6
Thangjam et al.45
2011–13
Manipur
3015
5–15
4
Ana Karina et al.46
2011–13
Goa
2023
5–15
16
Nair et al.47
2013–14
Trivandrum
2006
5–15
5.83
indication of a varied burden of RF/RHD across different regions, urban and rural areas, and/or temporal trends apart from methodological related factors.23,33-38 Survey studies with clinical screening confirmed by echocardiography after 2000: The survey studies in school children done after 200010,33,39-42 using similar screening methods that were followed in the 90s to 2000 revealed
consistent decline in the burden to less than 1/1000 across the country compared to figures reported from survey studies before 2000 (Figure 3). The survey study done by our group in urban and rural school children of Shimla in the early 90s and mid-2000, using similar screening methods in the same geographical region, demonstrated about a five-fold decline in the prevalence of RF/RHD.42 55
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This decline was associated with improvement in the indicators of socioeconomic state and health care services.
Valvular Heart Disease—Rheumatic Heart Disease
Echo-based screening studies in school children after 2000: The auscultation-based screening method has low sensitivity and specificity. The patients with RF/RHD with the mild valvular damage that may be asymptomatic and without an apparent murmur on auscultation thus could be missed on clinical screening. The ability to detect subtle signs of valvular dysfunction also would depend upon clinical skills of the investigator. Thus, the auscultationbased detection of RHD has limited sensitivity for detection of children with minimal valvular dysfunction. The echo-based survey studies 33,43-47 using evidencebased echocardiography criteria among school children in different parts of the country and other developing countries have reported the prevalence of subclinical RHD many folds higher than clinically evident RHD (Table 3C). The clinical significance of subclinical RHD needs to be established in appropriately designed large future studies in terms of probability of their progression and the efficacy of secondary prophylaxis on the progression of valvular dysfunction.
Figure 1: Trends of change in GDP of India from financial year 91 to 2015 Abbreviation: GDP, gross domestic product Source: Handbook of Statistics on the Indian Economy, Reserve Bank of India
DECLINE OF RHEUMATIC HEART DISEASE: IS IT REAL? Systematic review of available data on epidemiological studies of RF/RHD conducted in different points of time using clinical screening followed by echocardiography confirmation as the methods of detection of RF/RHD, across the country by individual authors and ICMR lead multicentric survey studies suggest declining trends especially after 2000 onwards (Figures 1 to 3). The twopoint survey study done over a gap of about 15 years among school children of an urban and rural area of Shimla by our group using similar screening methods also demonstrated five-fold decline in the prevalence of RF/ RHD.42 The reasons for the declining trends could be the improvement in the socioeconomic state of our country (Figure 1), access and affordability of healthcare services, and change in health-seeking behavior of the community leading to timely treatment of acute pharyngitis could be some of the important factors responsible for declining incidence of RF/RHD. It is important to recognize that India is witnessing transitions in socioeconomic and health care sector and also there is a rapid urbanization. However, there are wide disparities in socioeconomic state and quality and access to healthcare services across the states, within state and urban and rural areas. Since RF/RHD is believed to be a physical manifestation of poverty, the burden of RF/RHD is likely to be variable across the state. Unfortunately, no temporal data is available from states with poor health indicators to get insights about the disease trends.
Figure 2: Trends of changes in prevalence of RF/RHD from early 1990s to late 2000 using clinical screening confirmed with echocardiography
Figure 3: Trends of change in prevalence of RF/RHD in ICMR-led multicentric survey studies across country over a period of 40 years
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ESTIMATED BURDEN OF DISEASE
Limitations of all available data on trends of the burden of RF/RHD in India: The prospective active surveillance data of country and/or state representative sample is lacking to evaluate the trends of prevalence and incidence of RF/RHD in our country. There is lack of studies from most of the underdeveloped states of India, where the prevalence of the disease is likely to be high. The available reports on the prevalence of RF/RHD also are limited by methodological strength and statistical rigors, variable methods of screening, nonuniform diagnostic criteria, -the variable competence of survey teams to detect cases, different referral criteria for echocardiographic screening, and varied echocardiographic criteria used. The participation rate of eligible population, urban-rural population, etc. is not reported in a number of studies. Thus, reported figures of a burden of RF/RHD trends need to be viewed in this context. Though results of studies over the time period are showing declining trends of RHD, they cannot be extrapolated to the whole of the country.
CHALLENGES AND OPPORTUNITIES FOR PREVENTION AND CONTROL OF RHEUMATIC FEVER/RHEUMATIC HEART DISEASE The RF/RHD continues to be an important cause of disease burden in India affecting the population in their prime and productive phase of the life. India is a young country having 65% of the population younger than 35 years of age. Since RF/RHD affects predominately affects the younger population, their impact on productivity of the country is pronounced. Thus, it is imperative that the country must invest in prevention and control of RF/RHD. The health professionals have an important advocacy role to play to influence policy makers for initiating policy interventions for prevention and control of RF/RHD. The RF/RHD is a preventable cause of disease burden. The most effective intervention for prevention of RF/RHD could be to create enabling environment through policy intervention to promote sanitation, hygiene, better living conditions, nutrition, and access to affordable and quality healthcare equitably49 and health system strengthening of
CHAPTER
9 Decline of Rheumatic Heart Disease: Is it Real?
From available data from RHD studies, the estimated average prevalence is 0.5/1000 children in the age group of 5-15 years. There are expected to be more than 3.6 million patients of RHD estimated from 2011 Census. 48 Almost 44,000 patients are added every year and expected mortality of 1.5-3.3% per year. These figures still may be the underestimation of disease as no data is available from large populous, underdeveloped states such as Bihar, Jharkhand, etc.
primary health care services for detection of children with streptococcal pharyngitis, opportunistic screening for RF/ RHD, and implementing evidence-based primary and secondary preventive interventions. Establishing strong population-based registry centers for surveillance for monitoring trends, management practices, and outcomes that are important to evaluate the impact of primary preventive intervention implemented at community and health system level are required. The communitylevel interventions through existing community health volunteers (ASHAs) would play an important role in primordial and primary prevention through community health literacy initiatives as shown by Cuban experience.50 There is a need for allocating more funds in the health sector in prevention and control programs rather than in curative healthcare services, if we aim to decrease the disease burden and promote public health in a costeffective manner in India. The RHD has been forgotten by Western developed countries and there is a clear-cut decline in new research in the West. We need to invest in new research to fulfill the gaps of understanding of the disease. Making RHD a notifiable disease like in New Zealand, Australia, and South Africa and starting a national program can fill the gaps of implementation in care of RF/RHD.51 Availability of penicillin is a burning issue in most of the states in India. Healthcare personnel involved in providing injections must be educated about skin testing, proper technique, and allergic reactions thus improving the secondary prophylaxis rates, which can lead to control of RHD by preventing reoccurrences.52 As we can nar row dow n and fill the gaps of understanding of disease with new research and carry out better implementation in health care delivery, we are heading in the right direction to control or even think of eradicating the disease.
CONCLUSION The RF/RHD is the disease of poverty. India having more than 1.3 billion population with wide social and economic disparities, RF/RHD will continue to be a major public health problem. Although data on incidence and prevalence on a nationally represented sample is lacking, there is an indication of declining trends, especially after 2000 mirroring with improving economic growth of the country. There is a need for establishing populationbased surveillance system in the country for monitoring trends, management practices, and outcomes to formulate informed guidelines for initiating contextual interventions for the prevention and control of RF/RHD. 57
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REFERENCES
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1. Taranta A, Markowitz M. Rheumatic Fever. 2nd edn. Boston: Kluwer Academic Publishers.1989. pp. 1-18. 2. Krishna K. Epidemiology of Streptococcal pharyngitis. Rheumatic fever and rheumatic heart disease. In: Narula J, Virmani R, Reddy KS, Tandon R, editors. Rheumatic Fever. Washington DC: American Registry of Pathology. Armed Forces Institute of Pathology. 1999. pp. 41-78. 3. WHO Study Group on Rheumatic Fever/Rheumatic Heart Disease & World Health Organization. Rheumatic fever and rheumatic heart disease : report of a WHO study group [meeting held in Geneva from 30 March to 4 April 1987]. Geneva: World Health Organization. 1998 (Technical Report Series No 764). 4. Gordis L. The virtual disappearance of rheumatic fever in United States: lessons in the rise and fall of disease. T Duckett Jones memorial lecture. Circulation.1985;72(6):1155-62. 5. Markowitz M, Kaplan EL. Reappearance of rheumatic fever. Adv Pediatr. 1989;36:39-65. 6. Kaplan EL , Hill HR. Return of rheumatic fever : consequences, implications, and needs. J Pediatr. 1987; 111(2):244-6. 7. Dodu SR, Bothing S. Rheumatic fever and rheumatic heart disease in developing countries. World Health Forum. 1989;10(2):203-12. 8. Seckeler MD, HokeTR. The worldwide epidemiology of rheumatic fever and rheumatic heart disease. Clin Epidemiol. 2011;3:67-84. 9. Carapetis JR. Rheumatic heart disease in developing countries. N Engl J Med. 2007; 357(5):439-41. 10. Jai Vigyan Mission mode project on community control of RHD. Non-communicable diseases. Indian Council Med Res Annu Rep. 2007–8;63–4. 11. Kutumbiah P. Rheumatism in childhood and adolescence. Part 1. Indian J Pediatr.1941;8:65-86. 12. Sanjeevi KS. Heart disease in south India. Proc Association Physicians India. 1946;17-18. 13. Vakil RJ. Heart disease in India. Am Heart J. 1954;48(3):43948. 14. Padmavati S. A five year survey of heart disease in Delhi (1951-1955). Indian Heart J. 1958;10:33-40. 15. Devichand. Etiology and incidence of heart disease in India, with special reference to acquired valvular lesions. Indian Heart J.1959;11:117-9. 16. Mathur KS. Problem of heart disease in India. Am J Cardiol. 1960;5:60-5. 17. Malhotra RP, Gupta SP. Rheumatic heart disease in Punjab with special emphasis on clinical patterns that differ from those reported already. Indian Heart J. 1963;15:107-13. 18. Banerjea JC. Incidence of rheumatic heart disease in India. Indian Heart J. 1965;17(3):201-3. 19. Mishra TK, Routray SN, Behera M, Pattnaik UK, Satpathy C. Has the prevalence of rheumatic fever/rheumatic heart disease really changed? A hospital-based study. Indian Heart J. 2003;55(2):152-7. 20. Roy SB. Prevalence of rheumatic fever and rheumatic heart disease in Ballabgarh. Annual Report, Indian Council of Medical Research, 1968-1969;52.
21. Mathur KS, Banerji SC, Nigam DK,Prasad R. Rheumatic heart disease and rheumatic fever -- prevalence in a village community of Bichpuri Block Agra. J Assoc Physicians India. 1971;19(2):151-6. 22. Berry JN. Prevalence survey of chronic rheumatic heart disease and rheumatic fever in northern India. Br Heart J 1972;34(2):134-49. 23. Grover A, Dhawan A, Iyenger SD, Anand IS, Wahi PL, Ganguly NK. Epidemiology of rheumatic fever and rheumatic heart disease in rural community in northern India. Bull World Health Organ. 1993;71(1):59-66. 24. Lalchandani A, Kumar HRP, Alam SM. Prevalence of rheumatic heart disease in rural and urban school children of district Kanpur (Abstract). Indian Heart J. 2000;52:672. 25. Prevalence of rheumatic fever and rheumatic heart disease in school children: multicenter study. Annual Report. New Delhi: Indian Council of Medical Research. 1977. p. 108. 26. Koshi G, Benjamin V, Cherian G. Rheumatic fever and rheumatic heart disease in rural south indian children. Bull World Health Organ. 1981;59:599-603. 27. Pilot study on the feasibility of utilizing the existing school health services in Delhi for the control of RF/RHD. Annual Report. New Delhi: Indian Council of Medical Research, 1990. 28. Community control of rheumatic fever and rheumatic heart disease. Report of ICMR task force study. New Delhi: Indian Council of Medical Research, 1994. 29. Patel DC, Patel NI, Patel JD, et al. Rheumatic fever and rheumatic heart disease in school children of Anand. J Assoc Physicians India. 1986;34(12):837-9. 30. Avasthi G, Singh D, Singh C, Aggarwal SP, Bidwai PS, Avasthi R. Prevalence survey of rheumatic fever and rheumatic heart disease in urban and rural school in Ludhiana. Indian Heart J. 1987;39(1):26-8. 31. Padmavati S. Present status of rheumatic fever and rheumatic heart disease in India. Indian Heart J. 1995; 47(4):395-8. 32. Kumar P, Garhwal S, Chaudhary V. Rheumatic heart disease: a school survey in a rural area of Rajasthan. Indian Heart J. 1992;44(4):245-6. 33. Rama Kumari N, Bhaskara Raju I, Patnaik AN, et al. Prevalence of rheumatic and congenital heart disease in school children of Andhra Pradesh, South India. J Cardiovasc Dis Res.2013;4(1):11-4. 34. Agarwal AK, Yunus M, Ahmed J, et al. Rheumatic heart disease in India. J R Soc Health.1995;115(5):303-4, 309. 35. Gupta I, Gupta ML, Parihar A, et al. Epidemiology of rheumatic and congenital heart diseases in school children. J Indian Med Assoc. 1992;90(3):57-9. 36. Thakur JS, Negi PC, Ahluwalia SK, et al. Epidemiological survey of rheumatic heart disease among school children in the Shimla Hills of northern India: prevalence and risk factors. J Epidemiol Community Health. 1996;50(1):62-7. 37. Vashistha VM, Kalra A, Kalra K, et al. Prevalence of rheumatic heart disease in school children. Indian Pediatr. 1993;30(1):53-6. 38. Kaul RR, Masoodi MA, Wani KA,et al. Prevalence of rheumatic heart disease in school children (5-15 years) in a rural block of Srinagar. JK Practitioner. 2005;12:160-2.
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39. Jose VJ, Gomathi M. Declining prevalence of rheumatic heart disease in rural schoolchildren in India: 2001-2002. Indian Heart J. 2003;55(2):158-60. 40. Misra M, Mittal M, Singh R, et al. Prevalence of rheumatic heart disease in school-going children of Eastern Uttar Pradesh. Indian Heart J. 2007;59(1):42-3. 41. Periwal KL, Gupta BK, Panwar RB, et al. Prevalence of rheumatic heart disease in children of Bikaner: an echocardiographic study. J Assoc Physicians India. 2006;54:279-82. 42. Negi PC, Kanwar A, Chauhan R,et al. Epidemiological trends in RF/RHD in school children of Shimla in north India. Indian J Med Res. 2013;137(6):1121-7. 43. Bhaya M, Panwar S, Beniwal R, et al. High prevalence of rheumatic heart disease detected by echocardiography in school children. Echocardiogr. 2010;27(4):448-53. 44. Saxena A, Ramakrishnan S, Roy A, et al. Prevalence and outcome of subclinical rheumatic heart disease in India: the RHEUMATIC (Rheumatic Heart Echo Utilisation and Monitoring Actuarial Trends in Indian Children) study. Heart. 2011;97(24):2018-22. 45. Thangjam RS, Rothangpuii Irom A , Rameschandra TH, et al. Prevalence of subclinical RHD detected by echocardiography-Doppler study using WHF 2012 criteria in school going children aged 5-15 years of Manipur,
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Clinical Assessment of Severity CHAPTER 10 of Valvular Heart Disease Ajith Ananthakrishna Pillai, Devendra Kanshilal Sharma, Balachander Jayaraman
INTRODUCTION C linical diagnosis of hear t dis eas e by physical examination and cardiac auscultation still enthrals an astute clinical cardiologist despite the widespread usage of echocardiography. Physical examination still wields the charm in engaging the physician to diagnose and differentiate various forms of valve disease. Moreover, cardiac auscultation in itself is so much exciting and thrilling in assessing the severity of individual lesions in multivalve case scenarios. In this manuscript, we attempt to elucidate the clinical assessment of valve disease. The write up has been made keeping in mind the learning objectives of medicine postgraduates and cardiology trainees.
MITRAL STENOSIS Etiology of mitral stenosis (MS) is nearly always rheumatic. Less frequent causes include congenital lesions, mitral annular calcification, connective tissue disorders and storage disorders. Mitral annular calcification, a disease of the elderly usually leads to mitral regurgitation and often co-exists with calcific aortic valve disease and degenerative involvement of the conduction system. Congenital mitral stenosis and LV inflow obstruction—Parachute mitral valve, anomalous mitral arcade, supravalvular mitral ring and cortriatriatum usually present in childhood. Approximately 50% of patients with rheumatic MS have a history of acute rheumatic fever in childhood. In the remaining half, it is believed to be secondary to subclinical carditis. Carditis is very frequent when rheumatic fever occurs in children below the age of 5 years and is unusual with first attack of rheumatic fever occurring later in adult life. It is interesting to note that though pancarditis is known to occur in acute rheumatic fever, clinically significant myocarditis is unusual. Endocarditis mainly manifests as MR in isolation or with AR. Isolated aortic valve involvement without MR is uncommon and raises doubt about the etiology. MR is contributed by valvulitis, chorditis and annulitis. The natural history of MR is variable. 70% of mild MR tend to disappear on follow up whereas only around one third of severe MR who presented with heart failure are likely to have a normal heart at the
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end of 10 years. Most if not all mitral stenosis cases have significant MR (clinical or subclinical) to begin with and over the years, the severity of MR comes down and they develop progressive commissural fusion culminating in significant obstructive lesion. There is striking difference in the natural history and rate of progression of MS in the tropical countries compared to the western world. In the developed countries, it takes more than 5 years for MS to develop and it takes another 5 to 10 years to progress to a symptomatic status. In tropical countries, the entire latent period between acute rheumatic fever and severe MS can be shorter than 5 years. Though less frequent in India now, “Juvenile MS” is a major problem in many African countries. The pathological hallmark of rheumatic MS is commissural fusion leading to narrowing of the orifice. Chordal and cuspal fusion can also contribute to the narrowing but seldom exist without commissural fusion. Normal mitral valve area is 4 to 6 sq.cms in an adult. Significant diastolic transmitral gradient and an audible murmur develop when the orifice is reduced to less than 2.5 sq. cms. MV area less than 1 sq. cm per square meter surface area is considered very severe MS and will ordinarily require intervention. MS leads to increase in LA pressure and pulmonary venous hypertension. Normal LA pressure is 8 to 12 mm Hg. In severe cases of MS, LA pressures will be more than 25 mm Hg. This leads to passive pulmonary arterial hypertension (PAH). PAH in MS is also contributed by reactive pulmonary hypertension (precapillary, ‘second stenosis’) and obliterative PAH (in long standing cases).
History Gradually progressive dyspnea on exertion is the most common symptom in MS. As the commissural fusion and narrowing of the MV orifice gradually develop over a span of several years, the symptoms are also usually slowly progressive. This reflects pulmonary venous hypertension and the increased effort required for the inflation of the alveoli due to capillary and venous engorgement. Exertion leads to enhanced venous return, increase in the cardiac output and reduction of the diastolic filling period. When pulmonary capillary pressure exceeds 25
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Physical Findings and Assessment of Severity of MS
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10
General Appearance
Clinical Assessment of Severity of Valvular Heart Disease
mm Hg, transudation of fluid occur into the interstitium (interstitial pulmonary edema) and later into the alveoli (alveolar pulmonary edema). Paroxysmal nocturnal dyspnea (PND) is a very important symptom and usually is indicative of severe disease. Though not included in the NYHA classification, most of the patients with PND will have marked restriction of ordinary activity and come under NYHA class III. Orthopnea indicates severe and advanced disease. Hemoptysis in MS can be due to multiple factors—rupture of bronchopulmonary veins due to pulmonary venous hypertension (pulmonary apoplexy), pulmonary edema (including the pink frothy sputum classically described with PND), lower respiratory tract infection and pulmonary infarction (in long-standing cases usually with AF). Atrial fibrillation is a common arrhythmia in patients with severe MS. It is related not only to the severity of MS but also to the age of the individual and the initial age of rheumatic fever and the number of recurrences and the severity and extent of carditis during the previous episodes. AF is uncommon in juvenile MS even when it is severe but is common in elderly with milder degree of MS. Majority of MS patients above the age of 50 years are in AF (almost 80%) and this predisposes to thromboembolic episodes. 80% of patients with MS who develop stroke are in AF. Development of AF leads to significant deterioration of the functional class in MS patients due to increase in the LA pressure. This is primarily related to the reduction in the duration of the diastolic filling period due to the increase in the heart rate and also due to the lack of mechanical atrial contribution to left ventricular filling. An individual can become symptomatic for the first time with the onset of AF. Acute pulmonary edema can occur in a comparatively mildly symptomatic person. Paroxysmal AF could be the reason for the variation in the symptomatic status in some individuals on different occasions. Fast irregular palpitations if present certainly suggest development of AF but may not be present in all patients. As the disease progresses, PAH tends to become progressively severe and patient tends to develop right ventricular failure and secondary tricuspid regurgitation. Fatigue becomes an important symptom and can be more disabling than dyspnea on exertion. Pedal edema, abdominal distension and other evidence of right heart failure will become evident. Pregnancy is poorly tolerated by patients with significant MS. Increase in heart rate, blood volume and cardiac output lead to increase in LA pressure and pulmonary venous hypertension. Dyspnea and even acute pulmonary edema can occur for the first time during pregnancy. Symptoms usually will be prominent by the mid second trimester, when the hemodynamic abnormalities are pronounced. Severe MS is a contraindication for pregnancy and should be identified and corrected before becoming pregnant.
In cases of severe MS, especially with major PAH, “mitral facies” may be observed, i.e. a patchy, pinkish purple appearance of the cheeks resulting from dilated venules. Such subjects often manifest peripheral cyanosis as well.
Jugular Venous Pulse JVP is normal in MS unless there is associated AF, PAH or RV failure.
Arterial Pulses The arterial pulse in MS has a normal or decreased pulse volume and a normal contour.
Cardiac Examination Precordium: Cardiomegaly is not a feature of isolated MS. It can occur with pulmonary hypertension, RV systolic dysfunction and TR. The apex beat may be sometimes displaced laterally in some post op cases (post-closed mitral valvotomy with left anterolateral thoracotomy). Palpable S1 is felt inside or at site of LV apex beat. An increased P2 and less commonly, a pulmonary artery lift may be felt at the 2nd to 3rd left ICS. The opening snap (OS) often is palpable in the region between lower left sternal border and the cardiac apex. A diastolic thrill at the apex may occasionally be detected in the left decubitus position. Apex impulse is best examined in left recumbent position. The apex impulse is normal or of decreased amplitude, non-sustained and never associated with a palpable S4 or S3 unless an additional valve abnormality is present, such as MR or AS. Right ventricular impulse: It is detected as a gentle, low amplitude RV lift at the 3rd to 5th left ICS adjacent to sternum. To detect parasternal impulse firm pressure with heel of the hand must be used. In individuals with severe PAH, RV impulse can be very prominent, careful visual inspection can detect lateral retraction of the chest wall between normal left and right ventricular areas. In severe degrees of RV enlargement, the apex beat may be formed by the right ventricle. When PAH is severe right ventricular S4 or even rarely RVS3 is may be palpable.
Heart Sounds A loud S1 and an opening snap are hallmark features of MS. An accentuated P2 suggests associated PAH. First Heart Sound: S1 is loud and snapping in MS. The increased S1 is audible throughout the precordium and is heard maximally between lower sternal edge and the apex. 61
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Effect on A2-OS interval
Systemic hypertension
Increase
Valvular Heart Disease—Rheumatic Heart Disease
Table 1: Factors affecting A2-OS interval in MS Associated condition Mitral regurgitation
Decrease
Aortic regurgitation
Decrease or increase
Aortic stenosis
Increase
Calcified mitral valve
Increase
LV dysfunction
Increase
Bradycardia
Increase
Tachycardia
Decrease
Old age
Increase
Table 2: Differentiating features between A2-OS and A2-P2 Features
A2-OS
A2-P2
Best heard
Between apex and left sternal border
At pulmonary area
Interval
0.04–0.14 sec
15 mm Hg with arm raised
Lincoln sign
Pulsatile popliteal
Sherman sign
Dorsalispedis pulse unexpectedly prominent in age >75 years
Peripheral signs: The sudden rise and fall of arterial pulse wave causes a distinctive pounding or collapsing quality of that is accentuated in peripheral arteries. Marked systemic vasodilation may produce noncardiac phenomena such as increased sweating, warm flushed skin and accentuated retinal vein pulsations. These signs are not specific for AR and can be seen in patients with a hyperkinetic circulation and marked arterial vasodilation from other causes. Various eponymous peripheral signs of AR are listed in Table 5. Precordium: The apex impulse in mild to moderate AR is normal in size but is often hyperdynamic. Thus the amplitude is increased but there is no leftward displacement of the impulse. With advancing disease, the hyperkinetic impulse becomes more prominent and the cardiac apex is displaced inferiorly and laterally. When LV dilation or LV dysfunction sets in the apex impulse becomes sustained. In severe AR, the apex impulse is typically found in left anterior axillary line at the 5th or 6th intercostal space, usually occupies at least two interspaces and is sustained into late systole. The area medial to the LV apex may demonstrate prominent retraction. A palpable S4 may be found in lateral decubitus position suggestive of an elevated LVEDP and decreased LV compliance.
Heart Sounds First heart sound: The first heart sound is usually normal in mild to moderate AR. It can be soft with the onset of left ventricular dysfunction and in the presence of a prolonged PR interval.
10 Clinical Assessment of Severity of Valvular Heart Disease
Corrigan sign
Second heart sound: Longer LV ejection time delays the aortic valve closure. Low systemic vascular resistance due to chronic severe AR can delay the aortic hangout interval and can also rarely contribute to delayed aortic valve closure. Second heart sound is usually closely split. Paradoxical splitting of S2 is uncommon unless there is underlying LBBB. A2 is soft in valvular AR because of the damaged leaflets. But A2 can be normal or even loud in annulo aortic ectasia where the leaflets are usually normal. The classical example is the loud ringing second heart sound (tambour sound) described in syphilitic AR. Third heart sound: Unlike the situation in severe MR, presence of left ventricular third heart sound indicates LV dysfunction. One has to be careful in attributing an audible LVS3 in a child or youngadult to LV dysfunction because of the likelihood of a physiological third heart sound. But presence of an LV S3 in an older adult or elderly nearly always indicates LV dysfunction. Fourth heart sound: Audible S4 is found in moderate to severe AR. Prolonged PR interval increases the audibility of S4. Presence of S4 indicates an elevated LVEDP and decreased LV compliance. Ejection sounds: Aortic ejection clicks can be audible with congenital bicuspid aortic valve and in the presence of a dilated aortic root. In severe AR, the ejection click may merge with S1 and longer be audible as separate entity.
Murmur Three different murmurs may be found in patients with AR. (1) The classic decrescendo diastolic murmur from 67
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reflux of blood into the LV. (2) An ejection systolic murmur due to large stroke volume, increased rate of ejection and abnormal valve morphology. (3) The Austin Flint murmur heard as a low pitched diastolic murmur beginning in mid diastole and found only in severe AR. Diastolic murmur: The characteristic murmur of AR is a high pitched, soft, blowing, decrescendo early diastolic murmur best heard along the left sternal border. The maximal diastolic pressure difference between the aorta and LV occurs immediately after LV isovolumic relaxation when LV diastolic pressure falls to its lowest in early diastole. For this reason the murmur may have a brief early crescendo contour which may produce a “gap” between A2 and apparent onset of diastolic murmur. It is better heard with the patient sitting up, leaning forward and breath held in expiration. It is better appreciated with the diaphragm of the stethoscope. Faint early diastolic murmurs can be accentuated by increasing the peripheral resistance—squatting, isometric hand grip and administration of a vasopressor drug like phenylephrine. A soft AR murmur can disappear during pregnancy because of the fall in peripheral resistance. In the presence of dilated aortic root and ascending aorta and when marked atherosclerotic tortuosity pushes the ascending aorta anteriorly and to the right, the early diastolic murmur can be better audible along the right sternal border than the left sternal border. In older adults, especially those with COPD or CCF, the AR murmur may be maximal or may be heard only at the LV apex. In short patients, the AR murmur may be best heard in the axilla (Cole Cecil murmur). In AR due to perforation or rupture of an aortic cusp or retroversion of a leaflet, the murmur may be musical that may wax or wane throughout the diastole, and is called “cooing dove” or “seagull” murmur.
Systolic murmur: A systolic ejection murmur is common in moderate to severe AR. It results from an abnormally large stroke volume that is ejected with rapid force across a deformed valve into an enlarged proximal aorta. This murmur is short and peaks before second half of systole if there is no aortic valve obstruction. Austin flint murmur: Austin Flint murmur is a low pitched, apical diastolic rumble audible in severe AR. Its presence indicates a large diastolic leak with a regurgitant fraction of over 50%. It is due to the AR jet impinging on the septal surface of the anterior mitral leaflet and pushing it up, creating a relative mitral stenosis. It has a mid-diastolic and a presystolic component. Unlike the diastolic murmur of organic MS, presystolic accentuation does not usually happen. LV dysfunction leads to premature closure of the mitral valve and the Austin Flint murmur gets truncated. Elevation of the LV diastolic pressure by the regurgitant jet can exceed the LA pressure. This can produce diastolic MR in pre-systole. This also can possibly contribute to the Austin Flint murmur. Onset of LV dysfunction should be clinically suspected in the presence of reduction in the intensity of first heart sound, audible third heart sound and when the pre systolic component of the Austin Flint murmur disappears. Because the Austin Flint murmur is directly related to degree of AR manoeuvres that increase diastolic reflux will accentuate the murmur, and those that decrease the degree of AR will attenuate it. Thus handgrip, mild exercise, application of a bilateral blood pressure cuff and squatting all intensify the Austin Flint murmur, while amyl nitrate diminishes the intensity. Various differentiating features of Austin flint murmur of AR and diastolic rumble of MS are enlisted in Table 6. Severe AR is suggested by (Box 3) high volume collapsing pulse, cardiomegaly, forceful apex beat, narrowly split second heart sound, long early diastolic murmur and presence of Austin Flint murmur. Presence
Table 6: Differentiating features between murmur in MS and Austin Flint murmur of AR Austin Flint
Mitral stenosis
Left ventricular heave
Common
Absent
RV lift
Absent
Present
S1
Normal to decreased
Loud
Opening snap
Absent
Present
S3
Present
Absent
Amyl nitrate inhalation
Murmur attenuates
Murmur accentuates
Box 3: Clinical features of severe AR
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zz
High volume collapsing pulse
zz
Cardiomegaly
zz
Narrowly split second heart sound
zz
Long early diastolic murmur
zz
Austin Flint murmur
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ACUTE AORTIC REGURGITATION Acute or subacute bacterial endocarditis, aortic dissection, aortic valve perforation or rupture secondary to trauma or myxomatous degeneration are the most common causes for acute AR. It is a life-threatening condition due to sudden reflux of an excessive amount of blood into LV, which is unable to accommodate the large regurgitant volume. As management entails prompt surgical intervention accurate diagnosis and differentiation from chronic AR is mandatory. Table 7 shows differentiating features between acute and chronic AR.
AORTIC STENOSIS Valvular aortic stenosis (AS) has three major causes: rheumatic, congenital and degenerative. Rheumatic heart disease is an important cause for AS in the developing countries. It usually co exists with significant mitral valve disease and or AR. Isolated aortic stenosis is seldom due to rheumatic etiology. Congenital bicuspid aortic valve is seldom stenotic at birth. In the common variety, the left and right coronary cusps are fused and lead to fish mouth opening. Over the years, degenerative changes and calcification set in and is responsible for the reduction in the aortic valve area. Usually this happens beyond the third
decade. Degenerative disease affecting a trileaflet aortic valve is the commonest cause for AS in the elderly. This more often happens in individuals with some structural abnormality of the valve like congenital cuspal inequality. Aortic sclerosis slowly develops which in some individuals progresses to severe AS. Unlike rheumatic etiology, commissural fusion is not a feature of bicuspid aortic valve and degenerative calcific AS. Mild-to-moderate AS is likely to progress over the years and such individuals require regular follow up. This is in contrast to mild to moderate pulmonic valve stenosis which remains stable and is unlikely to progress over the years. Almost half of patients with severe AS are asymptomatic. Because many of these elderly individuals are sedentary, functional assessment of the symptoms may be difficult. The three important symptoms of patients with severe AS are effort related greying of vision (near syncope and syncope), effort angina and dyspnea on exertion. As many of the middle aged and elderly have multiple atherosclerotic risk factors, associated coronary artery disease is common which may also contribute to the symptoms. Natural history series have demonstrated that the average survival after the onset of angina is 5 years and that after syncope is 2 to 3 years. The survival is less than 2 years after the onset of dyspnea due to LV systolic dysfunction. But it is important to remember that some patients can have long standing mild dyspnea on exertion due to LVH and diastolic dysfunction. But a distinct deterioration in the symptomatic status is often correlated with the onset of LV systolic dysfunction.
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10 Clinical Assessment of Severity of Valvular Heart Disease
of peripheral signs indicate significant “run-off ” and wide pulse pressure suggesting severe AR. Significant symptoms, left ventricular dysfunction and pulmonary hypertension are correlated with severe AR.
Table 7: Features of acute vs. chronic AR
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Feature
Chronic AR
Acute AR
Presentation
Often symptomatic
Pulmonary edema, heart failure
Systolic blood pressure
Increased
Normal or slightly decreased
Diastolic blood pressure
Decreased
Normal or slightly decreased
Pulse pressure
Increased
Normal or slightly increased
Heart rate
Normal
Sinus tachycardia common
Peripheral pulses
Bisferiens and increased amplitude
Unremarkable
Peripheral signs
Present
Absent
Jugular venous pulse
Normal
Mean pressure may be elevated
Precordial motion
LV impulse in 5/6th ICS, left anterior axillary line, hyperdynamic or heaving. Palpable S3 or S4 common
Normal to slight LV enlargement. Bifid diastolic impulse with palpable S3, sustained late diastolic motion. RV impulse if severe PAH
S1
Normal to decreased
Decreased to absent
S2
Often unremarkable
Single, soft to absent A2, increased P2
S3
Very common
Always present
Ejection click
May be present
Common
AR murmur
Medium frequency, usually holdiastolic. May be short with rapid decrescendo, Intensity grade 3 unless CCF present
Medium frequency, often harsh, musical if ruptured cusp, usually not holodiastolic may be very short, rapidly decrescendo, intensity may be very soft
Austin Flint murmur
Common
Always present
Systolic murmur
Flow murmur at aortic valve
Mitral regurgitation murmur
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Normal aortic valve area is 3 to 4 square cm2. Reduction of valve area doesnot result in pressure drop across the valve at rest until at least 60% of the valve area is narrowed (AVA approximately 1 cm2). Symptoms start to appear when valve is reduced by 60–75% resulting in calculated valve area of 0.7–0.8 cm2. The major hemodynamic abnormalities in AS are low stroke volume and elevated LV pressures. The LV undergoes concentric hypertrophy to compensate for increased resistance to outflow, this causes a very thick walled chamber with no dilatation of the LV cavity. The diastolic pressures are elevated because of the concentric LVH and diastolic dysfunction leading to sympathetic vasoconstriction. Later systolic dysfunction tends to develop because of excessive afterload, decreased LV contractility, myocardial fibrosis and accompanying ischemia. Even in cases without evident LV dysfunction, LV will not be able to increase the cardiac output in relation to exercise. Severe AS carries a significant risk of arrhythmias and sudden cardiac death. Those with high systolic gradients, marked LVH, myocardial fibrosis and myocardial ischemia are at higher risk of sudden cardiac death (SCD). SCD is comparatively less in those who are totally asymptomatic.
Physical Findings and Assessment of Severity Arterial pulse: The pulse in severe AS is classically described as parvus (low volume) et tardus (slow rising). This character abnormality is best appreciated over the carotids. There is an associated systolic thrill or shudder on the upstroke of the pulse. The pulse pressure is narrow. In children and young adults, the systolic blood pressure tends to be low. But in elderly with severe calcific AS, it is not uncommon to have systolic blood pressure above 160 mm Hg. This is a reflection of the inelasticity of the aorta and the non-compliant vasculature. The estimation of severity of AS from carotid pulse analysis is unreliable.
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Precordium: The apex impulse is characteristically described as heaving—the palpating finger is elevated above the plane of the adjacent ribs and is sustained for more than half of systole. There is little or no leftward displacement of apex impulse. The duration and force of the LV impulse is increased due to increased LV mass, high intraventricular pressure and obstruction to ventricular outflow. A presystolic distension of LV (equivalent of palpable S4) may be felt over the apex in the left lateral position. In absence of other cardiovascular conditions, a palpable S4 correlates with a LV—aortic gradient of greater than or equal to 70 mm Hg. A systolic thrill may be felt at the first or second right intercostal space, with radiation upward and rightward towards the neck and right shoulder. The thrill is better appreciated in expiration with the patient sitting up in the leaning forward position.
Presence of a thrill indicates that AS is present but does not necessarily indicate severe obstruction.
Heart Sounds First heart sound: S1can be normal or may be reduced in intensity but is never accentuated in isolated AS. Second heart sound: The amplitude of the aortic ejection click and A2 are closely related. Both are prominent in a subject with pliable non-calcified bicuspid valve. Both are decreased in intensity in the presence of calcium and significant valvular thickening. The characteristic alteration of S2 is an increase in the Q-A2 interval with A2 moving into P2 and a tendency for S2 to become single. The delay in A2 is due to: (1) an increased duration of LV ejection and (2) the prolonged time for LV pressure to drop below aortic pressure at end systole due to a large LVaortic gradient. During paradoxical split, the split is wider and better appreciated during expiration. The presence of paradoxical splitting of S2 in a case of AS in absence of bundle branch block is indicative of severe obstruction. Third heart sound: Presence of S3 in an adult patient of AS is suggestive of significant LV dysfunction or CCF. Fourth heart sound: Audible left ventricular fourth heart sound in children or young adults with aortic stenosis indicates severe obstruction. But an audible LVS4 does not have the same significance in elderly with aortic stenosis. Audible S4 is common in people above the age of 60 years, especially in the presence of systemic hypertension and or coronary artery disease. But palpable S4 in any age is considered abnormal. Presence of LVS4 in a person under the age of 40 years indicates a peak gradient of at least 50 mm Hg. Aortic ejection click An aortic ejection click which is constant (non phasic) and heard over the base as well as sometimes over the apex indicates non calcified valve and may be audible in congenital AS in children and young adults. As the valve leaflets get calcified, loud ejection clicks are unusual beyond the age of 40 years even with bicuspid aortic valves. Aortic ejection clicks are usually absent in rheumatic AS. Presence of ejection click does not correlate with severity of AS. Murmur The turbulent flow across the stenotic aortic valve produces a harsh crescendo decrescendo ejection systolic murmur that begins after S1 and ends before S2. The murmur of severe AS is described as rasping, grunting or coarse and maximal at the second right intercostal space. In some patients the murmur may have maximum intensity in second or third left intercostal space (Erb’s area) and in older patients with large chests or COPD, the murmur may be loudest at the apex. The murmur is characteristically
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CHAPTER
Box 4: Clinical features of severe AS Slow rising, low volume pulse, narrow pulse pressure
zz
Heaving apex
zz
Palpable thrill
zz
Paradoxically split S2
zz
LV S4
zz
Long and late peaking ejection systolic murmur
zz
Apico-carotid delay
conducted to both carotids. The length of the murmur is proportional to the severity of valvular obstruction. The later the peak of the crescendo and longer the duration of the murmur, the more severe is the stenosis. A murmur that peaks in second half of systole indicates severe stenosis. The high frequency components of the ejection systolic murmur selectively tend to radiate to the apex and may sound musical or cooing simulating the murmur of MR. This is called the Gallavardin phenomenon. This is especially common in elderly patients with calcific aortic stenosis. This is less frequent in rheumatic AS because the commissural fusion may prevent the leaflets from vibrating and producing pure frequencies. The presence of coexistent AR will increase the stroke volume which in turn will increase length and intensity of the AS murmur. The murmur of severe AS can become short and soft with the onset of LV dysfunction because of the marked reduction in stroke volume. Severe AS is indicated by (Box 4) slow rising, low volume pulse, narrow pulse pressure, heaving apex with palpable presystolic expansion over the apex, palpable thrill over upper right sternal and or left sternal border, soft S1, Paradoxically split S2 with a muffled aortic component and an audible LVS4 over apex. The harsh ejection systolic murmur will be long and late peaking. Evidence of pulmonary hypertension and heart failure are indicators of severe lesion. But associated mitral valve disease should be ruled out.
TRICUSPID STENOSIS Normal tricuspid orifice measures 5 to 7 square cm. TV area less than 1 square cm indicates severe tricuspid stenosis (TS). Rheumatic TS almost always occur with mitral valve disease and associated aortic valve disease. Pathology is similar to rheumatic MS—commissural fusion often associated with subvalvular pathology. Carcinoid disease and congenital causes including Ebstein malformation of the tricuspid valve are the other two etiological factors. The left heart symptoms related to mitral valve disease (dyspnea on exertion, PND, hemoptysis, pulmonary edema) will be attenuated by the more proximal stenotic lesion. The clinical picture will be dominated by low cardiac output and systemic venous congestion. Fatigue, pedal edema and abdominal distension are the usual
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zz
symptoms. AF is common. Physical examination will reveal low volume pulse. JVP will be elevated and “a” waves will be prominent and the Y descent will be slow because of the slow emptying of blood from RA to RV. Auscultation over the lower left sternal border will reveal a mid-diastolic murmur, characteristically increasing with inspiration (Carvallo’s sign). Unlike MS, loud mid-diastolic murmurs are unusual. Most of the patients will be in AF and a faint mid diastolic murmur over the left sternal border can be picked up during inspiration on careful auscultation. In patients in sinus rhythm, pre-systolic expansion of the liver may be possible. A high index of suspicion is required to diagnose organic tricuspid valve disease.
TRICUSPID REGURGITATION Primary organic disease of the tricuspid valve leading to inadequate closure of the tricuspid orifice is rare. It can occur in rheumatic heart disease in association with mitral and often aortic valve disease. Ebstein anomaly, carcinoid heart disease and infective endocarditis are other causes. Right ventricular endomyocardial fibrosis, a form of restrictive cardiomyopathy can also lead to low pressure tricuspid regurgitation (TR). Isolated TR encountered in clinical practice is almost always secondary to pulmonary arterial hypertension, annular dilatation and right ventricular dysfunction. In hypertensive TR, the systolic pressure is reflected into the RA which is often markedly dilated. AF is a common arrhythmia. Pedal edema and ascites are the usual symptoms. JVP shows obliterated x descent, prominent CV wave (systolic wave), tall V waves and prominent y descent. Findings of PAH will be evident. Murmur due to secondary TR (high pressure TR) is a high pitched pansystolic murmur maximally audible over the lower left sternal border characteristically increasing with inspiration. It may be accompanied by RVS3 and a mid-diastolic flow murmur. Sometimes in severe pure MS with severe PAH and right ventricular dysfunction, the TR murmur may be widely audible including the lower left sternal border and the apex which is formed by the RV. Because the LV is displaced more posteriorly and because of the reduced forward flow across the mitral valve, the mitral mid-diastolic murmur may be totally inaudible (silent MS). The TR murmur may be mistaken for MR. The inspiratory augmentation of the murmur and the other
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findings of severe PAH and TR helps in the differentiation. The inspiratory augmentation will be reduced or lost with the onset of significant right ventricular dysfunction. Systolic hepatic pulsations are observed with severe TR. The murmur of primary TR (low pressure TR) tends to be low to medium pitched. It is often soft and has a late systolic decrescendo due to equalization of pressures between RV and RA. Inspiratory augmentation is usually less striking. In conditions like RVEMF and RV infarction, the murmur may be soft or inaudible.
PULMONARY STENOSIS
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Right ventricular outflow tract obstruction can be valvular, supra valvular and subvalvular/infundibular. As an isolated anomaly, “mobile dome-shaped” pulmonary valve stenosis is the most common type of right ventricular outflow tract obstruction. Different types of physical appearances/facies are described in pulmonary stenosis (PS). Round bloated facies is known to occur in infants with mobile dome shaped PS. Noonan syndrome, congenital rubella syndrome, William syndrome and Alagille syndrome are well known to be associated with RVOT obstruction. The pulmonary valve in Noonan syndrome is usually dysplastic—three thickened immobile cusps without commissural fusion and a non-dilated pulmonary trunk. The predominant site of obstruction in the other three syndromes is usually in the pulmonary artery and the branches (supravalvular or peripheral PS). The “a” wave in the JVP tends to be prominent in significant PS. The height of “a” wave increases progressively as the stenosis increases. Moderate to severe PS with intact inter ventricular septum is associated with left parasternal heave. Systolic thrill is sometimes palpable in moderate to severe PS. It is maximal in the second left intercostal space with radiation upward and to the left because the intrapulmonary jet is directed upward and towards the left pulmonary artery. Pulmonary ejection click coincides with abrupt superior movement of the mobile dome shaped pulmonary valve. It is phasic and better audible during expiration. Ejection sounds are absent with immobile dysplastic valves. The S1–EC interval varies inversely with the degree of stenosis. It is decided by the pressure difference between the right atrial “a” wave and the pulmonary artery diastolic pressure. Pre-systolic opening of the pulmonary valve is possible in very severe PS, when the right atrial “a” wave exceeds the pulmonary artery diastolic pressure. The severity of RVOT obstruction decides the duration of right ventricular ejection and the length of the ejection systolic murmur. With mild PS, the systolic murmur tends to be symmetric and ends before the aortic component of the second heart sound. The split of the second heart sound will be near normal and the intensity of P2 will be preserved. With moderate PS, the murmur ends at the aortic component of the second heart sound. The second sound tends to be
widely split with reduced intensity of P2. With severe PS, the murmur tends to be longer, late peaking and extending beyond A2, which is often inaudible. The second sound will be widely split with muffled P2. With very severe PS, the murmur has an asymmetric kite-shape (late peaking) reaching up to a delayed inaudible P2. A2 will also be inaudible as the loud murmur extends well beyond that. Audible S4 is correlated with severe PS.
PULMONARY REGURGITATION PR is usually secondary to pulmonary hypertension. Congenital pulmonary valve regurgitation is uncommon leading to low pressure pulmonary regurgitation (PR). Postoperative tetralogy of Fallot with trans-annular patch is a frequently encountered etiological factor. An impulse will be usually palpable in the second and third left intercostal space close to the sternum. Parasternal pulsations are usually seen but sustained left parasternal heave is unusual. The diastolic murmur of low pressure PR is low to medium frequency, is crescendo decrescendo and starts slightly after the pulmonary valve closure sound. It is usually short in duration because of equalization of pressures in mid to late diastole. The murmur is occasionally louder in inspiration and is often associated with a thrill. A pulmonary mid-systolic ejection murmur is usually present. The second heart sound is normally split or shows wide variable split and P2 is soft or even inaudible. The murmur sounds very much like a mid-diastolic murmur. In contrast, the murmur of PR related to pulmonary hypertension tends to be higher pitched and starts immediately after the pulmonary valve closure sound. The P2 is loud and often palpable. Constant vascular pulmonary ejection click is almost invariable. Left parasternal heave due to systolic overload of the right ventricle is seen in those with intact inter ventricular septum. As the diastolic gradient between pulmonary artery and right ventricle persists throughout diastole, the murmur tends to be long and even pan diastolic. The murmur of hypertensive PR classically has a decrescendo character and does not show respiratory variation.
MULTIVALVULAR LESIONS The commonest etiology with multi valvular lesions is rheumatic heart disease. The mitral valve is almost always involved followed by aortic valve involvement. Clinically significant tricuspid valve involvement is uncommon and pulmonary valve is usually not involved. Calcific aortic valve disease can co-exist with mitral annular calcification and MR. Connective tissue diseases can produce AR due to annuloaorticectasia and MR due to myxomatous degeneration of mitral leaflets and MR. Carcinoid heart disease is known to produce right sided valve involvement. Infective endocarditis can sometimes involve both mitral and aortic valves because of the extension of the infective
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MS and MR These two lesions frequently co-exist. The etiology is almost always rheumatic heart disease. Mitral annular calcification leads to predominantly MR but can also produce some degree of stenosis. It usually occurs in elderly individuals. Congenital mitral valve disease is infrequently encountered in children. Increase in the mitral inflow in MR can exaggerate the clinical features of associated MS. One should find out if the early diastolic sound is an opening snap or an LVS3. Classically opening snap is a loud high pitched widely audible crisp sound. Usually it is audible with maximum intensity midway between apex and left sternal border. LVS3 is a low pitched sound best appreciated in the left lateral position with the bell of the stethoscope. It is very often localized and may be palpable. Presence of a third heart sound practically rules out any significant MS. The mid-diastolic murmur heard in chronic severe MR follows the LVS3 and is decrescendo and does not have a pre systolic component. First heart sound tends to be loud in MS but is often soft in MR. S1 can sometimes be loud in mitral valve prolapse because of the fusion of S1 with an early non-ejection click. Significant MR in the presence of MS is suggested by the presence of LV type of forceful apex beat (shifted down and out) and pan-systolic murmur over the apex. Widely split second heart sound may suggest significant MR.
MS and AR MS being the proximal lesion can affect the assessment of AR. As a general statement, the severity of AR can be under estimated. Around one-third of patients with severe MS and pulmonary arterial hypertension have reduced pre load to the LV and hence reduced cardiac output. In such patients the pulse pressure tends to be less wide and the peripheral signs of AR may be less than expected. In a patient with AR, associated MS is suggested by presence of AF, loud S1, presence of opening snap, diastolic thrill over the apex, presence of pre-systolic accentuation for the mid diastolic murmur and evidence of pulmonary arterial hypertension. Opening snap may be soft or even inaudible in MS patients who have associated significant AR. This is because of the AR jet impinging on the ventricular side of anterior mitral leaflet restricting the excursion and opening.
MS and AS
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Patients will have low volume pulse. Sytolic blood pressure will be normal or low. Presence of atrial fibrillation in aortic stenosis will give a clue as to the presence of mitral valve disease. Severe aortic stenosis will soften S1. A2 intensity is also reduced. The elevated LV end diastolic pressures in aortic stenosis will lessen theLV-LA gradient in late diastole thus shortening the length of mitral diastolic murmur. The diastolic murmur may all together absent making it a silent MS. Presence of opening snap will give us clue for presence of MS.
10 Clinical Assessment of Severity of Valvular Heart Disease
process. Rarely congenital LV outflow obstruction can coexist with mitral inflow obstruction. The clinical findings of organic tricuspid valve involvement are usually subtle and can be easily missed unless very specifically looked for. The faint systolic murmur of organic TR and the short murmur of organic TS will be audible only on deep inspiration or passive leg raising. It will be difficult to pick up these murmurs when the loud left sided murmurs are easily audible over the precordium.
AS and AR The pulse volume will depend on the significance of AS, but generally high volume even with severe AS if AR is atleast moderate or severe. The systolic decapitation effect of AS will make the pulse pressure narrow. Cardiomegaly indicates significant AR. The systolic murmur of organic AS will be long and late peaking, as opposed to the functional flow murmur of AR which is early peaking. Prominent conduction to carotids is another clue as the existence of organic AS. The length and peaking of murmur thus gives us a clue as to the presence of organic AS. The A2 will be further soft and delayed leading to paradoxical splitting in severe AS.
SUMMARY We have made an attempt to elaborately discuss the different clinical examination finding in valvular heart disease. However, we believe that the clinical findings do vary from patient to patient depending on patient physique, chest wall thickness, hemodynamic state like presence of heart failure, etc. The most challenging part would be the multivalve state were in identifying the severity of individual lesions will continue to be challenging at the same time exciting for an enthusiastic clinical cardiologist.
SUGGESTED READING 1. Abrams J. Essentials of cardiac physical diagnosis. Philadelphia: Lea & Febiger; 1987. 2. Babu AN, Kymes SM, Carpenter Freyer SM. Eponyms and the diagnosis of aortic regurgitation: what says the evidence? Ann Intern Med. 2003;138(9):736-42. 3. Chandrasekhar Y, Westaby S, Narula J. Mitral stenosis. Lancet. 2009;374(9697):1271-83. 4. Constant J. Essentials of bedside cardiology. Totowa NJ: Humana Press; 1992. 5. Mackenzie J. The study of the pulse. Arterial, venous and hepatic and of the movements of the heart. Edinburgh: Pentland; 1902. 6. Perloff JK. The physiologic mechanisms of cardiac and vascular physical signs. J Am Coll Cardiol. 1983;1:184-98.
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Subclinical Rheumatic CHAPTER 11 Heart Disease RK Gokhroo, Kailash Chandra
SUMMARY Rheumatic heart disease (RHD) can be considered as a continuum of pathological process which progresses from a subclinical stage to overtly clinical established disease entity and is a long-term sequelae of acute rheumatic fever (ARF). In the last few decades, with the advent of easily available echocardiograms and early secondary prophylaxis even in the developing countries, a remarkable decrement in the global burden of the RHD has been noticed. Underdeveloped countries still remain a hub for this disease. The rheumatic process if diagnosed before clinical symptoms develop, i.e. in the early stage/latent period is referred as ‘subclinical RHD”. Criteria have been developed by World Heart Federation (WHF) to identify the disease in its early phase and to differentiate it from normal physiological variants. Early institution of secondary prophylaxis, in this cohort, will halt the disease process and improve morbidity as well as mortality of RHD.
INTRODUCTION Twenty first centur y, labeled as the era of noncommunicable diseases, is more so relevant for the developed part of the world. But still the developing countries, is struggling with infectious diseases. This also holds true for rheumatic heart disease (RHD), which is a common cause of cardiovascular morbidity, especially in children and young adults, only next to congenital heart defects. RHD is a sequelae of acute rheumatic fever (ARF), and attributed mostly to the lower socioeconomic status with overcrowding and poor sanitation status. The improved socioeconomic status with revolutionary use of benzathine penicillin in early phases of the disease process or even after pharyngitis, almost eliminated advanced RHD from the developed countries. However, in countries like India, though the prevalence has decreased, the burden of RHD is significant. According to a recent multinational registry (REMEDY) report, RHD is mostly diagnosed in advanced stages (63.9%) 1 , when valve replacement remains the only management option left. RHD pathogenesis can be considered as a long-term continuous process, where interventions in the early phase have been shown to minimize the structural damage of heart and offers
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survival benefit. Ignorance of prophylaxis in early phase along with poor socioenvironmental conditions leads to repeated attacks of ARF and reduces the latent period of RHD. This explains the usually long latent period seen in patients from developed countries, and an earlier onset of clinical RHD in the poor countries like India. RHD, when diagnosed in the latent phase, by means of screening echocardiography, has been termed latent or subclinical RHD, and further classified as borderline or definite.2
PREVALENCE OF CLINICAL AND SUBCLINICAL RHD The prevalence of RHD, based on previous studies is varies among different parts of the world and ranges between 3.4 to 444 cases per 1,00,000.3 Prevalence of clinical RHD in India is 0.8/1000, based on a survey study among school children in northern India,whereas it is 20.4/1000 for subclinical RHD, which is significantly higher and assures the role of screening echocardiography. 3 The burden of RHD worldwide ranges from 62 million to 78 million people, resulting in 1.4 million deaths per year from RHD and related complications.4 W i t h t h e a d v e n t o f n e w e c h o c a rd i o g r a p h i c techniques, RHD process has been tried to be fully addressed but variations in reporting still exist. In light of these existing differences, World Heart Federation (WHF) had developed standardized echocardiographic criteria for RHD diagnosis. 5 WHF has classified the echocardiographic findings as definite RHD, borderline RHD and normal. ‘Definite RHD’ and ‘borderline RHD are further subcategorized on into four and three subgroups respectively. Criteria to differentiate pathological mitral regurgitation (MR) and aortic regurgitation (AR) from functional variants have also been described, enabling definite diagnosis of early subclinical RHD. These criteria enable early, rapid and consistent diagnosis of RHD in individuals where clear history of ARF is lacking.
IS EARLY RECOGNITION BENEFICIAL? Recognition of rheumatic process in early phase with timely initiation of secondary prophylaxis is the main concern as it has been shown to halt the progression of
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DIAGNOSTIC CRITERIA FOR LATENT RHD According to WHF guidelines, suspected RHD cases should undergo echocardiography with the knowledge of patient’s clinical profile and pretest probability of RHD. It is important to exclude other possible causes of valvular heart diseases (congenital/acquired/degenerative) before stamping a rheumatic etiology. Echocardiographic criteria for ‘definite RHD’ and ‘borderline RHD’ are depicted in Boxes 1 to 3.
DEFINITE RHD Before interpreting echocardiograms, the pretest probability of RHD in the individual must be assessed. The subcategories of ‘definite RHD’ are as follows:
Subcategory A—RHD of the Mitral Valve with Regurgitation Defined as pathological MR and at least two morphological features of RHD of the mitral valve. Grade B recommendation for this subcategory inclusion in ‘definite RHD.’
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11 Subclinical Rheumatic Heart Disease
the disease process, leading to improved morbidity and mortality in these patients. The emphasis on mass screening of population by echocardiography is to provide the actual data regarding RHD burden in the community and for better understanding of the pathophysiologic process of rheumatism. This in turn may help in the planning and implementation of various RHD control programs at national or international levels. However, direct benefits of screening echocardiogram for recognition of RHD burden, and the influence it has on the natural course of disease, is yet to be established.
Subcategory B—RHD of the MV with Stenosis Defined as mitral stenosis (MS) with a mean gradient ≥4 mm Hg and at least two morphological changes of RHD of the MV. Grade B recommendation for this subcategory inclusion in ‘definite RHD’.
Subcategory C—RHD of the Aortic Valve Defined as pathological aortic valve (AV) and at least two morphological features of RHD of the AV.This subcategory only applies to individuals aged 20 years Definite RHD (either A, B, C, or D): (A) Pathological MR and at least two morphological features of RHD of the MV (B) MS mean gradient ≥4 mm Hg* (C) Pathological AR and at least two morphological features of RHD of the AV, only in individuals aged 40 years. Harmonic imaging tends to overestimate the measurements, and a thickness up to 4 mm should be considered normal in those aged ≤20 years. § Restricted leaflet motion of either the AMVL or the PMVL is usually secondary to commissural fusion, chordal fusion or shortening or leaflet thickening. || Excessive leaflet tip motion is the result of elongation of the primary chordae, and is defined as displacement of the tip of an involved leaflet towards the left atrium resulting in abnormal coaptation and regurgitation. Excessive leaflet tip motion does not need to meet the standard echocardiographic definition of MV prolapse disease, as it refers to a different disease process. This feature applies to only those aged RS; SL, sever subvalvular lesions; Low-pressure zone, balloon diameter < 2 mm of nominal balloon size; High-pressure zone, balloon diameter within 2 mm of nominal balloon size
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B Figures 3A and B: Simultaneous tracings of left atrial pressure and left ventricular pressure in a patient with MS, preprocedure and after serial balloon dilatations
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2
Complex Anatomy where BMV is Challenging
Valvular Heart Disease—Rheumatic Heart Disease
At the level of trans-septal puncture: — Abnormal septal profile — Thick septum — Bulging of IAS — Septal aneurysm — Double atrial membrane — Dextrocardia — IVC anomaly — Kyphoscoliosis. At the level of crossing the mitral valve: 2 — Critical MS < 0.5 cm — Small LA — Giant LA — Giant RA and small LA — Thick IAS — Severe submitral stenosis — Unfavorable IAS puncture site.
Gaint Left Atrium In the gaint LA, the interatrial septum (IAS) is shifted down and to the right and the operator is forced to make septal puncture more caudally to the ‘M-line’ because the septum begins its curvilinear shape more caudally. The IAS puncture is lower and anterior which will make the crossing of mitral valve also and unfavorable to maneuver the balloon. PA angio with levophase opacification of the LA will help to delineate the IAS better and facilitate successful septal puncture. There is a difficulty to cross MV by the usual stylet steering of the balloon. Crossing
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the mitral valve is more appropriately performed with over-the-wire method. Sometimes, even over-the-wire method may fail as the balloon introduced can prolapse back from LV to LA while maneuvering into LV over the wire. In such cases, one should try the reverse loop technique, especially when the septal puncture is low and anterior. Generally, low puncture of the IAS and over-thewire method of crossing the mitral valve will make BMV successful in giant LA (Figures 4A to F). The following are the tips to successfully perform BMV in giant LA. Tips: Use PA angio for levophase Increase the curvature of the puncture needle so that it faces more posteriorly Low puncture Reshape the stylet to cross the MV Over-the-wire technique Reverse loop of the balloon catheter
PERCUTANEOUS TRANSVENOUS MITRAL COMMISSUROTOMY (PTMC) IN LEFT ATRIUM CLOT Traditionally, LA clot is a contraindication for performing BMV as there is a high chance of embolism due to clot dislodgement while maneuvreing the Mullins sheath, guidewire, and balloon. BMV can be safely performed in some subsets of LA clot. Manjunath et al. have classified the LA thrombus according to their location in LA and LA appendage (Figure 5).10 In the presence of LA clot, we anticoagulate the patients adequately for 8 to 12
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Figures 4A to F: (A) Transthoracic echocardiography (TTE) showing large LA; (B) Increasing curvature of puncture needle; (C) Low septal puncture; (D) Reshaping the stylet; (E) Over-the-wire technique; (F) Reverse loop method to cross mitral valve
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4 Percutaneous Transvenous Mitral Commissurotomy: Tips and Tricks
Figure 5: Manjunath et al. classification of left atrial thrombus
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Figures 6A to F: Over-the-wire technique. (A) LA angiogram showing clot in LAA; (B) Low septal puncture; (C) LA guidewire directed towards the LV bypassing LA; (D) IAS dilated with dilator with guidewire in LV; (E) Accura balloon introduced over the wire into LV; (F) Balloon dilatation Abbreviations: LA, left atrium; LV, left ventricle; IAS, interatrial septum; LAA, left atrial appendage
weeks [international normalized ratio (INR)-2.5 to 3]. In cases of persistent clot despite anticoagulation, LA clot of type Ia, Ib, and IIa are still suitable for BMV. Adequate prior anticoagulation for 8 weeks prior is necesssary. The patient’s INR on the day of procedure should be less than 1.5. Case selection is the key.
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The following precautions one should take during BMV in this setting: Low septal puncture to facilitate crossing of the mitral valve Over-the-wire technique for crossing the valve (Figures 6A to F)11 Septal dilatation done using septal dilator.
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Valvular Heart Disease—Rheumatic Heart Disease
2
All exchanges and balloon dilatation should be done over the wire to avoid the contact with clot by the hardwares. 6 When two-thirds of the stretched balloon crosses the IAS, balloon stretching tube is withdrawn by 2–3 cm, so that the balloon navigates into mitral valve into LV without dislodgement of coiled guidewire.
MANJUNATH’S CLASSIFICATION OF LA CLOT (FIGURES 5 AND 6)
Type Ia: LA appendage clot confined to appendage Type Ib: LA appendage clot protruding to LA cavity Type IIa: LA roof clot limited to plane above fossa ovalis Type IIb: Below plane of fossa ovalis Type III: Layered clot over IAS Type IV: Mobile clot attached to LA free wall Type V: Ball valve thrombus.
Moderate MR and PTMC Mitral regurgitation (MR) in rheumatic MS is due to restriction of leaflet mobility. In a few of them, MR may actually decrease because of better coaptation of the MV leaflets following commissural release with BMV. While performing the balloon dilatation, one has to take care in going stepwise increase in the volume of the balloon for inflation with 2 cc less than the routine. Echocardiographic assistance is extremely important to assess the result and proceed further. The following patients with ≥ moderate MR patients are benefited by BMV:
Central jet on color flow No commissural MR Large LA Commissures free from calcium.
Severe Submitral Disease and PTMC Severe submitral fusion is a relative contraindication for BMV as the results may be suboptimal. The following features identify the submitral fusion: High LA pressure despite < moderate MS Disproportionate pulmonary arterial hypertension (PAH) Balloon impasse sign Difficulty in balloon reaching LV apex Frequent slipping of balloon during initial inflations. Submitral fusion can be very severe in some cases. In extreme submitral fusion, it may not be possible to maneuvre the balloon across the submitral fusion during BMV (Figures 7A to H). In this case, submitral fusion was dilated with an 8-mm peripheral balloon to facilitate the passage of Accura balloon for successfully performing BMV.
Calcific MS and PTMC In mitral stenosis with bicommissural calcification, BMV is contraindicated, because there is high probability of leaflet tear with resultant acute severe mitral regurgitation. But, BMV can still be attempted in patients with unicommissural calcification (Figures 8A to H).12
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Figures 7A to H: (A) PLAX view showing severe submitral disease; (B) Choral level orifice narrower than commissural suggesting severe submitral disease; (C) Commisural mitral orifice; (D) Post-Echo showing completely split medial commissure; (E) Balloon Impasse sign; (F) Guidewire exteriorized; (G) Retrograde submitral valvuloplasty performed with peripheral balloon; (H) Submitral plasty facilitated antegrade balloon passage and successful BMV
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4 B
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Percutaneous Transvenous Mitral Commissurotomy: Tips and Tricks
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Figures 8A to H: (A) Dense calcification confined to the lateral commissure; (B) The Inoue balloon across the mitral valve (MV) with the distal part of the balloon being inflated; (C) Both the proximal and distal part being inflated; (D) On further inflation, there is appearance of a waist, with the balloon assuming ‘dumbbell’-like configuration; (E) The medial commissure is beginning to split on inflation; (F) On maximal balloon inflation, the medial commissure seen to give way and the lateral commissure is unyielding; (G and H) Pre- and post-procedure echo showing severe calcified MV and medial commissure completely split after procedure
LUTEMBACHER’S—ASD/RHD SEVERE MS WITH SEVERE SUBMITRAL DISEASE The BMV in Lutembacher’s syndrome is associated with lower complications as it does not require septal puncture. Crossing the mitral valve can be challenging despite the presence of ASD. When ASD is very posterior, to facilitate LV entry, we may need to take separate anterior septal puncture, as the balloon anchors in the septum and maneuvering the balloon will be better. We had a patient with Lutembacher’s—ASD/RHD severe MS with severe submitral disease, with ASD was located more posteriorly. We could not cross the MV; hence, separate low anterior puncture was done to anchor the balloon across the septum and MV was crossed. Severe submitral disease did not allow Accura balloon entry into LV by the routine technique using stylet. Hence, an 8-mm peripheral balloon dilatation of submitral fusion was performed (facilitated the entry of Accura balloon into LV) followed by successful BMV done using Accura balloon (Figures 9 and 10).
Dextrocardia and PTMC Distorted cardiac anatomy makes fluoroscopy-guided transcatheter procedures difficult which become technically more challenging in the cases w ith percutaneous mitral valvotomy (PMV), where the cardiac malpositions substantially increase the complications beginning from interatrial septal puncture to left ventricular entry.13 We had a case of situs inversus with dextrocardia associated with severe bicuspid aortic stenosis and rheumatic severe MS with pulmonary hypertension. The standard Inoue technique was modified by trans-septal catheterization via the left femoral vein, image inversion on the monitor, delineation of the interatrial septal anatomy via levophase pulmonary angiography, septal contrast staining and pigtail catheter insertion in the noncoronary aortic sinus, interatrial septal puncture with the trans-septal needle rotated to a 7 o’clock position,14 and wire crossed across aortic valve into aorta. Balloon aortic valvotomy was performed and left ventricular entry done with over-thewire technique and successful BMV performed. 99
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Valvular Heart Disease—Rheumatic Heart Disease
2 A
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Figures 9A to D: (A) Separate low interatrial septum (IAS) puncture as balloon entry difficult; (B) Over-the-wire technique difficulty to cross MV due to severe submitral stenosis; (C) Guidewire exteriorised and retrograde submitral valvuloplasty performed with ATB 8 x 30 mm balloon; (D) Submitral plasty facilitated antegrade balloon passage and successful BMV
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Figures 10A to I: (A) PA angiogram in levophase defining interatrial septum (IAS); (B) Septal puncture left anterior oblique (LAO) 30 view; (C) Balloon catheter passed over wire into left atrium (LA) into left ventricle (LV) and aorta; (D) Snaring of wire from right femoral venous approach; (E) Balloon aortic valvuloplasty (BAV) performed using peripheral balloon, (F to I) Over-the-wire technique used to perform successful BMV
Venous Anomalies and PTMC
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BMV is routinely performed succesfully through femoral venous access; however, certain congenital or acquired anomalies of the IVC or iliofemoral veins may preclude this option and necessitate the use of alternative access routes. The challenge is to perform a safe septal puncture. We have encounterd cases of venous anomalies, interruption of IVC, and absent right SVC with persistent left SVC with severe mitral stenosis which make BMV challenging. The transjugular approach for BMV is a useful alternative in patients with venous anomalies that preclude the conventional
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femoral venous approach (Figures 11A to F). 15,16 We had another case of severe MS patient with absent right SVC and aneurysmally dilated coronary sinus (CS). The aneurysmally dilated CS caused distortion of anatomy and septal bulge. As every time we tried to probe fossa ovalis, the assembly used to slip down to CS. This was the area of concern as it could lead to CS perforation. Septal stain method and echocardiographic assistance was helpful in septal puncture in AP and RAO view. Successful PTMC was performed using Accura balloon dilatation using over-the-wire technique (Figures 12A to F).17
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4
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F
Figures 11A to F: (A and B) Computed tomography (CT) and invasive venogram showing hepatic inferior vena cava (IVC) interruption and continuation of azygous and hemiazygous veins; (C) Septal puncture using Brockenbrough needle by right jugular venous approach; (D) Balloon catheter maneuvered over the coiled wire into left ventricle (LV); (E) Accura balloon dilatation, (F) Post-procedure echo bicommisural split with mitral valvular orifice area (MVOA)—1.9 cm2 16
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Percutaneous Transvenous Mitral Commissurotomy: Tips and Tricks
A
Figures 12A to F: (A) Right subclavian venogram showing absent right superior vena cava (SVC) and right innominate vein draining into left SVC which in turn drained into right atrium (RA) through an aneurysmally dilated coronary sinus; (B) Right anterior oblique (RAO) view showing dye from Brokenbrough needle causing opacification of dilated coronary sinus and left SVC; (C) Septal stain; (D) Septal puncture done in RAO view; (E and F) RAO view showing mitral valvotomy using Accura balloon, over-the-wire technique of BMV
Tips: Endry’s/Pediatric Brockenbrough needle PA angio levophase—LA opacification Pigtail in the noncoronary cusp (NCC) of aorta Reduce the curvature of the puncture needle Direction indicator of needle—7– 8 o’clock Clockwise rotation on the stylet
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Reshape stylet to ‘S’ shape
Right internal jugular vein approach in IVC anomaly
Post-Mitral Valve Repair Stenosis and PTMC BMV can safely be performed for most patients after commissurotomy, either surgical or percutaneous. Two
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Valvular Heart Disease—Rheumatic Heart Disease
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Figures 13A to F: (A) Septal puncture in right anterior oblique (RAO) view with mitral and tricuspid rings; (B) Difficult mitral ring negotiation using cobra catheter; (C) Mitral valve post negotiation; (D) Mitral valve crossed with coiled guidewire; (E) Passage of balloon catheter over the wire in left ventricle (LV); (F) Successful balloon dilatation
major mechanisms are responsible for valvular restenosis: commissural refusion and progression of subvalvular thickening/degeneration. Patients with mitral restenosis caused by symmetrical commissural refusion obtain better results from repeat procedures compared with patients with restenosis in whom the pathological mechanism of restenosis is mainly subvalvular and commissures are not bilaterally fused but rather unilaterally or bilaterally split (Figures 13A to F).
PTMC During Pregnancy
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Prophylactic BMV is offered to women with severe MS who are planning pregnancy in the hope of preventing the expected clinical worsening in the second trimester and peripartum.18,19 However, BMV is performed in pregnant patients with moderate-to-severe asymptomatic or mildly symptomatic MS because of variable maternal and fetal outcomes reported in literature. 20,21 Pregnant patients often present with exacerbation of symptoms of MS in the second trimester as a result of the hemodynamic burden imposed by physiologic circulatory changes of pregnancy. In symptomatic patients, BMV is usually electively done at the end of the second or the beginning of the third trimester, at about 24–26 weeks of gestational age (Figures 14A to C). During BMV, Inoue balloon is the preferrred technique because of shorter procedure time and low radiation exposure. External shielding and saving fluoroscopic images, avoiding high-dose cineradiography, and reducing the frame rate of fluoroscopy (15 frames/sec
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or lower) reduces radiation toxicity. Avoiding angulated views, working in AP view and keeping intensifier as close as possible to the patient also reduces radiation exposure. Doses greater than 100 mGy should termination of pregnancy be considered on the basis of exposure.
PTMC in Kyphoscoliosis The presence of severe kyphoscoliosis increases the risk of inadverent perforation of neighboring cardiac structures resulting in cardiac tamponade which occurred in our case (Figures 15A to F). Angiography to delineate the LA and IAS profile and septal stain methods of septal puncture facilitate septal puncture. Over-the-wire technique helps in crossing mitral valve in such cases. In some cases, it may be difficult to successfully perform BMV through femoral venous approach. Jugular approach facilitates to successfully perform BMV in kyphoscoliosis.
BMV in Juvenile MS Special features of MS in children are fibrotic, rubbery valve with severe subvalvular disease. Calcification is rare and AF is less common. Significant PAH is seen in majority of children. In our series of 12,550 cases, 4% were less than 10 years (youngest was 7 years old) and 14% were in the age range of 10–20 years. BMV in children appears to be safe and effective similar to adult patients. In the longterm follow-up there was no significant difference in the incidence of restenosis and event-free survival.
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4
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Percutaneous Transvenous Mitral Commissurotomy: Tips and Tricks
A
C
Figures 14A to C: (A) Shielding of gravid abdomen with lead sheet; (B) Balloon catheter over the coiled wire in left atrium (LA); (C) Accura balloon dilatation
A
B
C
D
E
F
Figures 15A to F: (A) Demonstrating severe kyphoscoliosis; (B) Demonstrating two pigtails one in noncoronary cusp (NCC) and the other in pericardial cavity (for pericardiocentesis to treat cardiac tamponade); (C) Septal puncture in right anterior oblique (RAO) view; (D) Balloon catheter passed over the coiled guidewire in left ventricle (LV), balloon prolapsed back; (E) Reverse loop method to enter LV; (F) Successful balloon dilatation
Complications of BMV Death Mortality is usually 0.2–3%.22 The most common causes of death include cardiac tamponade, acute MR, and cerebrovascular events.
Acute Mitral Insufficiency Although varying degree of MR occurs in up to 25% of patients undergoing percutaneous balloon valvotomy (PBV), only 3–8% develops severe MR.23,24 Acute mitral insufficiency results from leaflet tear, annular tear, chordal or papillary muscle rupture, as seen in surgical25
and autopsy 26 findings. Commissural calcification, 27 severe submitral disease, and balloon overinflation are associated with increased risk of this complication. The large regurgitant volume delivered to the relatively noncompliant LA causes an acute increase in LA pressure and V-waves, resulting in acute pulmonary edema. Cardiac output also is impaired, as the acuteness of the MR does not allow the LV to use its compensatory mechanism of preload reserve for pumping the excess volume.2D echo and color Doppler is useful in assessing the site of tear and quantifying MR. Our SJICR data of 50 cases by Manjunath et al. out of 3,855 BMV procedures, 1.3% developed acute severe MR requiring emergency mitral valve replacement 103
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SECTION
2
Symptoms
No.(%)
Hypotension
37 (74%)
Valvular Heart Disease—Rheumatic Heart Disease
Table 3: Symptoms of acute severe mitral regurgitation28
Hypoxia
32 (64%)
Orthopnea
7 (14%)
Pulmonary edema
6 (12%)
Table 4: Causes of acute severe mitral regurgitation 28 No.(%) Anterior mitral leaflet (AML) tear
36 (72%)
Posterior mitral leaflet (PML) tear
5 (12.5%)
Paracommissural tear with annular involvement
7 (14%)
Chordal tear
2 (5%)
(MVR) (Tables 3 and 4).28 In-hospital mortality was 12%. Mortality was higher in those who underwent MVR >24 hours compared with those who underwent urgent MVR (27 kg 1200,000 U IM once 2. Amoxicillin: 50 mg/kg (maximum 1 g) daily orally in 2–3 divided dosage for 10 days 3. Penicillin V: ≤ 27 kg 250 mg 2–3 times daily, > 27 kg 500 mg 2–3 times daily for 10 days
IB
II aB
* Based on the American Heart Association Scientific Statement13
Table 4: Secondary prophylaxis* Rating A. Penicillins: Benzathine penicillin G: zz ≤27 kg 600,000 units IM every 3–4 weeks, zz >27 kg 1200,000 units IM every 3-4 weeks**
IA
Penicillin V: 250 mg twice daily
IB
B. For patients allergic to penicillin: 1. Sulfadiazine: 500 (≤27 kg) to 1000 (≥27 kg) mg once daily orally
IB
2. Macrolide or azalide orally can be given
IC
* Based on the American Heart Association Scientific Statement13 ** For high-risk population 3 weekly dosing is preferred.
Thus, the M-protein-based vaccine is not likely to be effective in preventing GAS infection. The other vaccine targets tried include GAS C5, a peptidase, fibronectinbinding protein sfb 1, and the chimeric peptide J8 from the conserved region of the M-protein.18 Till date, no effective antistreptococcal vaccine is available; and hence, primary prevention of RF at community level has to wait till such time when it becomes available.10,11
Secondary Prevention Secondary prevention of RF consist of preventing infection of the upper respiratory tract with GAS and the development of recurrent rheumatic fever using antibiotics continuously to cases who have had RF or welldocumented RHD.4,19 Secondary prevention is best achieved through comprehensive register-based control program, identifying all cases of RF or RHD, providing health education to parents who should understand the importance of sore throat in causing heart disease and need to get antibiotics for its treatment, to bring children for 3–4 weekly injections of benzathine penicillin to prevent disease progression. The penicillin prophylaxis is necessary due to the fact that RF has a tendency for recurrence in those who had RF in past, each new attack causing further valve damage making the disease worse than before.3,20
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Strategy of secondary prophylaxis has been proven in randomized controlled trials for preventing RF recurrence. A Cochrane meta-analysis concluded that for prevention of RF recurrences intramuscular benzathine penicillin was superior to oral penicillin (penicillin V) (87–96% reduction).21 The regular secondary prophylaxis prevents disease progression and reduces the severity of RHD is proven without doubt.22,23 The antibiotic regimen for secondary prophylaxis is given in Table 4. Benzathine penicillin can be given alone or with lignocaine to reduce injection site pain. The benefits of secondary prophylaxis using benzathine penicillin on long-term outweigh the rare risk of anaphylaxis and fatality. The allergic and anaphylactic reactions to benzathine penicillin are reported in 3.2 and 0.2% patients, respectively; and deaths are extremely rare. 24,25 Table 5 gives the recommended duration of secondary prophylaxis in RF/RHD cases.
Secondary Prophylaxis during Special Situations Pregnancy and Breastfeeding Penicillins and erythromycin are considered safe for use in pregnancy.26 Penicillins are considered safe for use during breastfeeding since their excretion into breast milk is in low concentrations. Erythromycin is also excreted into breast milk in low concentrations and has been considered safe in breast feeding.26
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SECTION
Table 5: Secondary prophylaxis duration*
Valvular Heart Disease—Rheumatic Heart Disease
2
Rating A. Rheumatic heart disease: For 10 years or until 40 years of age or lifelong
IC
B. Rheumatic fever with carditis with no residual valvular disease: For 10 years or until 21 years of age (whichever is longer)
IC
C. Rheumatic fever without carditis: For 5 year or until 21 years of age (whichever is longer)
IC
* Based on the American Heart Association Scientific Statement13
Secondary Prophylaxis in Anticoagulated Patients Benzathine penicillin injections are safe in patients with prosthetic mechanical heart valves who need life-long anticoagulation therapy excepting when there is evidence of active bleeding or the International Normalized Ratio is over 4.5.19
8.
9.
CONCLUSION The combination of primary prevention and long-term secondary prophylaxis strategies makes the prevention and eradication of RHD possible. WHF and its working group on RF and RHD provide the platform for RHD control. Comprehensive RF/RHD control programs (registerbased), benzathine penicillin access globally, developing public leadership for control programs, expanding training hubs and supporting vaccine development are five key strategic targets provided by WHF. 27
ACKNOWLEDGMENTS
10.
11. 12.
13.
We thank Shri Ajay Malviya, Department of Medicine, MGM Medical College, Indore, Madhya Pradesh, India, for secretarial assistance.
REFERENCES
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1. Denny FW, Wannamaker LW, Brink WR, et al. Prevention of rheumatic fever: treatment of preceding streptococcal infection. J Am Med Assoc. 1950;143(2):151-3. 2. Dajani AS. Current status of nonsuppurative complications of group A streptococci. Pediatr Infect Dis J. 1991;10 (10 Suppl):S25-7. 3. Feinstein AR, Spagnuolo M. Mimetic features of rheumatic fever recurrences. N Engl J Med. 1960;262:533-40. 4. World Health Organization. Rheumatic fever and rheumatic heart disease. World Health Organ Tech Rep Ser. 2004;923:1-122. 5. Carapetis JR, Steer AC, Mulholland EK, et al. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5(11):685-94. 6. Ramakrishnan S, Kothari SS, Juneja R, et al. Prevalence of rheumatic heart disease: has it declined in India? Natl Med J India. 2009;22(2):72-4. 7. Kumar R, Sharma M. Jai Vigyan Mission Mode Project on Community Control of Rheumatic Fever/Rheumatic Heart
14.
15.
16.
17.
Disease in India. Comprehensive Project Report (20002010) New Delhi: Indian Council of Medical Research. 2015. pp. 1-160. Bharani A, Tandon R, Sharma N, et al. Prevalence of rheumatic fever/rheumatic heart disease in India: lessons from active surveillance and a passive registry. J Am Coll Cardiol. 2010;55(10A Suppl 1):E1415. Reményi B, Wilson N, Steer A, et al. World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease—an evidence-based guideline. Nat Rev Cardiol. 2012;9(5):297-309. Shah B, Sharma M, Kumar R, et al. Rheumatic heart disease: progress and challenges in India. Indian J Pediatr. 2013;80(Suppl 1):S77-86. Kumar R, Tandon R. Rheumatic fever and rheumatic heart disease: the last 50 years. Indian J Med Res. 2013;137(4):643-58. Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015;131(20):1806-18. Gerber MA, Baltimore RS, Eaten CB, et al. Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009;119(11):1541-51. Veasy LG, Wiedmeier SE, Orsmond GS, et al. Resurgence of acute rheumatic fever in the intermountain area of the Unites States. N Engl J Med. 1987;316(8):421-7. Veasy LG. Lessons learned from the resurgence of rheumatic fever in the United States. In: Narula J, Virmani R, Reddy KS (Eds). editors. Rheumatic fever. Washington DC: American Registry of Pathology. Armed Forces Institute of Pathology; 1999. pp. 69-78. RHD Australia (RF/RHD writing group) National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. The Australian guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic heart disease (2nd edition); 2012. Smeesters PR, McMillan DJ, Sr iprakash KS. The streptococcal M protein: a highly versatile molecule. Trends Microbiol. 2010;18(6):275-82.
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23. Taranta A, Kleinberg E, Feinstein AR, et al. Rheumatic fever in children and adolescents: a long-term epidemiologic study of subsequent prophylaxis, streptococcal infections, and clinical sequelae, V: relation of the rheumatic fever recurrence rate per streptococcal infection to preexisting clinical features of the patients. Part 5. Ann Intern Med. 1964;60:58-67. 24. International Rheumatic Fever Study Group. Allergic reactions to long-term benzathine penicillin prophylaxis for rheumatic fever. Lancet. 1991;337(8753):1308-10. 25. Markowitz M, Lue HC. Allergic reactions in rheumatic fever patients on long-term benzathine penicillin G: the role of skin testing for penicillin allergy. Pediatrics. 1996;97:981-3. 26. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation, 9th edition. Philadelphia: Lippincott Williams & Wilkins; 2011. pp. 831-3. 27 Remenyi B, Carapetis J, Wyber R, et al. Position statement of the World Heart Federation on the prevention and control of rheumatic heart disease. Nat Rev Cardiol. 2013;10(5): 284-92.
CHAPTER
17 Prevention of Rheumatic Fever/Rheumatic Heart Disease
18. McMillan DJ, Davies MR, Browning CL, et al. Prospecting for new group A streptococcal vaccine candidates. Indian J Med Res. 2004;19(Suppl):121-5. 19. Heart Foundation of New Zealand. New Zealand guidelines for rheumatic fever: diagnosis, management and secondary prevention of acute rheumatic fever and rheumatic heart disease: 2014 update. Available at: www.heartfoundation.org.nz 20. Dajani A, Taubert K, Ferrieri P, et al. Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: a statement for health professionals. Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease of the Council on Cardiovascular disease in the young, the American Heart Association. Pediatrics. 1995;96: 758-64. 21. Manyemba J, Mayosi BM. Penicillin for secondary prevention of rheumatic fever. Cochrane Database Syst Rev. 2002;(3):CD002227. 22. Tompkins DG, Boxerbaum B, Liebman J. Long-term prognosis of rheumatic fever patients receiving regular intramuscular benzathine penicillin. Circulation. 1972;45(3):543-51.
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Valvular Heart Disease—Others Newer Valve Guidelines: What Suits Indians and What does not?
Rajiv Ananthakrishna, Srinivas B Chikkaswamy Role of Two- and Three-dimensional Echocardiography in Valvular Lesions
Raziye E Akdogan, Ahmed Y Salama, Hanan Fadala, Navin C Nanda Pitfalls in Assessment of Valvular Heart Disease
Jagdish C Mohan, Vishwas Mohan, Madhu Shukla Nonrheumatic Mitral Regurgitation
CM Nagesh, Laxmi H Shetty Bicuspid Aortic Valve in 2018: What we Must Know?
KM Krishnamoorthy, Deepa S Kumar Low-gradient Aortic Stenosis
Vishal Batra, Mohit D Gupta, Girish MP Infective Endocarditis: What is New?
SK Dwivedi, Mahim Saran Prophylaxis for Infective Endocarditis in India
KH Srinivasa, Nishanth KR Mechanical Prosthetic Valve Thrombosis
S E C T I O N
Ganesan Karthikeyan Percutaneous Valve Interventions beyond Transcatheter
Aortic Valve Implantation
Vijay Kumar Trehan, Safal, Siddhant Trehan
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Newer Valve Guidelines: What Suits Indians and CHAPTER 18 What does not? Rajiv Ananthakrishna, Srinivas B Chikkaswamy
“It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.” —William Osler
INTRODUCTION The burden of valvular heart disease (VHD) in India is significantly high and is a major cause of concern. The spectrum of VHD varies from predominantly rheumatic heart disease (RHD) in adolescents and adulthood, to degenerative valve disease in the elderly. The universal access to health care in India is not optimal and certain modalities of treatment, such as transcatheter valve replacement, remains expensive. Clinical practice guidelines summarize available evidence intended to help clinicians in selecting the optimal strategy for an individual patient with a given condition. The most recent guidelines for the management of VHD are from the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS), and the American Heart Association (AHA)/ American College of Cardiology (ACC).1,2 Management of VHD in Indian population presents unique challenges as the pattern of VHD is distinct, as compared to the Western population. In addition, the population perception regarding VHD, cultural beliefs and socioeconomic conditions are also quite different. In this review, we summarize the salient features of the recent guidelines and relevance to Indian population. It is recommended to go through the 2017 ESC/EACTS, and ACC/AHA guidelines for the management of VHD beforehand, for better understanding of the current review.
VALVULAR HEART DISEASE: THE INDIAN PERSPECTIVE In the era of transcatheter valve interventions, the focus of VHD in India is still predominantly RHD and it continues to be a major cause of morbidity and mortality.3 In one of the largest echocardiographic studies from India regarding the pattern of VHD, RHD was the most common etiology. In addition, multiple valves were involved in more than a third of all the cases.4 RHD is primarily affecting the younger generation during their period of maximum productivity. Consequently, RHD has a devastating impact not only on
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the individual, but the community as well. In developed countries, VHD related to RHD has declined significantly and left-sided degenerative lesions in the elderly were the most common etiology.5 The new guidelines published in 2017 are primarily based on the data from the developed countries. In addition, the percutaneous interventional techniques [transcatheter aortic valve implantation (TAVI), percutaneous mitral valve edge-to-edge repair) are commonly performed in developed countries, while India is still in the early phase of the learning curve.
GENERAL CONSIDERATIONS IN EVALUATING VALVULAR HEART DISEASE Preprocedure patient evaluation and risk stratification are appropriately described in the guidelines. The vital points to be kept in mind are emphasized below: Accurate assessment of symptoms and its correlation to underlying VHD are important in the patient management. 2D echocardiography is the key to assess the etiology, severity and prognosis of patients with VHD. The assessment of severity should not rely on a single criterion, rather a combined approach including various criteria is recommended. Invasive investigations apart from preoperative coronar y angiography is limited to situations where noninvasive evaluation is inconclusive (ventriculography and aortography to assess the severity of regurgitant lesions). The presence of comorbidities and general condition require attention, especially in the elderly patients. Exercise testing is useful to unmask the objective occurrence of symptoms and determine the level of recommended physical activity. There are two important areas to be stressed upon during the evaluation of VHD in Indians. There is a rapid increase in the burden of coronary artery disease (CAD) over the past few decades, and CAD occurs at a younger age in Indians.6,7 During planned intervention or surgery for VHD, the presence of untreated significant CAD has a negative impact on the immediate and long-term patient outcomes. Hence, it is important to determine if concomitant coronary revascularization is indicated.
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Valvular Heart Disease—Others
3
The threshold for the evaluation of CAD should be low, with meticulous assessment of cardiovascular risk factors including family history of premature CAD. The use of stress tests to detect CAD in patients with significant VHD is inappropriate because of their low diagnostic value and possible risks. Coronary angiography is appropriate in patients with intermediate to high probability of CAD. Alternatively, coronary computed tomography (CT) should be considered to exclude CAD in patients at low risk. The concept of ‘Heart Team’ has been endorsed by both the European and ACC/AHA guidelines and is the subject of interest in the management of cardiovascular disease. This allows the patients to have a one-stop shop wherein all the issues are taken care of by a specialist team working together. The main goal of ‘Heart Team’ is to provide a ‘patient-centric’ approach where the alternatives and outcomes of treatment options are discussed in detail, to understand and meet the family expectations. In India, this concept is currently not uniformly implemented. It is recommended the approach of ‘Heart Team’ be adopted in all the major cardiac centers to deliver better quality of care. In dealing with VHD, there are two situations where this concept should be mandatory: (a) Patients at high risk of surgery (based on the EuroSCORE II and the Society of Thoracic Surgeons score) and (b) Surgery or intervention is being planned in an asymptomatic subject with severe VHD.
SPECIFIC VALVULAR LESIONS Mitral Valve Disease Mitral Stenosis
128
The most common cause of mitral stenosis (MS) is RHD. The incidence of rheumatic MS has significantly declined in developed countries, but continues to be endemic in India and is a major public health concern. 8,9 Balloon mitral valvotomy (BMV) is the most common intervention performed for acquired VHD in India, and has had a major impact on the management of rheumatic MS. Guidelines recommend intervention (BMV or surgery) in all patients with a valve area ≤1.5 cm2. However, in our practise, if symptoms are well tolerated, it is reasonable to closely follow-up the patient till the valve area is ≤ 1.0 cm2. The choice of treatment should be decided not only based on the echocardiographic features, but should consider local expertise as well. Considering the vast experience and high-volume BMV centers in India, the following deviations from guidelines may be reasonable: The presence of left atrial thrombus has long been regarded as an absolute contraindication for BMV. As described by Manjunath CN et al., in selected patients of MS and left atrial thrombus (Type Ia, Ib and IIa), BMV can be safely performed with a modified overthe-wire technique.10
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One of the mechanisms of mitral regurgitation (MR) in rheumatic MS is due to restriction of leaflet mobility. Following BMV, there may be improvement in leaflet excursion and consequently degree of MR. Hence, in patients with moderate MR (central jet), it may be reasonable to attempt BMV. In a small study by Desabandhu V et al. BMV was safe and provided sustained symptomatic benefit in patients with severe MS and moderate MR.11 The presence of severe concomitant aortic valve disease is considered a contraindication for BMV. Patients with aortic valve disease have an elevated left ventricular end-diastolic pressure, and these patients are less likely to tolerate mitral regurgitation following BMV. A carefully performed BMV, with active surgical back-up is reasonable in such a setting. If the BMV is successful, aortic valve surgery may be postponed depending on the symptom status, left ventricular function and the rate of progression of aortic valve disease. The most common scoring system to predict the outcome of BMV is the Wilkin’s scoring system.12 Patients with a score ≤ 8 have a favorable outcome following BMV. This scoring system does not assess the commissural calcium, and this is one of the major limitations. The presence of bicommissural calcification is an absolute contraindication for BMV. However, BMV is still feasible in the presence of dense leaflet calcification, provided the commissures are free of calcium. Further, BMV can be performed successfully in the presence of unicommissural calcification. 13 The modality of intervention (BMV vs surgery) in patients with unfavorable anatomy is still a matter of debate. Based on the available literature in Indian patients and local resources, we recommend the following protocol for the management of patients with rheumatic MS (Figures 1 and 2).
Mitral Regurgitation Mitral regurgitation (MR) is a common valvular disorder, and key to the management lies in understanding the etiology and pathophysiology. It is important to distinguish acute from chronic, and primary from secondary MR. In primary MR, one or more of the components of mitral valve apparatus are directly affected resulting in valve incompetence. Although the most frequent etiology of primary MR is a myxomatous mitral valve in developed countries, RHD is the most common etiology in India.4 Acute MR is due to disruption of the mitral valve apparatus. The common causes include infective endocarditis, spontaneous chordal rupture and papillary muscle rupture in the setting of myocardial infarction. Guidelines uniformly recommend urgent surgery for acute severe MR. 1,2 From an Indian perspective, two additional important causes for acute severe MR needs to be considered. First, the presence of rheumatic activity
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CHAPTER
18
contributing to acute MR, especially in adolescents and early adulthood needs to be considered in the differential diagnosis. Majority of these patients are effectively managed with medical therapy. The second scenario is the setting of acute severe MR following BMV. In this setting, early surgery (50 mm Hg and new onset of atrial fibrillation. The essential points from the guidelines relevant to our practise are highlighted below: The decision to intervene based solely on pulmonary artery systolic pressure should be confirmed by right heart catheterization. Mitral valve repair should be the preferred technique of intervention for primary MR when feasible. Surgery should be considered in all symptomatic patients with LVEF of >30%. In asymptomatic subjects, surgery is indicated with the onset of left ventricular dysfunction (left ventricular end-systolic diameter ≥45 mm, LVEF ≤60%), new onset atrial fibrillation or pulmonary artery systolic pressure of >50 mm Hg at rest. In the presence of severe left ventricular systolic dysfunction (EF 30% during coronary artery bypass grafting or LVEF 60 mm Hg confirmed by invasive measurement. The choice of intervention (surgery vs TAVI) should be based on the available resources and individual characteristics after comprehensive evaluation by the ‘Heart Team’. The key factors influencing the decision are the surgical risk score (STS/EuroSCORE II), age of the patient, prior cardiac surgery, frailty, porcelain aorta, prior chest radiation and suitability of access for TAVI. Surgery is recommended in patients at low risk (STS or EuroSCORE II 50 mm (>25 mm/m2 body surface area). In the presence of dilated aorta, accurate measurements of diameter are critical to guide the timing of surgery. Surgery is indicated in Marfan’s syndrome with maximal ascending aortic dimeter ≥50 mm or ≥45
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Tricuspid Valve Disease Tricuspid stenosis is uncommon, while significant tricuspid regurgitation is more often secondary. In the setting of RHD, tricuspid stenosis is often accompanied by tricuspid regurgitation and left-sided valvular lesions. Surgery is indicated for patients with tricuspid stenosis while undergoing valve replacement for left-sided pathology. Percutaneous balloon valvuloplasty for tricuspid stenosis can be performed following a successful BMV or can be attempted if tricuspid stenosis is isolated. Surgery for tricuspid regurgitation is based on the need for left-sided valve surgery, the mechanism and severity of tricuspid regurgitation (primary or secondary), size of the tricuspid annulus, right ventricular function, and severity of pulmonary hypertension. Surgery for tricuspid regurgitation is indicated in: (a) symptomatic severe primary tricuspid regurgitation and (b) at the time of left-sided valve surgery (in the presence of severe secondary tricuspid regurgitation or moderate regurgitation with tricuspid annular dilatation and/or signs of right heart failure).
OTHER CONSIDERATIONS
Combined valvular and multivalvular heart diseases are commonly encountered in RHD. There is a lack of data, with no evidence-based recommendations. In the presence of stenosis and regurgitation on the same valve, treatment should follow the recommendation concerning the predominant VHD. In the presence of balanced lesions (moderate stenosis and regurgitation affecting the same valve), the management should be based on symptoms and hemodynamic consequences rather than the indices of stenosis or regurgitation alone. Similarly, in multivalvular heart disease, it is vital to consider the interaction between different valve lesions. Proximal valvular lesion leads to underestimation of the severity of distal lesion (the presence of mitral regurgitation will underestimate the severity of aortic stenosis). The presence of atrial fibrillation which is common in rheumatic mitral valvular disease, contributes to substantial morbidity and mortality due to increased risk of thromboembolism. During valve surgery, surgical ablation of atrial fibrillation and left atrial appendage excision should be considered. In the presence of risk factors for stroke, long-term
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anticoagulation should be continued postoperatively. The use of nonvitamin K antagonist oral anticoagulants is contraindicated in moderate-to-severe mitral stenosis, and in all patients with a mechanical valve. The choice of prosthetic valve (mechanical vs bioprosthesis) is determined based on the risk of bleeding and the indication for long-term anticoagulation, risk of structural valve deterioration, compliance issues, life expectancy, and the desire of the informed patient. In patients with a mechanical prosthesis, oral anticoagulation with vitamin K antagonist is recommended lifelong. The most devastating complication of a mechanical prosthetic valve is thrombosis. Guidelines recommend urgent valve replacement for obstructive and large (>10 mm) thrombi. In India, most of the cases are managed with fibrinolysis because of the risks associated with reintervention and the higher cost of surgery.
COMMON CASE SCENARIOS IN ROUTINE CLINICAL PRACTICE Mitral Stenosis with Left Atrial Thrombus A 32-year-old female is being evaluated for New York Heart Association (NYHA) class III dyspnea of 6 months duration. Echocardiography reveals RHD, severe MS (valve area of 0.9 cm 2, Wilkin’s score of 8), trivial MR, mild tricuspid regurgitation, pulmonary hypertension (pulmonary artery systolic pressure of 64 mm Hg), and atrial fibrillation with a Type Ib soft left atrial thrombus (clot in left atrial appendage protruding into cavity). Guidelines recommend surgery as the treatment, and BMV is considered a contraindication.1 However, it is reasonable to consider therapeutic anticoagulation for 8–12 weeks and reassess the left atrial thrombus with transesophageal echocardiography. BMV can be safely performed subsequently with a modification of the overthe-wire technique.10
CHAPTER
18 Newer Valve Guidelines: What Suits Indians and What does not?
mm in the presence of additional risk factors. In the presence of bicuspid aortic valve with additional risk factors or coarctation, surgery is indicated with a maximal ascending aortic diameter ≥50 mm. Valve-sparing aortic surgery to be considered in select cases with surgical expertise.
Rheumatic Aortic Stenosis with Left Ventricular Dysfunction A 45-year-old male, known case of RHD, status post BMV 10 years prior, is being treated for congestive cardiac failure. His comorbidities include diabetes mellitus on insulin therapy, severe chronic obstructive lung disease and renal dysfunction (creatinine clearance of 55 mL/ min). Evaluation reveals severe AS (mean gradient of 36 mm Hg, LVEF of 30% with preserved contractile reserve), mild MS (valve area of 1.8 cm2), mild MR, mild TR and pulmonary hypertension (pulmonary artery systolic pressure of 50 mm Hg). The patient is in sinus rhythm, and coronary angiogram is normal. The patient is referred for surgical aortic valve replacement. In view of EuroSCORE II of 6.15%, surgery
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3
is deemed high risk by the ‘Heart Team’. Data on TAVI is limited for patients less than 75 years of age, and all the trials have enrolled degenerative tricuspid aortic valve disease. In the given scenario, the indication for TAVI may have to be expanded, and should be considered in rheumatic AS who are not candidates for surgery.15
Rheumatic Multivalvular Heart Disease A 37-year-old male is admitted with NYHA class II dyspnea of 12 months duration. Evaluation reveals RHD, severe MS (valve area of 1.0 cm2, Wilkin’s score of 9), mild MR, severe AR (left ventricular end-systolic diameter of 41 mm), mild aortic stenosis (gradient of 43/27 mm Hg), mild tricuspid regurgitation, and pulmonary hypertension (pulmonary artery systolic pressure of 55 mm Hg). The LVEF is 60%. In the presence of severe concomitant aortic valve disease, BMV is contraindicated.1 In the given case, the symptoms are likely due to severe MS. It is reasonable to perform BMV with active surgical backup. Following a successful BMV, the symptoms should be reassessed and the need for aortic valve replacement can be considered later depending on the indication. An initial strategy of double valve replacement, with a higher mortality rate can be avoided.
THE FUTURE There have been specific Indian guidelines and consensus for the management of pediatric acute rheumatic fever, hypertension, dyslipidemia, and ST elevation myocardial infarction.16-19 The burden of VHD in India is alarmingly high and is a major health problem. Therefore, it is imperative that guidelines be set for the management of VHD in Indians, with special focus on RHD and newer modalities of percutaneous intervention.
CONCLUSION The recent guidelines (2017 ESC/EACTS, and ACC/AHA) have a global impact and facilitate decision making in daily practice for majority of the cases. The concept of ‘Heart Team’ approach should be uniformly implemented in all the tertiary cardiac care centers in India, to plan on the best treatment strategy for a given patient. Based on clinical judgement, deviations from guidelines may be appropriate in certain clinical circumstances depending on the local available resources and the wishes of the wellinformed patients.
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1. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38(36):2739-91. 2. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ ACC Focused Update of the 2014 AHA/ACC Guideline for the management of patients with valvular heart disease. A report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017;135(25): e1159-95.
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3. Arora S, Ramm CJ, Bahekar AA, et al. Evaluating health of emerging economies through the eyes of heart valve disease in the transcatheter era. Glob Heart. 2017;12(4):301-4. 4. Manjunath CN, Srinivas P, Ravindranath KS et al. Incidence and patterns of valvular heart disease in a tertiary care highvolume cardiac center: a single center experience. Indian Heart J. 2014; 66(3):320-6. 5. Andell P, Li X, Martinsson A, et al. Epidemiology of valvular heart disease in a Swedish nationwide hospitalbased register study. Heart. 2017;103(21):1696-703. 6. Prabhakaran D, Jeemon P, Roy A. Cardiovascular diseases in India: current epidemiology and future directions. Circulation. 2016;133(16):1605-20. 7. Iyengar SS, Gupta R, Ravi S, et al. Premature coronary artery disease in India: coronary artery disease in the young (CADY) registry. Indian Heart J. 2017; 69(2):211-6. 8. Iung B, Vahanian A. Epidemiology of acquired valvular heart disease. Can J Cardiol. 2014;30(9):962–70. 9. Shah B, Sharma M, Kumar R, et al . Rheumatic heart disease: progress and challenges in India. Indian J Pediatr.2013;80 Suppl 1:S77-86. 10. Manjunath CN, Srinivasa KH, Ravindranath KS, et al. Balloon mitral valvotomy in patients with mitral stenosis and left atrial thrombus. Catheter Cardiovasc Interv. 2009;74(4):653–61. 11. Desabandhu V, Peringadan NG, Krishnan MN. Safety and efficacy of percutaneous balloon mitral valvotomy in severe mitral stenosis with moderate mitral regurgitation: a prospective study. Indian Heart J. 2016;68(6):783-7. 12. Wilkins GT, Weyman AE, Abascal VM, et al. Percutaneous balloon dilatation of the mitral valve: an analysis of echocardiographic variables related to outcome and the mechanism of dilatation. Br Heart J. 1988;60(4):299–308. 13. Khandenahally Shankarappa R, Dwarakaprasad R, Karur S, et al. Balloon mitral valvotomy for calcific mitral stenosis. JACC Cardiovasc Interv. 2009;2(3):263-4. 14. Nanjappa MC, Ananthakrishna R, Hemanna Setty SK, et al. Acute severe mitral regurgitation following balloon mitral valvotomy: echocardiographic features, operative findings, and outcome in 50 surgical cases. Catheter Cardiovasc Interv. 2013;81(4):603-8. 15. Gunasekaran S, Ganesapandi R, Sivaprakasam MC, et al. SAPIEN 3 valve implantation in rheumatic aortic stenosis with a functioning mitral prosthesis: first case report from India. AsiaIntervention. 2018;4:35-7. 16. Working Group on Pediatric Acute Rheumatic Fever and Cardiology Chapter of Indian Academy of Pediatrics, Saxena A, Kumar RK, Gera RP, et al. Consensus guidelines on pediatric acute rheumatic fever and rheumatic heart disease. Indian Pediatr. 2008;45(7):565-73. 17. Association of Physicians of India. Indian guidelines on hypertension (I.G.H.) - III. 2013. J Assoc Physicians India. 2013;61(2 Suppl):6-36. 18. Iyengar SS, Puri R, Narasingan SN, et al. Lipid Association of India Expert Consensus Statement on Management of Dyslipidemia in Indians 2016: Part 1. J Assoc Physicians India. 2016;64(3):7-52. 19. Guha S, Sethi R, Ray S, Bahl VK, et al. Cardiological Society of India: Position statement for the management of ST elevation myocardial infarction in India. Indian Heart J. 2017;69(Suppl 1):S63-97.
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Role of Two- and Threedimensional Echocardiography CHAPTER 19 in Valvular Lesions Raziye E Akdogan, Ahmed Y Salama, Hanan Fadala, Navin C Nanda
INTRODUCTION Echocardiography has become an indispensable modality in the noninvasive assessment of cardiac valvular disease entities. Many patient-related decisions in day-to-day clinical practice are based on this technology and recourse to other modalities including cardiac catheterization has been obviated in a large number of patients leading to cost savings and reduced morbidity.1-3
MITRAL STENOSIS AND REGURGITATION (TABLES 1 TO 7 AND FIGURES 1 TO 6) The most common cause of mitral stenosis in developing countries is rheumatic involvement and presents on M-mode echo with a decreased diastolic slope, absence of A wave in patients with normal sinus rhythm, posterior mitral leaflet moving parallel to anterior leaflet, and multiple linear bright echoes due to calcification and collagen deposition. On real-time two-dimensional
transthoracic (2DTTE) and 2D-transesophageal echocardiography (2DTEE), diastolic doming with a typical hockey stick appearance of the mitral leaflets, commissural fusion with narrowing of the mitral orifice as well as thickening and shortening of the subvalvular mitral apparatus are noted. Because of enlargement of the left atrium from mitral orifice obstruction with consequent low flow state, thrombi may form in the left atrial appendage and occasionally in the body of the left atrium. Most commonly, severity of mitral stenosis is estimated by 2D echo by planimetry of the mitral orifice at its flow-limiting tip and noting increased velocities and pressure gradients across the mitral valve by conventional Doppler methods. The pressure half-time method derived from Doppler gradients has also been found useful in deriving mitral orifice area in patients with mitral stenosis. Pitfalls in using 2D/echo Doppler techniques and how some of them can be avoided are described in the accompanying Tables 1 to 7. Live/real-time three-/four-dimensional (3D/4D)
Table 1: Causes of mitral stenosis Rheumatic heart disease Most common cause worldwide. Commissural fusion, thick MV leaflets with restricted mobility, thickened and shortened chordae Severe mitral annular calcification Age-related changes, chronic kidney disease Congenital Double orifice MV, parachute MV (caused by either one papillary muscle, two fused papillary muscles, or chordae attached to one head of a papillary muscle), congenitally thickened or dysplastic MV leaflets Secondary to systemic disease (may result in thickened and restricted leaflets/chordae) SLE, MPS, Fabry’s disease, carcinoid disease, endomyocardial fibrosis, Whipple’s disease Infective endocarditis (vegetations)/tumor (left atrial myxoma)/ball valve thrombus When large may obstruct MV orifice Radiation induced Thick MV with stenosis may occur 10–20 years after radiation Abbreviations: MV, mitral valve; MPS, mucopolysaccharidosis; SLE, systemic lupus erythematosus
Table 2: Diagnosis of mitral stenosis by echocardiography M-mode findings Decreased MV diastolic E–F slope, multiple linear echoes suggestive of thickening/calcification, posterior MV leaflet (PML) moves parallel to anterior MV leaflet (AML), absence of mitral A-wave in patients in normal sinus rhythm 2D echo findings Morphology of MV/subvalvular apparatus: Thickened (>4 mm), calcified (increased echogenicity), and deformed MV. Diastolic doming of the AML, restricted movement of PML; fusion of commissures with reduced MV orifice area, shortened and thickened subvalvular structures with increased echogenicity 3D echo findings Same as 2D echo but more accurate Abbreviations: Echo, echocardiography; MV, mitral valve; 2D, two-dimensional; 3D, three-dimensional
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Table 3: Assessment of mitral stenosis severity
Valvular Heart Disease—Others
3
Severity
Mild
Moderate
Severe
MVA by direct 2D/3D TTE/TEE planimetry (cm²)a,b
>1.5
1–1.5
220
Mean pressure gradient by 2DTTE/ TEE (mm Hg)d
10
Supportive finding: Pulmonary artery systolic pressure (mm Hg)
50
Pressure half-time (PHT) method by 2DTTE/TEE (ms)c
PHT divided by 220 gives MV area in cm2 since PHT of 220 ms equals MVA of 1.0 cm2 a
Planimetry is not affected by cardiac chamber compliance or associated valvular lesions. However, reflections from heavily calcified MV or very high 2D gain may cause MV orifice to appear falsely smaller. MVA is averaged from several beats in AF. b 3DTTE/TEE is the gold standard for MV planimetry because the cutting plane can be placed exactly parallel to the MV orifice at the tip that may not be possible by 2DTTE/TEE because MV is not viewed in three dimensions. c Changes in LV/LA compliance or pressure across MV will affect PHT (significant AR, diastolic heart failure, restrictive cardiomyopathy, constrictive pericarditis, following MV valvuloplasty). d Tachycardia, significant MR and anemia can increase the gradient leading to overestimation of MS while low cardiac output states decrease the gradient causing underestimation. Abbreviations: AF, atrial fibrillation; AR, aortic regurgitation; LA, left atrium; LV, left ventricle; MV, mitral valve; MVA, mitral valve area; MS, mitral stenosis; MR, mitral regurgitation; PHT, pressure half time; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography; 2D, two-dimensional; 3D, three-dimensional. Source: Reproduced with modification and permission from Nanda NC, Karakus G, Degirmencioglu A; Manual of Echocardiography, Jaypee Brothers, New Delhi, India; 2016.
TTE/TEE provides incremental value over 2D echo and is currently considered the gold standard in the assessment of mitral stenosis severity.4 This is because the entire mitral valve together with the surrounding structures can be captured in the 3D data set allowing examination from multiple vantage points including en face visualization of the mitral orifice from both atrial and ventricular aspects. The cropping plane can be placed exactly parallel to the mitral orifice at its tip providing the most accurate assessment of stenosis severity. The 3D echo also facilitates systematic and comprehensive step-by-step examination of the left atrium and appendage for thrombi; and when present, they can be sectioned to evaluate the presence, extent, and progression of echolucent areas related to lysis (liquefaction) and eventual clot dissolution. In contrast, 2D echo provides only a thin slice of a cardiac structure, such as the mitral valve, at any given time making it difficult to ascertain whether the section taken is indeed parallel to the orifice tip potentially leading to inaccuracies in orifice area measurement. This limitation of 2D echo also precludes systematic and complete examination of the left atrium and appendage for thrombi which can be easily missed, especially if they are small. Regarding mitral regurgitation, 2D echo/Doppler provides a reasonably reliable semi-quantitative assessment of severity. Mitral regurgitation jet area by color Doppler occupying more than 40% of the left area cavity is a good indicator of severe mitral incompetence provided careful attention is paid to the Nyquist limit and color gain as outlined in the Tables 1 to 7 in this section. In most patients, eye balling is enough to judge the proportion of mitral regurgitation color Doppler signals occupying the left atrium which is a distinct advantage since complicated measurements are avoided. Eccentric
Table 4: Assessment of mitral valve morphology in mitral stenosis (Wilkins score) by 2DTTE/TEE Grade
134
Mobility
Thickening¹
Calcification
Subvalvular thickening
1
Highly mobile MV with only leaflet tips restricted
MV near normal in thickness (4–5 mm)
A single area of increased echo brightness
Minimal thickening just below MV
2
MV mid and base portions have normal mobility
Mid leaflets normal, considerable thickening of margins (5–8 mm)
Scattered areas of brightness confined to leaflet margins
Thickening of chordal structures extending to onethird of chordal length
3
MV continues to move forward in diastole, mainly from base
Thickening extending through the entire MV (5–8 mm)
Brightness extending into the mid-portions of MV
Thickening extends to distal third of chordae
4
No or minimal forward movement of MV in diastole
Considerable thickening of MV (>8–10 mm)
Extensive brightness throughout much of MV
Extensive thickening and shortening of all chordal structures extending down to papillary muscles
Abbreviations: LA, left atrium; LAA, left atrial appendage; MV, mitral valve; MR, mitral regurgitation; MVBV, mitral balloon valvuloplasty; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography; 3D, three-dimensional Note: Sum of four parameters (Wilkins score) 11 suboptimal results and score of 16 is a contraindication for MVBV. Wilkins score does not take into account MV commissural thickening/ calcification which if significant results in poor outcome (commissural tear with severe MR). Also, does not take into account presence of thrombus in LA body (contraindication for MVBV) or LAA (relative contraindication) and other comorbidities. MV, commissures and chordae often better visualized by 3DTTE/TEE. ¹ MV thickening may be more objectively done by comparing MV thickness to posterior aortic wall thickness. Normal ratio 5 severe MV thickening Source: Reproduced with modification and permission from Nanda NC, Karakus G, Degirmencioglu A. Manual of Echocardiography, Jaypee Brothers, New Delhi, India; 2016.
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Table 5: Causes of primary mitral regurgitation
CHAPTER
Rheumatic heart disease: Most common cause in developing countries. Thickened and distorted MV. Often associated mitral stenosis
19
Myxomatous degeneration/MV prolapse (Marfan syndrome, Ehler-Danlos syndrome, Barlow’s disease, fibroelastic disease): Leaflets are thickened/redundant and prolapse beyond the annular plane into left atrium. MV chordae may rupture. Mitral annular calcification: Age-related changes, chronic kidney disease Calcification may involve MV base and body, tip usually free. MR occurs because of MV leaflet malcoaptation and annulus dysfunction. MV or LV papillary muscle injury: Direct/indirect chest wall trauma, LV infarction especially inferior wall Congenital: MV clefts, parachute mitral valve Secondary to systemic disease: Collagen vascular disease, carcinoid syndrome, hypereosinophilic syndrome. Thickened MV. Drug induced: Anorectic drugs, dopamine agonists, ergot derivatives. Thickened MV. Abbreviations: LV, left ventricle; MR, mitral regurgitation; MV, mitral valve.
Figure 2: Rheumatic mitral stenosis and regurgitation. Twodimensional transthoracic echocardiography. Parasternal long-axis view. Shows thickened noncoapting mitral leaflets resulting in severe mitral regurgitation (MR). The left atrium is severely enlarged. Abbreviations as in Figure 1 Source: Reproduced with permission from Nanda, NC (Ed). Comprehensive Textbook of Echocardiography, Jaypee Brothers Medical Publishers, New Delhi, India; 2013;1:865.
Table 6: Causes of functional mitral regurgitation Ischemic MR: MV leaflet tethering and displacement of coaptation point into LV produced by LV remodeling and dilatation with displacement of papillary muscles apically and laterally from myocardial infarction. Results in reduced/malcoaptation of MV with often asymmetric MR. MV annulus may be flattened. ‘Sea gull’ appearance of MV may result from a kink in the mid-portion of anterior leaflet produced by a stretched strut chord.
Role of Two- and Three-dimensional Echocardiography in Valvular Lesions
Infective/marantic endocarditis/tumors: Most common cause in developed countries. Destruction of MV tissue. Vegetations seen as thickening or mobile masses involving MV
Nonischemic MR: Dilated CMP, long-standing HT, restrictive CMP, hypertrophic CMP (MR commonly pansystolic but may be nonpansystolic if it results from SAM). Mechanism same as above but MR often symmetric as LV dilatation symmetric. AF results in MR from dilated LA and MV annulus. RV pacing (especially apical) creates LV dyssynchrony which may lead to MR. Abbreviations: AF, atrial fibrillation; CMP, cardiomyopathy; HT, systemic hypertension; LA, left atrium; LV, left ventricle; MR, mitral regurgitation; MV, mitral valve; RV, right ventricle; SAM, systolic anterior motion
Figure 1: Rheumatic mitral stenosis. Two-dimensional transthoracic directed M-mode echocardiography. Note the flat mitral valve (MV) diastolic slope and thickening Abbreviations: AO, aortic valve; LA, left atrium; LV, left ventricle; RV, right ventricle.
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Figure 3: Rheumatic mitral stenosis. Live/real time three-dimensional transthoracic echocardiography. Arrow head points to the tip of the narrow MV orifice Abbreviations as in previous Figures Source: Reproduced with permission from Singh V, Nanda NC, Agrawal G, et al. Live three-dimensional echocardiographic assessment of mitral stenosis. Echocardiography. 2003;20:743-50.
mitral regurgitation can also be graded successfully if the area of the laminar flow signals moving and swirling with the turbulent portion of the regurgitation is also added when evaluating regurgitation severity. This is an important consideration and one needs to realize that when the eccentric jet impinges on the adjoining leaflet or left atrial wall immediately after its exit from the mitral valve, it loses its energy and the high velocity mosaic colored turbulent flow signals are reduced to low velocity laminar red and blue signals; but they are still part of mitral regurgitation; and hence need to be taken into account when assessing the regurgitation area. However, quantitative assessment of mitral regurgitation
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Valvular Heart Disease—Others
3
A
B
C
D
Figures 4A to D: Rheumatic mitral stenosis and regurgitation. Live/real time three-dimensional color Doppler transthoracic echocardiographic technique for assessment of mitral regurgitation vena contracta (VC) area. 3D color Doppler data set showing MR, (A) cropped from top to the level of the VC (arrowhead, B) and tilted to view it en face (C and D) Other abbreviations as in previous Figures Source: Reproduced with permission from Khanna D, Vengala S, Miller AP, Nanda NC, Lloyd SG, Ahmed S, et al. Quantification of mitral regurgitation by live three-dimensional transthoracic echocardiographic measurements of vena contracta area. Echocardiography. 2004;21:737-43
A
B
Figures 5A and B: Mitral valve prolapse with ruptured chordae tendinae. Live/real time three-dimensional transesophageal echocardiography. (A) Arrowheads point to some of the ruptured chordae of P2 and P3 scallops of posterior mitral leaflet (PML). Both P2 and P3 scallops show prominent prolapse; (B) Arrowhead shows a ruptured chord of severely prolapsing A2 segment of anterior mitral leaflet (AML) in another patient Abbreviation: LAA, left atrial appendage Other abbreviations as in previous figures Source: Reproduced with permission from Manda J, Kesanolla S, Hsuing MC, Nanda NC, et al. Comparison of real time two-dimensional with live/real time three-dimensional transesophageal echocardiography in the evaluation of mitral valve prolapse and chordae rupture. Echocardiography. 2008;25(10):1131–7.
136
severity requires the use of 3D TTE/TEE. This is because the cropping plane in the 3D color Doppler data set can be positioned exactly parallel to the vena contracta and its size accurately planimetered in short axis. The vena contracta essentially represents the ‘hole’ in the mitral valve through which regurgitation occurs and the larger the size, the more severe is the regurgitation. Using the Doppler principle, the regurgitation volume
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can be quantified by multiplying the vena contracta area with the velocity time integral of the regurgitation jet obtained by conventional continuous wave Doppler. 5,6 With 2D echo, only one or two dimensions of the vena contracta can be measured and even if one is able to view it in short axis in an occasional patient, it is not possible to decide whether the plane passing through it is parallel or obliquely oriented compromising the validity of vena
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Abbreviations: AO, aortic; CW, continuous wave; EROA, effective regurgitant orifice area; LA, left atrium; LV, left ventricle; MV, mitral valve; MR, mitral regurgitation; OR, operating room; PISA, proximal isovelocity surface area; Vol, volume; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography; VTI, velocity time integral; 2D, two-dimensional; 3D, three-dimensional ¹ Influenced by many other factors (LV diastolic function, atrial fibrillation, LA pressure, etc.) ² aKeep Nyquist limit between 50 and 60 cm/s and b adjust color gain so it is just below the level at which one observes artifactual stationary echoes (random noise).c In eccentric MR, laminar blue/red signals swirling and moving with mosaic turbulent flow signals also represent MR and need to be taken into account to avoid underestimation of MR severity. Thus, area of laminar signals should be added to area of turbulent signals to assess MR severity. Also, check if MR is pansystolic or not. Quantitation of nonpansystolic MR is similar to nonpansystolic TR and is described under TR severity assessment (Section III, Table 3) ³The PISA method is based on the assumption it is hemispherical in shape which is mostly incorrect.
Figure 6: Mitral valve prolapse. Live/real time three-dimensional transesophageal echocardiography. Mitral valve quantification analysis demonstrates the extent of A1 prolapse Abbreviations: AL, anterolateral; PM, posteromedial; P, posterior Other abbreviations as in previous figures
CHAPTER
19 Role of Two- and Three-dimensional Echocardiography in Valvular Lesions
Table 7: Assessment of mitral regurgitation severity by echocardiography MR severity (MR diagnosed by noting reverse color Mild Moderate Severe Doppler flow signals moving from LV into LA) Mitral valve morphology Flail MV with ruptured chordae, ruptured papillary muscle, systolic noncoaptation of MV leaflets, severe tenting of MV, systolic expansion of LA (very useful criteria If present) LV and LA size¹ Mostly normal Normal or mild Mostly dilated dilatation Mitral inflow¹ A-wave dominant Variable E-wave >1.5 m/sec Pulmonary vein flow Mostly normal Normal or systolic Systolic flow reversal blunting (very useful in OR for checking residual MR severity) MV/AO TVI >1.4 Maximum MR jet area using multiple planes/LA 40% area in the same frame² (Most commonly used criterion in clinical practice) >10 (15) MR jet area by TEE (LA area not used as LA posterior wall not fully visualized) cm2 commonly used in OR and catheterization laboratory MR jet intensity and contour by CW Doppler Faint/Partial or Dense/Parabolic Dense and triangular parabolic or triangular Vena contracta width (cm) by 2D color Doppler 65%
PR jet length extension
Within 1 cm of TV2
PR index (PR duration/total diastole)
50% cases of MR and echocardiography remains the only bedside modality for its accurate diagnosis. Quantification of MR severity, rather than inaccurate, eyeball grading of color Doppler jets, has been encouraged. Quantitative parameters for severe MR include regurgitant fraction ≥50%, regurgitant volume ≥60 mL, and effective regurgitant orifice area ≥0.4 cm2. Newer 3D-based quantification methods effectively
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CHAPTER
20
Figure 2: Systolic blood flow movement in left heart by color Doppler. Turbulent jet of mitral regurgitation is seen crossing the mitral valve (red ring) and spreading in the left atrium to a variable extent depending upon the physical constraints Abbreviation: LV, left ventricle
Figure 3: Regurgitant fraction (RF) is ratio of mitral stroke volumeaortic stroke volume/mitral stroke volume Abbreviations: LV, left ventricular; IVCT, isovolumic contraction time; IVRT, isovolumic relaxation time; ECG; electrocardiogram
Figure 4: Two jets of mitral regurgitation in transesophageal echocardiography (TEE) view Abbreviations: LA, left atrium; LV, left ventricle; MV, mitral valve; LAA: left atrial appendage
overcome the limitations of 2D methods for assessing severity and mechanism of regurgitation and provide new cut-off values for the estimation of severity of MR. The basic principle of flow quantification in MR hinges on the accurate measurement of flow velocity and the cross-sectional area of the regurgitant flow, the two multiplied providing flow rate, and flow rate integrated over time providing flow volume (Figures 1 and 2). Total amount of blood flow which goes to the left atrium (LA) per beat is called regurgitant volume. Re gurgitant volume nor malize d to total left ventricular (LV) stroke volume (SV) is regurgitation fraction (Figure 3). The orifice through which regurgitant volume enters the LA is called effective regurgitant orifice area (EROA). There can be more than one such orifices of different shapes and also of dynamic nature (Figure 4).
Mitral valve repair may also result in two orifices which leak to some extent. All these parameters are used to judge severity of MR.8 Total LV SV can be obtained by 2D or 3D echocardiographic volumetry. Forward SV can be obtained from LV outflow tract flow using the formula of: volume = area × velocity-time intergral. Table 1 provides criteria for volumetric severity of MR.9
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Pitfalls in Assessment of Valvular Heart Disease
Figure 1: Schematic diagram showing mitral regurgitation during systole Abbreviations: Ao, aorta; LA, left atrium; LV, left ventricle
Sources of Variations during Assessment
The regurgitant volume (RV) depends upon the regurgitant orifice and the systolic pressure gradient between LV and LA. The observed degree of MR depends on hemodynamic conditions at the time of examination.9 Any increase in preload or afterload, and any decrease in myocardial contractility, causes LV dilatation, enlargement of the mitral annulus, and an increase in EROA. Vice versa also occurs especially after inducing anesthesia.
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Table 1: Regurgitant volume and regurgitant orifice area to assess severity of organic mitral regurgitation [American College of Cardiology/American Heart Association (ACC/AHA, 2014)]
Valvular Heart Disease—Others
3
Quantification of organic MR based upon regurgitant volume (RV) z z z z
Absent: Mild: Moderate: Severe: RV
0 RV RV ≤ 30 mL (ERO ≤20 mm2) 31–59 (ERO 21–39 mm2) ≥60 mL (ERO > 40 mm2)
Abbreviation: ERO, effective regurgitant orifice
In acute MR, the atrium is noncompliant ; and therefore, mechanical energy generated by the left ventricle causes an increase in intra-atrial pressure. Acute MR in RHD can occur in rheumatic carditis or valve tear during balloon mitral valvuloplasty (Figures 5 and 6). In chronic MR, the atrium is more compliant; and therefore, mechanical energy generated by the ventricle causes volume overload and atrial enlargement rather than an increase in intra-atrial pressure (Figures 6 and 7). In severe MR, transthoracic echocardiography (TTE) shows left atrial and ventricular enlargement. Without LV enlargement, it is not correct to diagnose significant MR.
Figure 5: Schematic diagram displaying continuous-wave Doppler spectrum of acute mitral regurgitation. Large V wave of left atrial pressure cut-off the ascending limb obliquely Abbreviations: MR, mitral regurgitation; LV, left ventricle; LA, left atrium
METHODS TO ASSESS SEVERITY OF RHEUMATIC MITRAL REGURGITATION There are several indirect clues to the severity of MR such as LA and LV enlargement, dense continuous-wave (CW) Doppler spectrum, pulmonary vein systolic flow reversal, increased mitral flow E wave velocity (>1.50 m/sec) in the absence of mitral stenosis (MS), and en face view of the mitral valve during systole in 3D. 9 However, in clinical practice, the following methods are routinely used.
Figure 6: Different continuous-wave Doppler spectrum of chronic versus acute mitral regurgitation
Color Flow Jet Area in Left Atrium
150
Not long back, at default Nyquist limits, MR color jet area in the LA was predominantly used to assess the severity of MR. A color jet area 1.4 indicates severe MR. This ratio 4.0 (mean G > 40)
≤1.0
The TR should be routinely followed by echocardiography after left-sided valve intervention.
ASSESSMENT OF AORTIC VALVE Complete assessment of the degree of AS requires: Measurement of the transvalvular flow Determination of the transvalvular pressure gradient Calculation of the AVA Calculation of energy loss coefficient Calculation of valvuloarterial impedance (may not be relevant in rheumatic AS). Conventionally, severity of AS is judged by the above parameters using criteria shown in Table 4.38,39 Recent ACC/AHA guidelines first published in 2014 and then updated in 2017, have labeled mild and moderate AS as progressive AS. 9 These guidelines redefine truly severe AS that having AVA 40 mm Hg with symptoms of angina or syncope or ischemic ST-T–wave changes on electrocardiography at rest or with exercise. The gradients recommended are in patients sedated during cardiac catheterization. Catheter gradients in patients under general anesthesia may be lower. High-peak instantaneous gradients of transthoracic echocardiography do not equate to peak-to-peak or simultaneous gradients in the catheter laboratory. Class IIb recommendations are for asymptomatic patients with a catheter-obtained peak systolic gradient of 50 mm Hg. Also, BV should be performed irrespective of the gradient if systolic ventricular dysfunction is present.
Procedure of Balloon Valvuloplasty
CHAPTER
22 Bicuspid Aortic Valve in 2018: What we Must Know?
ventricular function. With improved catheterization techniques, BV has little mortality and minimal morbidity and is the intervention of choice in most centers for severe congenital AS.16
Sick newborns need monitoring of central venous and arterial pressure as well as urine output. They are electively ventilated. Prostaglandin infusion is useful to keep ductus open and maintain systemic perfusion. Babies in cardiogenic shock need require ionotropic support. Hypoglycemia should not be overlooked. The BV is performed under general anesthesia. Deep sedation may be considered in older patients undergoing nonemergent BV. In neonates, infants, and critically ill patients, a 4F short sheath is placed at the access site and the valve is crossed with a 0.018-inch floppy-tipped wire advanced through a 4F Judkins right catheter. Annulus is measured from preprocedural transthoracic echocardiography. A low-profile Tyshak Mini balloon (NuMEDInc, Hopkinton, NY, USA) is used to dilate the valve. A balloon 2 cm in length and 1 mm less than the measured annular diameter is used. Balloon to annulus diameters of >1 leads high incidence of postprocedural AR. 26 Gradients following dilatation may be estimated with a Multitrack Catheter (NuMEDInc) or a 5F guide in a larger child. Rapid right ventricular pacing is usually not required in neonates as the heart rate is fast and stroke volume small. In older children, the valve is crossed with a 0.035-inch straight-tipped guide and exchanged for a stiffer 0.035inch J-tipped wire kept in the left ventricular apex. Pacing is done to reduce systolic blood pressure. Aortogram may be considered to assess the degree of postvalvuloplasty AR. A balloon diameter to aortic valve annulus diameter ratio of 0.9:1 is recommended. Dilemma may be faced in deciding to upsize (or not) the balloon with moderate residual gradients. Increasing the balloon size leads to a lower residual gradient and, therefore, longer freedom from AVR. This may also result in an increased amount of AR which would negate the above benefit. 195
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Valvular Heart Disease—Others
3
Complications of Balloon Valvuloplasty Postprocedural AR Femoral arterial compromise Thromboembolic events Cardiac arrhythmias including complete heart block Damage to the mitral valve, in antegrade venous approach Perforation of the ventricular myocardium. Moderate-to-severe AR is an independent predictor for earlier surgical reintervention following valvuloplasty.27 The incidence of AR is approximately 25%,27 with higher risk in older patients. There are reports of progressive AR over time irrespective of the initial balloon size used and may be related to valve morphology. 28 Femoral arterial compromise is particularly common in neonates and infants. Alternative arterial access has less chances of arterial compromise, and may be useful in younger infants.20
Outcome after Balloon Valvuloplasty Although excellent gradient relief is obtained after BV, reintervention is required with eventual surgical repair or replacement of the valve. Mean survival free from valve reintervention at 5 years was 72%. A lower postdilation gradient and less postdilation AR leads to longer freedom from AVR.27 Less than 50% required valve replacement at 20 years of follow-up. Lower postdilatation gradient and lower grade of AR were associated with longer freedom from AVR. Even mild postprocedural AR was associated with the need for valve replacement. This suggests that AR may worsen with time. Based on age at BV, patients undergoing BV 1 month had 70% surgery-free survival.29 Another study30 showed balloon reinterventions were more common in newborns (16%) than in those outside the newborn period (10%). This multicentric study of 1,004 patients showed a surgery-free survival of 70% at 5 years and 50% at 10 years of followup. Patients with functionally bicuspid valves had better outcomes compared functionally unicuspid, dysplastic, true bicuspid, and true unicuspid valves.31 One study evaluated outcomes in neonates undergoing either surgical valvotomy or balloon valvuloplasty for critical AS.32 Higher residual transvalvar gradients were present in the surgical group, whereas significant AR was seen more commonly in balloon valvuloplasty group. Time-related survival was 72% at 5 years, similar in both groups. Freedom from reintervention was 48% at 5 years, with no difference seen between the groups. Results are similar in older children and adults in spite of a perception that surgery is more appropriate in them.33 Another study showed that gradient reduction, AR and the need for reintervention were worse for BV.34 In a systematic review and meta-analysis 13 to compare survival in children
after (BV) and surgical aortic valvotomy (SAV), it was found that there was no difference between SAV and BV in hospital mortality or moderate AR at discharge. Also, there was no difference in long-term survival or freedom from AVR. There was more reintervention in the BV group. First surgery is not curative and these patients still have a reoperation risk as they age, with additional comorbidities. The more complex the initial operation is, the more challenging the second operation may be, with an incremental operative risk. This is a more realistic concern than the risk of aortic dissection.35
SURGICAL AORTIC VALVULOPLASTY The infant is assessed for a biventricular surgery. Absolute indications for surgical aortic valvuloplasty (SAV) are the need for a single ventricle repair and the presence of additional defects that require surgical intervention on their own merit: small aortic annulus, sub- or supra-valvar AS, coarctation, etc. A relative indication is dysplastic aortic, with no clear leaflets or commissures. Follow-up over 3 decades of 67 slightly older children, showed that congenital AS in children can be controlled surgically until adulthood.36 Most patients will need eventual aortic valve repair, replacement, or even cardiac transplantation. Severe residual AS/AR, left ventricular or dysfunction are indications for AVR. This is deferred off as long as possible in children with small annuli, monitoring LV function. This ensures an optimal patient-valve match for better valve longevity and interval between re-do surgery. Options for AVR are: mechanical prosthetic or bioprosthetic valves, Ross procedure and recently, transcutaneous aortic valve implantation.
INDICATIONS OF SURGERY FOR AORTOPATHY In asymptomatic patients with BAV, if the diameter of the aortic root or ascending aorta is >5.5 cm, then operative intervention to repair or replace the aortic root (sinuses) or replace the ascending aorta is class I indication, level of evidence B.37 Cutoff is reduced to 50 mm in patients with a family history of dissection or in whom dilatation progression is >5 mm/year. When AVR is done in a BAV patient, aorta is to be repaired if it measures >45 mm.38
PREGNANCY AND BAV Severe AS and/or aortopathy at risk for complications during pregnancy. The BV or SAV can be done during pregnancy only when necessary. Women with moderate and severe AS who become symptomatic in the antepartum period fail to increase LV twist. 39 Pregnancy hastens indications for surgery postpartum by affecting the ability of the LV to adapt to the fixed outflow obstruction. Women with BAV and ascending aorta diameter >4.5 cm should be counseled against the high risk of pregnancy.37
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Aortic dilatation is present in less than 10% pregnant women with BAV, but the rate of progression of aneurysm increases during pregnancy.9
14.
Patients with severe AS or AR with left ventricular dilation (left ventricular dimensions >65 mm) should not participate in competitive athletics. Those with or without aortic valve disease who have dilated aortic roots (>45 mm) are advised only low-intensity competitive sports. No restrictions exist for those with BAV with no significant valve dysfunction or aortopathy (3 cm beyond right lateral vertebral border or >4.5 cm from the anatomic midline may also suggest RA enlargement.
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33 Chest X-ray in Congenital Heart Disease
Pulmonary Venous Hypertension
pleura. This usually occurs when systemic venous pressure is also elevated, as in right heart failure. Several radiologic findings have been correlated with the level of PCWP in patients with acute and chronic heart failure.
Left Atrium The left atrium (LA) does not take part in the formation of any cardiac border in the PA projection in normal subjects. It lies in the mid-line in a posterior location. The earliest enlargement of LA is usually in the superior direction and this results in lifting up of the left main bronchus. As the LA enlarges further in this direction, the carinal angle widens as the carina forms the superior limit of the normal left atrium. The normal carinal angle ranges between 51° and 71°. With LA enlargement, it becomes right or obtuse angled. The LA may project beyond the left ventricle, producing localized convexity of the left border of cardiac silhouette just below the pulmonary conus. When enlargement reaches this stage, the chamber is often large enough to produce an oval shaped, localized density on the right side, and projecting outside the lower right cardiac border. This can be seen in frontal projection as a double density within the cardiac shadow on the right side (Figure 2). In the presence of double density,
Figure 2: Chest radiograph showing left atrial enlargement causing uplifting of left main bronchus with characteristic double density appearance
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the margin of LA is differentiated by that of RA by the fact that the LA margin never touches the right diaphragm and turns medially behind the heart shadow before reaching the diaphragm. The right heart margin that touches the diaphragm is produced by the RA.
Left Ventricle The left ventricle (LV) enlarges mainly to the left and posteriorly, and only slightly to the right and anteriorly. Hypertrophy produces rounding of the cardiac apex, whereas dilatation causes elongation either to the left or to the left and downwards, often combined with rounding of the apex.
Right Ventricle The right ventricle (RV) does not take part in the formation of any heart border in the PA projection in normal subjects. It lies in the mid-line in an anterior location. It enlarges mainly to the left and anteriorly. The outflow tract enlarges first and this is best seen in right anterior oblique (RAO) and lateral views. When the enlargement is significant, pulmonary conus becomes prominent in PA view. In some cases, the left border may be formed by this ventricle and may cause rotation of LV to the left with elevation of the apex. In such situations, the left lower heart border appears lifted up and has a double convexity produced by the enlarged RV, and displaced and rotated LV. This rotation tends to swing the aorta to the right, so that the aortic knuckle becomes less prominent. In lateral view, there is encroachment upon the retrosternal space in the upper part.
Aorta
mildly enlarged with LV configuration, aortic knuckle is obliterated or replaced by a bulge, pulmonary conus is enlarged, and lung vascularity is increased. In addition, pulmonary arterial hypertension (PAH) may be present. If the ascending aorta is enlarged disproportionate to the aortic knuckle, the L-R shunt is at the aortic root level. The causes include a ruptured aneurysm of the sinus of Valsalva (RSOV), aortopulmonary window (APW), and coronary arteriovenous fistula (AVF). Ruptured aneurysm of the sinus of Valsalva: The heart size is usually enlarged with a biventricular or LV configuration. An abnormal shadow of the aneurysm is usually present at the level of the aortic root. There may be curvilinear calcification in it. The aorta is enlarged with a disproportionate dilatation of the aortic root. The pulmonary conus is prominent and lung vascularity is increased. In addition, in symptomatic patients, some evidence of PVH is also present. Usually, the right coronary sinus is involved and ruptures into the RV. Simultaneous presence of pulmonary plethora and PVH is characteristic of an RSOV. Aortopulmonary window: The heart size is usually enlarged with an LV configuration, there is disproportionate enlargement of the aortic root, pulmonary conus is prominent, lung vascularity is increased, and PAH is usually present. Coronary arteriovenous fistula: The heart size is usually normal and there may be LV configuration. There is disproportionate enlargement of the aortic root, pulmonary conus is prominent and lung vascularity is normal or increased. Chest radiograph may be normal because the shunt is usually small.
The ascending aorta does not usually contribute to the cardiac borders in PA view. The assessment of the aorta on chest X-ray should include a comment on its looping, position of aortic knuckle, enlargement and aortic calcification, which may have a specific localizing value for the diagnosis.
Normal Aorta
CHEST X-RAY AND CHD CLASSIFICATION: SIMPLIFIED APPROACH (TABLE 1)
Pre-tricuspid shunt: The pre-tricuspid shunt is produced by an atrial septal defect or a what about TAPVC anomalous pulmonary venous drainage. Atrial septal defect (ASD): The heart size is usually normal (Figure 3). There may be mild cardiomegaly in approximately 25% of the patients. There is right atrial enlargement with right-sided configuration of the heart. Aortic shadow is normal in size with the ascending aortic shadow usually conspicuous by its absence in the upper right cardiac border. This sign is characteristic of an ASD. The heart appears to be shifted to the left and lung vascularity is increased. PAH may be present. Associated mitral valve disease should be suspected if LA/LA appendage is enlarged,
Left-to-Right (Acyanotic) Shunt Chest radiograph is useful in localizing the site of L-R shunts in CHD. If the aortic knuckle is enlarged, the shunt is extracardiac; and if the aorta is normal, the shunt is intracardiac.7,8
Large Aorta If the aortic knuckle is enlarged disproportionate to the ascending aorta, the L-R shunt is caused by patent ductus arteriosus (PDA). The heart is usually normal or
Normal or apparently small aortic knuckle and inconspicuous ascending aortic shadow in a frontal chest radiograph in the presence of increased lung vascularity in a pink patient suggest an intracardiac L-R shunt. This shunt can be at pre- or post-tricuspid level.
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Table 1: Basic chest radiographic approach towards congenital heart disease Left-to-right shunt
33
Right-to-left shunt
Normal aorta (Intracardiac shunt)
Decreased lung vascularity
AK>AA
AA>AK
Pre-tricuspid level Post-tricuspid level
Large aorta
Normal aorta
Small aorta
Large aorta
PDA
RSOV
ASD
TOF
Ebstein’s anomaly
D-TGA
Truncus arteriosus
APW
PAPVC
VSD with pulmoanry atresia
Valvular PS
VSD
Coronary AVF
Increased lung vascularity
TAPVC
TGA with VSD and PS Tricuspid atresia DORV with PS
Abbreviations: AK, aortic knuckle; AA, ascending aorta; PDA, patent ductus arteriosus; RSOV, ruptured sinus of Valsalva; APW, aortopulmonary window; AVF, arteriovenous fistula; ASD, atrial septal defect; PAPVC, partial anomalous pulmonary venous connection; VSD, ventricular septal defect; TOF, tetralogy of Fallot; TGA, transposition of great arteries; PS, pulmonary stenosis; DORV, double outlet right ventricle; D-TGA, dextrotransposition of great arteries; TAPVC, total anomalous pulmonary venous drainage
Figure 3: Chest radiograph showing near normal sized heart with convex pulmonary artery segment in a patient with atrial septal defect
Figure 4: Chest radiograph shows cardiomegaly with left atrial enlargement and pulmonary plethora in a patient with ventricular septal defect
PVH (especially if Kerley’s lines) is present, or if the mitral valve is calcified. The association of ASD with mitral stenosis of rheumatic etiology is called ‘Lutembacher’s syndrome’. Partial anomalous pulmonary venous drainage: This should be suspected if, in the presence of radiographic features of ASD, there is an abnormally enlarged shadow of SVC or rarely an abnormally directed pulmonary vein is seen.
present. In addition, there may be evidence of differential increase in lung vascularity in the right upper zone. In 3–5% of the patients, an associated right-sided aortic arch may be present.
Post-tricuspid L-R Shunt Ventricular septal defect: This is the most common form of acyanotic CHD. The findings on chest radiograph in ventricular septal defect (VSD) depend on the shunt size and the direction of predominant flow. In small (2:1) shunt, the heart size is usually enlarged with a left or a biventricular configuration, and there is evidence of LA enlargement, a normal aorta, and increased lung vascularity (Figure 4). The PAH may be
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Large aorta (Extracardiac shunt)
Right-to-Left (Cyanotic) Shunt Although chest radiographic features of most of the following conditions can be characteristic, it is important to remember that typical features are not usually seen in most patients. As with L-R shunts, the size of the aortic shadow is important in the localization of R-L shunts.
Large Aorta with Decreased Lung Vascularity Large aortic knuckle in the presence of cyanotic CHD and decreased vascularity is produced by tetralogy of Fallot (TOF), pulmonary atresia with VSD, tricuspid atresia, transposition of great arteries (TGA) with VSD and pulmonary stenosis (PS), and double outlet right ventricle (DORV) with PS.
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Figure 5: Tetralogy of Fallot with characteristic coer-en sabot heart with wide vascular pedicle
Figure 6: Chest radiograph shows cardiomegaly with enlarged bilateral central pulmonary arteries and peripheral oligemia in a patient of tetralogy of Fallot with absent pulmonary valve
Figure 7: Chest radiograph shows severe cardiomegaly (in comparison to tetralogy of Fallot with normal sized heart) with uplifted cardiac apex a patient of ventricular septal defectpulmonary atresia
Figure 8: Chest radiograph shows straight right heart border and pulmonary oligemia in a patient of tricuspid atresia with pulmonary stenosis
Tetralogy of Fallot : This is the most common form of cyanotic CHD in children. It classically includes malaligned VSD, infundibular PS, overriding of the aorta and RV hypertrophy. Additional valvular PS and hypoplasia of the main PA are also frequently present. The chest radiograph shows a characteristic picture produced by a normal heart size, RV configuration with an uplifted apex (coer-en sabot appearance), a large aortic knuckle, presence of pulmonary bay, and pulmonary oligemia (Figure 5). A right-sided aortic arch is present in approximately 25% of the cases. Rarely, TOF may be associated with an absent pulmonary valve. This produces a pathognomonic appearance consisting of an enlarged heart, large central pulmonary arteries with peripheral oligemia in the setting of TOF (Figure 6). In addition, a host of lung abnormalities largely due to a defective bronchial cartilage and resultant tracheobronchomalacia may be associated. Occasionally, TOF may be associated with congenital absence of a PA, left more commonly than
right. When this happens, parenchymal lung abnormalities are frequently associated.9
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VSD with pulmonary atresia: There is mild cardiomegaly of RV configuration, a large aortic knuckle that frequently crosses the sternoclavicular joint into the neck, pulmonary bay, and peripheral oligemia (Figure 7). Aortic arch is right-sided in 30–40% patients. Bronchial collateral circulation is frequently present. Rib notching may be seen. Tricuspid atresia: The chest radiographic picture depends on the relationship of great vessels, presence of PS, and the degree of RV hypoplasia. A typical picture is seen in only 15–20% of the cases and consists of a normal-sized or mildly enlarged heart, LV configuration, straight right heart border (Figure 8), some evidence of LA enlargement, enlarged aorta, pulmonary bay, and decreased vascularity, provided that there is PS and the great vessels are normally related. The aortic arch is right-sided in one-third of
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Figure 10: Chest radiograph shows typical snowman or ‘Figure of 8’ appearance in a patient of supracardiac nonobstructive total anomalous pulmonary venous drainage
the cases. If the pulmonary arteries are not located in their normal position, an abnormal relationship of great vessels should be suspected. In the absence of PS, there is evidence of increased lung vascularity.10
more often seen on the left side. The aortic arch is right sided in about 50% of the cases.
Dextro-transposition of great arteries (D-TGA), VSD and PS: A chest radiograph may superficially resemble TOF. The heart size is usually normal or may be mildly enlarged. The aortic knuckle is normal or the pedicle may appear narrow. The PA segment is not present in the normal position and is located in a high and medial position. The lung fields are oligemic.
Small Aorta with Increased Vascularity D-TGA: This is the second most common cause of cyanotic heart disease in infancy. It is caused by a ventriculoarterial discordance in which the aorta originates from RV and PA from LV. The chest radiographic findings are characteristic, consisting of an enlarged heart, narrow pedicle, abnormally located pulmonary arteries, and increased lung vascularity. The shape of the heart is typical and resembles an ‘egg-on-side’” (Figure 9). There may be a differential increase in right lung vascularity, especially in the upper zone. This pathognomonic picture is seen in patients in whom there is no evidence of PS. The typical chest radiograph findings are seen in about half the patients.
Large Pedicle with Increased Vascularity This combination is seen in truncus arteriosus, total anomalous pulmonary venous drainage (TAPVC), and tricuspid atresia without PS. Truncus arteriosus: The heart is usually enlarged, there is LV configuration, the aorta is enlarged, PA is not in its usual position, and lung vascularity is increased. The abnormal location of the PA may produce a characteristic picture described as ‘comma or water-fall’ sign. This is
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Figure 9: Chest radiograph shows typical ‘egg-on-side’ appearance with narrow vascular pedicle in a patient of dextro-transposition of great arteries
Total anomalous pulmonary venous drainage: This may be divided into four main groups according to the site or sites of connection; supracardiac, cardiac, infracardiac, and mixed. The chest radiographic picture depends on the type of TAPVC. In supracardiac type, which is also the most common, the heart is enlarged, the pedicle is wide with a classical “figure of 8 or Snowman’s” appearance, produced by the dilated left vertical and left innominate veins and the right SVC (Figure 10). The left atrium is small and there is increased flow, as evidenced by pulmonary plethora. In cardiac or mixed types, the picture may be nonspecific and consists of cardiomegaly, normal or enlarged aorta, and increased lung vascularity. Shadow of an enlarged abnormal pulmonary vein may be seen. The scimitar sign is seen in the infradiaphragmatic type of TAPVC and is caused by the drainage of the right pulmonary vein into the IVC, hepatic or portal vein. This syndrome is often associated with hypoplasia or sequestration of the right lung.
Normal Aorta with Decreased Lung Vascularity This combination can be seen in patients with Ebstein’s anomaly, and valvular PS in failure. Ebstein’s anomaly: This produces a characteristic radiographic picture. There is cardiomegaly, evidence of RA enlargement, sharp, well-delineated cardiac margins, as if drawn by a pencil, normal aorta, and pulmonary oligemia (see Figure 1). It can superficially resemble pericardial effusion, valvular PS in failure, tricuspid regurgitation caused by chronic rheumatic heart disease (RHD), dilated cardiomyopathy (DCM), and Uhl’s anomaly. The pulmonary vascularity is important in differentiating these conditions. In pericardial effusion, the lung vasculature is normal and no specific chamber
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enlargement is present. In RHD, there is PVH and tell-tale signs of the underlying valvular disease are always present. In DCM, there is evidence of PVH. The LA and LV may be enlarged. Valvular PS: A chest radiograph may be normal except for prominent pulmonary conus till there is severe PS with congestive failure. In such cases, there is cardiomegaly, RA enlargement, a normal aorta, prominent pulmonary conus produced by poststenotic dilatation of main and left PA, and peripheral pulmonary oligemia.
Other Conditions Coarctation of Aorta This refers to a narrowing of the distal aortic arch and/or proximal descending aorta due to a discrete membrane or narrowing of the aortic isthmus. Findings on chest radiograph depend on the age of the patient, location of the coarctation, ventricular function, competence of the aortic valve, and associated abnormalities. In an uncomplicated isolated coarctation, the heart size is usually normal. There may be left ventricular configuration. The classical feature of bilateral notching of the posterior and inferior margins of the 4th-8th ribs is usually not seen in the first decade of life. The coarcted segment is usually located in the juxtaductal region. Occasionally, it can be postductal and rarely preductal. Postductal or juxtaductal coarctation produces typical radiographic features in the cardiac configuration, ribs, and aorta. Rib notching is caused by the hypertrophied intercostal arteries that run along the posterior and inferior margins of the ribs (Figure 11). In juxtaductal coarctation, the fourth to eight ribs are usually involved. Coarctation proximal to the origin of the left subclavian artery results in unilateral right-sided rib
Figure 11: Chest radiograph shows characteristic bilateral inferior rib notching with normal sized heart in a patient of coarctation of aorta
notching. If the coarctation is proximal to an aberrant right subclavian artery, unilateral notching of the left ribs occurs. Abnormal appearance of the aorta is seen in most patients. The ascending aorta is slightly dilated. The ‘Figure of 3’ appearance of the descending aorta is characteristic but not commonly seen. The upper convexity is formed by the dilated subclavian artery and the lower convexity by the poststenotic dilatation of the descending aorta. Usually, a prominent or a flat knuckle is seen. If there is associated left ventricular decompensation, PVH may be present.11,12
CONCLUSION Detailed sequential interpretation of chest radiograph provides important clues to the underlying heart disease and the functional impairment produced by it. Moreover, chest radiograph also serves as a useful method for followup after treatment in most cardiac conditions. Distinctive radiographic abnormalities in CHDs allow them to be differentiated from each other before resorting to other forms of cross-sectional imaging.
REFERENCES 1. Radiology of the heart. Braunwald E (Ed). Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders; 1992. pp. 204-324. 2. Coussement AM, Gooding CA. Objective radiographic assessment of pulmonary vascularity in children. Radiology. 1973;109(3):649-54. 3. Chang CH. The normal Roentgenographic measurement of the right descending pulmonary artery in 1085 cases. Am J Roentgenol Ther Nucl Med. 1962;87:929-35. 4. Roberts WC. Radiologic differentiation of common anomalies. Adult Congenital Heart Disease. 1988. pp. 191219. 5. Moes CA. Analysis of the chest in the neonate with congenital heart disease, Radiol Clin North Am. 1975;13(2):251-76. 6. Jefferson K, Rees R (Eds). Clinical Cardiac Radiology. Butterworth: London; 1980. 7. Roberts WC. Radiologic differentiation of common anomalies. In: Carol A Warnes. Adult Congenital Heart Disease. 1988. pp.191-219. 8. Bessolo RJ, Vincent WR. Diagnosis of congenital heart disease in first two weeks of life. Calif Med. 1969;110(3):200-6. 9. Gyepes MT, Vincent WR. Severe congenital heart disease in the neonatal period. Am J Roentgenol Ther Nucl Med. 1972;116(3):490-500. 10. Elliot LP, Van Mierop LH, Gleason DC. Roentgenology of tricuspid atresia. Semin Roentgenol. 1968;3:399-409. 11. Sharma S. Proceedings of symposium and workshops in Cardiovascular and Interventional Radiology.1997. 12. Lapierre C, Dery J, Guerin R, et al. S egmental Approach to Imaging of Congenital Heart Disease. RadioGraphics. 2010;30(2):397–411.
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Traps and Pitfalls in Echocardiographic Diagnosis of CHAPTER 34 Congenital Heart Disease K Sivakumar
INTRODUCTION In the pre-echocardiographic era before 1980s, diagnosis of congenital heart disease (CHD) traditionally was considered to be resting on three pillars namely clinical examination, chest X-ray, and electrocardiography. Once echocardiography came into clinical practice, it has completely transformed the way diagnosis is made in pediatric cardiology and in evaluation of grown-up congenital heart (GUCH) diseases. Echocardiography has become the key investigation of choice in the diagnosis and in many instances the only final investigation to be done before a final corrective intervention is performed, either surgically or in the catheterization laboratory. The increasing comfort of the correct diagnosis provided by this diagnostic tool has made many institutions to avoid more invasive additional imaging even in complex CHD, where the accuracy of the data matters the most. One spectacular example is the complete reliance of echocardiography in diagnosing the coronary artery patterns before arterial switch operation in d-transposition of great arteries (dTGA), where the success of the surgery depends on the harvest of the coronary buttons and their anastomosis to the neo-aortic root.1 Echocardiography defines the morphological and functional findings in CHD, as completely as possible in almost all the cases. It requires a different approach compared to other forms of heart diseases by providing information on the heart position in the thorax, the viscera-atrial situs, the venoatrial and the atrioventricular connections, the relationship between the ventricles, the ventriculoarterial connection and the relationship of the great arteries which is described as systematic segmental analysis. It also assesses the ventricular function for optimal pre- and postoperative management in patients with CHD using ‘pump indices’ (i.e. ejection fraction or fractional shortening), which unfortunately depend on loading conditions and heart rate. As a consequence, indices to reflect intrinsic myocardial contractility like fiber shortening or rate-corrected velocity of circumferential fiber shortening—end-systolic stress relationship, Doppler myocardial imaging, strain/strain rate, and backscatter are increasingly adopted to get regional, functional, and textural findings of the myocardium. However, long-term
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Table 1: Common errors in CHD echocardiography I: Anatomical errors 1 2 3 4 5 6 7 8 9 10
Coarctation of aorta Aortic arch interruption Peripheral pulmonary artery stenosis Supravalvar aortic stenosis Aortopulmonary window Anomalous pulmonary venous drainage Pulmonary vein stenosis/atresia Venacaval anomalies with or without cyanosis Sinus venosus or coronary sinus defects Muscular ventricular septal defects
II: Functional errors 1 2 3 4 5 6
Assessment of right ventricle Assessment of single ventricle Diastolic function in congenital heart disease Quantify valvar regurgitation in hypoplastic/dysplastic valves Quantify valve area in stenotic valves Ventricular mass in right/single ventricle
follow-up studies will be necessary to better define their real impact in the clinical setting.2 In this context, it is mandatory for the operators to clearly understand the traps and pitfalls in this modality of imaging for recognizing its limitations. This knowledge is crucial for ordering additional three-dimensional imaging investigations such as computed tomography (CT) or magnetic resonance (MR). It also may clarify the precise role of diagnostic cardiac catheterization and angiography which lost its favor in routine practice due to its invasiveness and ionizing radiations.3 The errors in the assessment of patients with CHDs can be broadly be grouped as shown in Table 1.
ANATOMICAL ERRORS Coarctation of Aorta Coarctation of aorta accounts for 6-8% of all forms of CHD and is commonly missed in clinical practice due to nonreliance of simple clinical examination of femoral pulses. Poor suprasternal windows in extreme premature neonates, obese infants or grown-up adolescents may pose challenges in the diagnosis.4 When good aortic arch views are not obtained, the following clues might indicate a possibility of an underlying coarctation:
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A
B
C
D
Figures 1A to D: Pitfalls in diagnosis of coarctation. Clues to diagnose include: (A) Low velocity abdominal aortic spectral Doppler signals; (B) Mild increase in mitral inflow gradients; (C) Unexplained left ventricular hypertrophy; (D) Unexplained pulmonary artery hypertension
Low velocity abdominal aortic spectral pulse Doppler Mild unexplained dilatation of left ventricle (LV) in an infant or a child in apical views or mild LV hypoplasia in a neonatal echocardiography Mildly increased mitral inflow Doppler gradients in the absence of mitral stenosis Identification of a bicuspid aortic valve Unexplained pulmonary arterial hypertension (PAH) Unexplained increased LV hypertrophy (Figures 1A to D) A suspicion based on these clues should alert the clinician to resort to additional imaging like CT.
Aortic Arch Interruption
290
Arch interruption is classified into three types depending on the level of interruption, whether it is beyond or before the left subclavian or it is between the right innominate and left carotid artery. It is likely to be missed especially when it coexists with other anomalies like truncus arteriosus or other conotruncal malformations.5 Once again, simpler clinical tools, such as four-limb pulse oximetry, may show light about the possibility of this association. Identification of a third vessel arising from the main pulmonary artery which represents the ductus arteriosus (Figure 2) and detection of diastolic flow reversal in the ductus with color Doppler flows back into the pulmonary artery from descending aorta due to relatively lower pulmonary
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Figure 2: Aortic arch interruption Type A. In view of large duct perfusing the descending aorta at systemic pressures, there will not be any turbulence on color Doppler and the arch may appear to be anatomically continuous to the descending thoracic aorta Abbreviations: PDA, patent ductus arteriosus; AA, ascending aorta; DA, descending aorta
vascular resistance is a valuable clue that points to the presence of aortic arch interruption, which can be confirmed by CT.
Peripheral Pulmonary Artery Stenosis Significant stenosis of pulmonary arteries especially in the post-hilar regions or isolation of the pulmonary arteries
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B
Figures 3A and B: Peripheral pulmonary artery stenosis. The only clues in the absence of detectable abnormality in the pulmonary arteries will be (A) Unexplained right ventricular hypertrophy and dilatation; and (B) High tricuspid regurgitation Doppler velocities indicating elevated right ventricular systolic pressure
are again notorious for misses in the clinical practice. Indirect clues in patients with bilateral pulmonary artery stenosis are evidence of high right ventricular (RV) systolic pressures through tricuspid regurgitation Doppler interrogation and hypertrophied RV with or without chamber dilatation, corroborated with evidence of peripheral long systolic lung field murmurs (Figures 3A and B). In unilateral severe pulmonary artery stenosis, the pulmonary blood flows are redirected to the contralateral nonstenotic side and so the indirect clue will be reduction in the pulmonary venous return from the ipsilateral side. This can be recognized by low velocity of spectral Doppler on the pulmonary veins or less bright color signals on color Doppler study compared to contralateral pulmonary veins (Figure 4).
Supravalvar Aortic Stenosis The part of aorta above the sinotubular junction may sometimes be not clearly delineated by echocardiography from parasternal views. This will lead to misdiagnosis of supravalvar aortic stenosis. If there is color flow turbulence in aortic root associated with high velocity continuous Doppler signal, it is often interpreted as valvar aortic stenosis and these patients may get scheduled for balloon aortic valvotomy.6 The real diagnosis will be shown once an aortic root angiogram is performed. In rare instances, where there is very poor visualization of the entire supravalvar aorta, the diagnosis is missed altogether. One of the way of circumventing this problem is clinical examination which demonstrates an outflow ejection murmur on right sternal border with Coanda effect, where the right arm pulses are bounding and have high pulse pressures than left arm counterparts. Additional imaging with CT might confirm the diagnosis.
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A
Figure 4: Severe intrahilar left pulmonary artery stenosis. The only clue for this diagnosis in a neonate who presents with severe unexplained pulmonary artery hypertension diagnosed as persistent pulmonary hypertension of newborn was identification of bright color signals in right pulmonary vein indicative of redistribution of blood flow to the right lung
Aortopulmonary Window Lack of awareness of this relatively uncommon CHD is one of the major reasons for missing this lesion on echocardiography. 7 As most of the aortopulmonary window (APW) are nonrestrictive and large, there is often no gradient between the aorta and pulmonary arteries, which makes it difficult to identify with color Doppler echocardiography. Indirect clues are dilatation of left atrium and ventricle on apical views, unexplained PAH and dilatation of the aortic root. Delays in identification of this large shunt lesion leads to undetected progression of the hemodynamics to irreversible pulmonary vascular disease within the first decade of life. If the lesion is suspected, but not convincingly diagnosed on echocardiography, it is better dealt with diagnostic aortic root angiography.
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Figures 5A to D: Right pulmonary vein atresia. The color Doppler pattern (A and B) in the pulmonary artery (PA) bifurcation shows brisk color flows into the left PA and poor flows in right PA. Spectral Doppler in RPA; (C) Shows sharp early systolic signal with very short pulmonary acceleration indicative of high vascular resistance in right lung, trace in LPA; (D) Shows normal flow pattern, which indicates that lung perfusion is selectively redistributed to the left lung
Pulmonary Vein Stenosis Unilateral pulmonary vein stenosis or atresia may present with respiratory distress in neonates or infants as it leads to severe PAH. If there is a complete occlusion of the pulmonary veins, there will not be any turbulence in the flow in the left atrium and this will not alert the echocardiographer of this possibility.9 Often, pulmonary vein stenosis, atresia or veno-occlusive disease gets misdiagnosed as persistent PAH of newborn and medically managed with pulmonary vasodilators, which worsens the clinical situation by causing pulmonary edema. This clinical entity is another difficult diagnosis on echocardiography. Identification of reduced velocities in the blood flows in ipsilateral pulmonary artery either spectral Doppler or reduced color signals on color Doppler will serve as a clue since blood is redistributed to the lung without pulmonary vein stenosis (Figures 5A to D).
Anomalous Pulmonary Venous Drainage Pa r t i a l o r t o t a l a n o m a l o u s p u l m o n a r y v e n o u s connections (TAPVC) are often misdiagnosed on routine echocardiography.8 Failure to identify the latter is often serious, as 90% of infants born with the disease do not survive beyond the first birthday. TAPVC often gets diagnosed as secundum atrial septal defect (ASD), but careful identification of flows from right atrium to left atrium in the former will prevent misdiagnosis. Familiarity with subxiphoid and suprasternal views will help in preventing misses of infra- and supracardiac types of
TAPVC. The hallmark of diagnosis of TAPVC in a neonate presenting with respiratory distress is identification of right-to-left shunt across the ASD and nonvisualization of connections between any pulmonary vein and the left atrium. While the former is easy to recognize, an untrained echocardiographer may miss the latter. As all symptomatic neonates with TAPVC have significant PAH, they often get misdiagnosed as persistent PAH of newborn (Figures 6A to D).
Venous Anomalies Leading to Cyanosis Cyanosis in the absence of clinically detectable murmurs and findings on precordial examination baffles the examiner. A group of conditions ranging from pulmonary arteriovenous fistula, anomalous systemic venous drainage to left atrium, and pulmonary artery to left atrial window may lead to this cyanosis. None of these clinical conditions cause cardiomegaly, forcible precordial pulsations, alterations in heart sounds, and do not lead to any clinically detectable murmurs. An apical view of echocardiogram shows a normal study, which might prompt the echocardiographer to write the report as a ‘normal echo study’. Adopting agitated saline contrast echocardiography will show immediate filling of the left atrium after injection in a systemic vein, that will alert to the possibility of these diseases. Filling of left atrium direct from the systemic veins excludes pulmonary arteriovenous fistula and pulmonary artery to left atrium connections (Figures 7A to F).
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Figures 6A to D: Total anomalous pulmonary venous return: right atrial and right ventricular dilatation on apical view (A) and high tricuspid regurgitation Doppler signal indicative of pulmonary artery hypertension (B) should alert the clinician about possibility of abnormal pulmonary venous return. Suprasternal view demonstrates supracardiac total anomalous pulmonary venous connections (TAPVC) through left vertical vein (C) and subxiphoid view shows infracardiac through a vertical vein (D) in another patient
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Figures 7A to F: Systemic venous anomalies may present with normal apical view (A), but subxiphoid view (B) with color Doppler (C) indicates anomalous drainage of right superior vena cava to left atrium causing cyanosis. Agitated saline injection from right arm vein demonstrates immediate filling of the left atrium (D) confirming the diagnosis. Anomalous left superior vena cava draining through a completely unroofed coronary sinus into the roof of the left atrium (E) also causes cyanosis as shown in the color Doppler study (F) Abbreviations: RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle; IVC, inferior vena cava; Ao, aorta; PA, pulmonary artery; LSVC, left superior vena cava; SVC, superior vena cava
Venous Anomalies without Clinical Findings Some venous anomalies may not result in any cyanosis, if the systemic venous blood ultimately reaches the right atrium.10 One such example is interruption of the suprarenal part of inferior vena cava (IVC) with azygos continuation, leading to drainage of the IVC to the lower part of superior vena cava (SVC). This relatively benign anomaly of no major clinical significance may cause significant difficulty in cardiac catheterization laboratory to perform a right heart cardiac catheterization and more troubles to perform interventions in the heart like device
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closures (Figures 8A to D). Unroofed coronary sinus is yet another example, where left atrial blood enters the unroofed coronary sinus to drain to the right atrium and contribute to an interatrial shunt.
Sinus Venosus Defects and Coronary Sinus ASD The ASD represents one of the common forms of CHD; two rare forms of interatrial septal communications namely sinus venosus ASD and coronary sinus ASD are more likely to be missed on echocardiography. Sinus venosus ASD is
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Figures 8A to D: Systemic venous anomalies always do not lead to cyanosis, as shown in interrupted inferior vena cava with azygos continuation to right superior vena cava (A), confirmed on color Doppler signal (B). This patient also had a secundum atrial septal defect (C) which was closed with a device (D) through the right jugular vein as femoral venous access fails to get a stable sheath position into the heart Abbreviations: RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle; SVC, superior vena cava
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Figures 9A to D: Anterior marginal and posterior marginal muscular ventricular septal defect seen in parasternal short axis (A) and subxiphoid short axis (B) are easy to miss on echocardiography unless carefully looked for. When there is a large ventral septal defect, additional defects also may be missed as seen in this example with a large perimembranous defect, mid-muscular defect and apical defect shown by three color jets (C) from left ventricle to right ventricle. Swiss cheese defects (D) also may need careful evaluation Abbreviations: RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle; Ao, aorta
difficult to image from apical views or parasternal views and tends to be underdiagnosed often. Unless subxiphoid views are routinely utilized, SVC type of sinus venosus defects is likely to be underdiagnosed. Some of the clues that point to the presence of these defects are unexplained right-sided chamber enlargement. Transesophageal echocardiogram in yet another useful investigation to avoid these misses. Raghib’s defect refers to unroofed coronary sinus with persistent left SVC, where interatrial communication leads to right chamber enlargement.11
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While perimembranous, inlet and outlet VSD are diagnosed with ease in echocardiography, muscular defects especially in the marginal areas and Swiss cheese muscular defects may get missed out on echocardiography (Figures 9A to D). This is often the case when these muscular defects coexist with large membranous or outlet defects.12 Muscular defects between the apex of the right ventricular infundibulum and apex of the left ventricle is more notorious to be missed on echocardiography.13 If the possibility of additional muscular defects cannot
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be excluded, conventional left ventriculography in catheterization laboratory is justified before surgical correction.
FUNCTIONAL ERRORS Ventricular Function Assessment Conventional assessment of ventricular systolic function relies on LV volume assessments by Simpson method, ventricular shortening fraction on M mode echocardiography. The load dependence of these indices forced the clinician to depend on parameters like velocity of circumferential shortening; however, the normative values in various forms of operated and unoperated CHDs are largely unknown.14 The complexity increases when there is single ventricle or systemic RV which needs the detailed analysis. New echocardiographic techniques namely tissue Doppler imaging, speckle tracking with strain and strain rate, vector velocity imaging (VVI), myocardial performance index, myocardial acceleration during isovolumic acceleration (IVA), the ratio of systolic to diastolic duration (S/D ratio), and two-dimensional
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Figures 10A to D: Assessment of valvar regurgitations. In common atrioventricular valve with multiple leaflets (A), quantification of multiple jets of regurgitation (B) is challenging. Similarly in a truncus arteriosus (C), quantification of regurgitation across the truncal valve (D) is also not clearly defined
measurements of systolic right ventricular (RV) function (e.g., tricuspid annular plane systolic excursion, TAPSE) along with three-dimensional assessment with volumes and speckle tracking. These may become valuable indicators of ventricular performance, compliance, and disease progression; however, data on normative values are not available.15
Valvar Quantifications Conventional parameters used in decision making in interventions for regurgitant valvar lesions include assessment of regurgitant volume, regurgitant fraction, and orifice area. Similar parameters used in stenotic valves include valve area by planimetry or other measures. 16 In complex CHDs with hypoplastic or dysplastic valves, which have a combination of stenosis and regurgitation, clear guidelines do not exist. Normative data for children of various ages and weight also do not exist. The errors get compounded in the setting of common atrioventricular valve or common truncal valve (Figures 10A to D).
REFERENCES 1. Pasquini L, Sanders SP, Parness IA, et al. Diagnosis of coronar y arter y anatomy by two-dimensional echocardiography in patients with transposition of the great arteries. Circulation. 1987;75(3):557-64. 2. Pacileo G, Di Salvo G, Limongelli G, et al. Echocardiography in congenital heart disease: usefulness, limits and new techniques. J Cardiovasc Med (Hagerstown). 2007;8(1):17-22. 3. Lange RA, Hillis LD. Cardiology patient pages. Diagnostic cardiac catheterization. Circulation. 2003;107(17):e111-3. 4. Sun Z, Cheng TO, Li L, Zhang L, Wang X, Dong N, et al. Diagnostic value of transthoracic echocardiography in patients with coarctation of aorta. PLoS One. 2015;10(6): e0127399.
5. Kaulitz R, Jonas RA, van der Velde MR. Echocardiographic assessment of interrupted aortic arch. Cardiol Young. 1999;9(6):562-71. 6. Cuenza LR, Adiong AA. Isolated supravalvar aortic stenosis without William’s syndrome. J Cardiovasc Echogr. 2015;25(3):93-5. 7. Kiran VS, Singh MK, Shah S, et al. Lessons learned from a series of patients with missed aortopulmonary windows. Cardiol Young. 2008;18(5):480-540. 8. Chin AJ, Sanders SP, Sherman F, et al. Accuracy of subcostal two-dimensional echocardiography in prospective diagnosis of total anomalous pulmonar y venous connection. Am Heart J. 1987;113(5):1153-9. 9. Pazos-López P, García-Rodríguez C, Guitián-González A, et al. Pulmonary vein stenosis: etiology, diagnosis and management. World J Cardiol. 2016;8(1):81-8. 10. Arunakumar P, Ayyappan A, Sasikumar D, et al. Anomalous systemic and pulmonary veins – an unusual coexistence. Echocardiography. 2018;35(5):733-4. 11. Johri AM, Rojas CA, El-Sherief A, et al. Imaging of atrial septal defects: e chocardio graphy and CT correlation. Heart. 2011;97(17):1441-53. 12. Ludomirsky A, Huhta JC, Vick GW 3rd, Murphy DJ Jr, Danford DA, Morrow WR. Color Doppler detection of multiple ventricular septal defects. Circulation. 1986;74(6): 1317-22. 13. Kumar K, Lock JE, Geva T. Apical muscular ventricular septal defects between the left ventricle and right ventricular infundibulum. Diagnostic and interventional considerations. Circulation. 1997;95(5):1207–13. 14. Cotts T, Khairy P, Opotowsky AR, et al. Clinical research priorities in adult congenital heart disease. Int J Cardiol. 2014;171(3):351–60. 15. Koestenberger M. Transthoracic echocardiography in children and young adults with congenital heart disease. ISRN Pediatr. 2012;2012:753481. 16. Unger P, Clavel MA, Lindman BR, et al. Pathophysiology and management of multivalvular disease. Nat Rev Cardiol. 2016;13(7):429-40.
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Fetal Echocardiography: Current Status and Role in Management CHAPTER 35 of Congenital Heart Defects Balu Vaidyanathan
INTRODUCTION Prenatal diagnosis of congenital heart disease (CHD) is accurately possible in the current era by fetal echocardiography, even in the early stages of gestation.1 This has provided a major impetus to the field of pediatric cardiology since counseling and management of the heart lesion can start even before the baby is born. Prenatal diagnosis offers a dual advantage to the management of CHD that is particularly relevant for low- and middleincome countries (LMIC). Early prenatal diagnosis can reduce the burden of very complex forms of CHD and those associated with multisystem anomalies. Prenatal diagnosis and planned peripartum care improves postnatal outcomes with infants with critical CHD. This review focuses on the recent developments in the field of fetal echocardiography and discusses its role in the modern-day management of children with CHD.
CONCEPT OF UNIVERSAL SCREENING OF FETAL HEART Since most forms of CHD occurs in low-risk pregnancies, it is important to perform a basic screening of the fetal heart in all pregnancies. A combination of the four-chamber view and outflow tract view enables accurate screening of the fetal heart and most anomalies can be suspected using these 2 views.2,3 In high-risk pregnancies (Table 1), a direct referral for a fetal echocardiography may be considered.4 The optimal timing for fetal echo is between 16 and 20 weeks of gestation. Detailed guidelines have been
established for the practice of fetal echocardiography by various clinical societies.5 The protocol typically includes evaluation of the fetal lie and cardioabdominal situs, four-chamber view, the left and right ventricular outflow tracts (crossing), the three vessel and the three vessel tracheal view. Additional views include the sagittal views for systemic veins (bicaval view), the ductal and the aortic arches. Color Doppler evaluation and an evaluation of the fetal heart rate and rhythm complete a typical cardiac evaluation protocol. Figures 1A to F summarize the common views in the conduct of a mid-trimester fetal cardiac evaluation. Table 1 summarizes the recommended indications for fetal echocardiography.
3D/4D STIC FETAL ECHOCARDIOGRAPHY One of the promising developments in the field of prenatal diagnosis is the development of 3D/4D technology with spatiotemporal image correlation (STIC).6 In this technology, using specialized transducers including the recently introduced matrix probes, a volume dataset of the fetal heart is obtained. It is possible to display a multiplanar model of the fetal heart from this volume dataset and then use postprocessing tools to render and display the information in multiple ways. This also permits functional studies of the fetal heart including volumetric assessments of the ventricular function and cardiac output. Recent studies have shown the incremental benefit of this technology in the evaluation of extracardiac
Table 1: Indications for fetal echocardiography Fetal
Maternal
Familial
1. 2. 3. 4. 5. 6. 7. 8.
1. Maternal CHD 2. Teratogen exposure 3. Metabolic disorders—diabetes mellitus 4. Maternal autoimmune disease 5. Intrauterine infections
1. Previous child with CHD 2. Paternal CHD 3. Mendelian syndromes—TS, Noonan’s, DiGeorge
Abnormal 4C view Extracardiac anomalies—GIT, spina bifida Chromosomal anomalies—VACTERL, Trisomies, Digeorge Increased first trimester NT scan Non-immune hydrops Irregular heart beat—tachy/bradyarrhythmias Abnormal cardiac axis IVF/ICSI ?
Abbreviations: GIT, gastrointestinal tract; VACTERL, vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities; NT, nuchal translucency; IVF, in vitro fertilization, ICSI, intracytoplasmic sperm injection; CHD, congenital heart disease; TS, Turner syndrome
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Figures 1A to F: Common views used in the conduct of fetal cardiac evaluation. (A) Abdominal situs showing the aorta (A) and stomach (St) on left side and liver (L) and IVC (v) on the right side; (B) Four-chamber view; (C) The left ventricular outflow tract; (D) The right ventricular outflow tract and branch pulmonary arteries (color); (E) The three vessel view—PA (P) anterior and left, aorta (A) in middle and SVC (S) posterior and right; (F) The 3-vessel tracheal view showing equal sized ductal (PA) and aortic arches (Ao) with color flow in same direction. Sp denotes spine position. MB denotes moderator band (B)
vascular structures like aortic arch, branch pulmonary arteries, and anomalies of systemic and pulmonary veins.7,8 It permits postprocessing of the volume dataset, thereby reducing initial evaluation time besides offering the possibility of re-interpretation of the cardiac anatomy in very complex CHDs like isomeric hearts. Development of automatic fetal heart evaluation algorithms like fetal intelligent navigation echocardiography (FINE) may simplify fetal heart evaluation further in future and make wide spread screening in large population more feasible and cost effective.9 Figures 2A to E show the utilization of 3D/4D STIC fetal echocardiography in generating rendered images of the normal fetal heart.
IMPACT OF FETAL ECHOCARDIOGRAPHY AND PRENATAL DIAGNOSIS OF CHD The principal role of a pediatric/fetal cardiologist comes after the diagnosis of CHD has been made in utero. The counseling plan has to be individualized and will depend upon several factors like the gestational age at diagnosis, complexity of the CHD, socioeconomic, cultural and religious factors and access to tertiary pediatric cardiac care. Several centers in India are now undertaking complex surgical procedures in very small hearts with excellent short-term and intermediate outcomes. 10 However, it is generally agreed that the prognosis even after palliation is suboptimal for very complex forms of
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CHD (typically the single ventricle heart) and if the cardiac lesion is associated with major extracardiac or genetic abnormalities. 11 The challenges on quality of life and long-term complications in adult survivors of complex CHDs are enormous.12 According to the American College of Cardiology (ACC) Bethesda conference task force in 2001, it was estimated that 787,800 adult patients with CHD lived in the USA in 2000 (of which 117,000 were severe lesions), corresponding to a prevalence of 3.51 cases of all CHD and 0.52 of severe CHD per 1000 adults, respectively.13 It is quite possible that these challenges may prove overwhelming for LMIC countries in future with an ever-increasing number of patients surviving tertiary cardiac care into adult life. Many states in India have started developing government-aided schemes and projects for supporting care of children with CHD (e.g. Hridyam scheme in Kerala).14 Early prenatal diagnosis by implementing a mandatory screening policy may be a very cost-effective strategy for care of children with CHD by reducing the burden of complex CHDs, permitting more efficient utilization of resources towards the care of more correctable CHDs.
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Changing the Natural History of Complex CHDs Impact of Early Prenatal Screening of the Fetal Heart These include CHDs with an anatomic or functional form of univentricular heart as well as CHDs that are
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Figures 2A to E: The 4-dimensional spatiotemporal image correlation (4D STIC) rendering of the normal heart. (A) Four-chamber view; (B) Crossing of outflow tracts; (C) Aortic arch; (D) Ductal arch; (E) Pulmonary veins draining into the left atrium
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associated with multisystem anomalies or genetic syndromes. Typical examples include hypoplastic left heart syndrome, isomeric hearts with single ventricle, pulmonary atresia with intact ventricular septum and other forms of anatomic and functional single ventricle. Most of these conditions can only be palliated at best and the adult survival with palliation even in the developed societies is not optimal. 15–18 Recently, selected centers in developing countries have started doing very complex neonatal palliative procedures like the Stage 1 Norwood Operation with reasonable results.19 However, it remains extremely contentious whether embarking on a program for palliation of extremely complex CHD is a priority of LMICs, considering its overall burden on health economic and long-term quality of life.20 Several studies have reported higher prevalence of termination of pregnancy when the prenatal diagnosis of CHD is made in early gestation.21-27 Bull et al. reported a termination of pregnancy rates of 70% and 61% when diagnosis of CHD was made before 19 and 23 weeks, respectively.23 A study from Boston Children’s Hospital reported a higher rate of termination for fetuses with univentricular hearts when the diagnosis was made before 24 weeks.24 In a population-based study from Paris, of the 703 fetuses diagnosed with CHD, 46% were terminated, with 3.2 times higher odds of termination in those diagnosed before 22 weeks.27 Hence, screening the fetal heart in all mid-trimester anomaly scans becomes particularly important in the current era, especially in the LMICs. Most of the complex forms of CHD of the univentricular type can be detected using the four-chamber view with high degree of sensitivity. 28 First trimester screening resulted in a
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lower prevalence of complex CHDs of the univentricular type during the second trimester as well as postnatal period.21 In India, the legal limit for medical termination of pregnancy is up to 20 weeks of gestation and termination may be considered if ‘there is a substantial risk of the child born to suffer from such physical or mental abnormalities as to be seriously handicapped’. 29 This is particularly important for LMICs like India since it can have a very significant impact on healthcare policies for CHDs.
Concept of Planned Peripartum Care for Critical CHD This scenario applies to those cardiac conditions that are potentially lethal in the neonatal period without intervention and where corrective surgery offers excellent long-term outcomes. In most of these conditions, the survival of the infant depends on the continued patency of the arterial duct after birth to maintain pulmonary or systemic blood flow. This is accomplished by starting an infusion of prostaglandin E1 when indicated. Once the duct starts to close, these babies can present with severe cyanosis or shock. It may be extremely hazardous to transport such sick babies to a tertiary care pediatric cardiac facility after they have started showing symptoms of decompensation. Typical examples of these CHDs include transposition of great arteries, critical forms of obstruction to the outflow tracts resulting in ductdependent circulatory states (pulmonary atresia, left heart obstruction) and obstructed form of total anomalous pulmonary venous drainage. The counseling in these patients should include detailed information about the cardiac diagnosis, expected timing of interventions after birth, nature of the postnatal interventions including the costs and the expected outcomes in a given institution.
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Figures 3A to F: Common CHDs diagnosed by fetal echocardiography. (A) Hypoplastic left heart; (B) Ebstein’s anomaly; (C) Right isomerism with single ventricle; (D) Tetralogy of Fallot with over-riding aorta; (E) Transposition of the great arteries; (F) Coarctation of aorta
Studies have shown that the major determinant of outcomes after corrective intervention in such patients is the preoperative status of the baby. 30 An excellent coordination between all concerned specialties (cardiology, obstetrics, cardiac surgery, neonatology, anesthesia, nursing, and counselor) is required to ensure that there is a smooth transition of care for these critically ill infants. Hence, in such conditions, the best possible option after prenatal diagnosis would be to plan delivery in a center with pediatric cardiac facility so that immediate care can be delivered to the baby after birth. Studies have shown that such a strategy may improve outcomes in babies with critical forms of CHD.31-34 Recent studies from developing countries have shown the benefit of a planned peripartum care on outcomes of neonatal cardiac surgery in infants with critical forms of CHD.35 Figures 3A to F summarize some of the common CHDs that can be diagnosed by fetal echocardiography.
the tachycardia and continue pregnancy till term. Most infants require continued medications after birth. Recent reports from LMICs also highlight the role of prompt diagnosis and aggressive transplacental and direct fetal therapy in achieving optimal outcomes in fetuses with tachyarrhythmias.37
In Utero Therapy for Rhythm Disorders
Bradyarrhythmias: The most significant bradyarrhythmia that requires treatment in utero is congenital complete heart block. Many cases are associated with maternal autoimmune disease (Ro/La antibodies). Since transplacental transfer of these antibodies occurs principally after 18 weeks, most of these cases manifest by around 20–24 weeks. The overall prognosis of fetuses with complete heart block in the absence of associated structural heart disease and high-risk features is very good and the majority survives till term without need for any intervention.38 Studies have identified high-risk features associated with fetal demise; and in such fetuses, targeted transplacental therapy with maternal steroids (dexamethasone) in conjunction with beta-agonists may improve outcomes.39
This includes fetuses diagnosed with various types of tachy- and bradyarrhythmias.
Fetal Interventions for Structural Heart Defects
Tachyarrhythmi as : The most common for ms of tachyarrhythmias in the fetus include supraventricular tachycardia and atrial flutter. Most of these arrhythmias are diagnosed between 20 and 30 weeks of gestation. Many of these tachyarrhythmias can be effectively managed using transplacental therapy.36 The various drugs given to the mother include digoxin, flecanaide, amiodarone, etc. Frequent monitoring of both the mother and the fetus is required. In most cases, it is possible to effectively control
At present, the scope of fetal interventions is limited to very few conditions especially severe obstruction to the outflow tracts.40 The most common fetal intervention reported is fetal balloon aortic valvuloplasty for critical aortic stenosis with left ventricular dysfunction. Preliminary data suggest that this intervention may prevent progression of aortic stenosis into a more ominous form of heart disease, hypoplastic left heart syndrome.41 Fetal balloon pulmonary valvuloplasty also has been successfully
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performed for fetuses with critical pulmonary stenosis.42 The third fetal cardiac intervention reported is balloon atrial septostomy (enlargement of the restrictive atrial septal communication) in fetuses with hypoplastic left heart syndrome and restrictive patent foramen ovale in order to decompress the left atrium.43 Needless to say, these interventions are extremely resource intense and require a multidisciplinary team approach. At present, the scope of fetal cardiac interventions in developing countries is very limited.
CONCLUSION Fetal cardiology has evolved into a separate discipline within the field of pediatric cardiology with widespread implications on the diagnosis and management of CHD in the current era. 44 For LMICs, it offers the unique opportunity to stratify and prioritize the limited healthcare resources for the management of children with CHD by the twin strategy of reducing burden of complex CHD and planned peripartum care for critical CHDs. Hence, the necessity of educating obstetricians and radiologists on early prenatal screening of the fetal heart should become a major priority for policy makers in LMICs.45 A coordinated multidisciplinary system for diagnosis, early referral, counseling and peripartum care needs to be established for optimal care of the pregnancy once the diagnosis of CHD is made.46
REFERENCES
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1. Smreck JM, Berg C, Geipel A, et al. Detection rate of early fetal echocardiography and in utero development of congenital heart defects. J Ultrasound Med. 2006;25(2):18796. 2. Allan L. Technique of fetal echocardiography. Pediatr Cardiol. 2004;25(3):223-33. 3. Barboza JM, Dajani NK, Glenn LG, et al. Prenatal diagnosis of congenital cardiac anomalies: a practical approach using two basic views. Radiographics. 2002;22(5):1125-37. 4. Small M, Copel JA. Indications for fetal echocardiography. Pediatr Cardiol. 2004;25(3):210-22. 5. Allan L, Dangel J, Fesslova V, et al. Recommendations for the practice of fetal cardiology in Europe. Cardiol Young. 2004;14(1):109-14. 6. Araujo E Jr, Tedesco GD, Carriho MC, et al. 4D fetal echocardiography in clinical practice. Donald School J Ultrasound Obstet Gynecol. 2015;9(4):382-96. 7. Yagel S, Cohen SM, Rosenak D, Messing B, Lipschuetz M, Shen O, et al. Added value of three-/four-dimensional ultrasound in offline analysis and diagnosis of congenital heart disease. Ultrasound Obstet Gynecol. 2011;37(4):4327. 8. Vaidyanathan B, Vijayaraghavan A, Karmagaraj B, et al. Prenatal diagnosis of distal aortopulmonary window with type A aortic arch interruption with 4-dimensional spatiotemporal image correlation rendering. Circ Cardiovasc Imaging. 2018;11(5):e007721.
9. Yeo L, Romero R. Fetal Intelligent Navigation Echocardiography (FINE): a novel method for rapid, simple and automatic examination of the fetal heart. Ultrasound Obstet Gynecol. 2013;42(3):268-84. 10. Bakshi KD, Vaidyanathan B, Sundaram KR, et al. Determinants of early outcome after neonatal cardiac surgery in a developing country. J Thorac Cardiovasc Surg. 2007;134(3):765-71. 11. M a r i n o B S , L i p k i n P H , N e w b u r g e r J W , e t a l . Neurodevelopmental outcomes in children w ith congenital heart disease: evaluation and management. A scientific statement from the American Heart Association. Circulation. 2012;126(9):1143-72. 12. Lantin-Hermoso MR, Berger S, Bhatt AB, et al. The Care of Children with Congenital Heart Disease in Their Primary Medical Home. Pediatrics. 2017;140(5):1-12. 13. van der Bom T, Zomer AC, Zwinderman AH, et al. The changing epidemiology of congenital heart disease. Nat Rev Cardiol. 2011;8(1):50-60. 14. National Health Mission - Hridyam for little hearts. Available at: http://hridyam.in/chd.php. Accessed June 14, 2018. 15. Moons P, Bovijn L, Budts W, et al. Temporal trends in survival to adulthood among patients born with congenital heart disease from 1970 to 1992 in Belgium. Circulation. 2010;122(22):2264-72. 16. Nieminen HP, Jokinen EV, Sairanen HI. Late results of pediatric cardiac surgery in Finland; a population-based study with 96% follow-up. Circulation. 2001;104(5):570-5. 17. Fixler DE, Nembhard WN, Salemi JL, et al. Mortality in the first 5 years in infants with functional single ventricle born in Texas, 1996 to 2003. Circulation. 2010;121(5):644-50. 18. d’Udekem Y, Xu MY, Galati JC, et al. Predictors of survival after single-ventricle palliation: the impact of right ventricular dominance. J Am Coll Cardiol. 2012;59:1178-85. 19. Balachandran R, Nair SG, Gopalraj SS, et al. Stage one Norwood procedure in an emerging economy: initial experience in a single center. Ann Pediatric Cardiol. 2013;6(1):6-11. 20. Iyer KS. Treating hypoplastic left heart syndrome in emerging economies: heading the wrong way? Ann Pediatr Cardiol. 2013;6(1):12-4. 21. Jicinska H, Vlasin P, Jicinsky M, et al. Does firsttrimester screening modify the natural history of congenital heart disease? Analysis of outcome of regional cardiac screening at 2 different time periods. Circulation. 2017;135(11):104555. 22. Sonek JD, Kagan KO, Nicolaides KH. Inverted pyramid of care. Clin Lab Med. 2016;36(2):305-17. 23. Bull C. Current and potential impact of fetal diagnosis on prevalence and spectrum of serious congenital heart disease at term in the UK. British Paediatric Cardiac Association. Lancet. 1999;354(9186):1242-7. 24. Beroukhim RS, Gauvreau K, Benavidez OJ, et al. Perinatal outcome after prenatal diagnosis of single-ventricle cardiac defects. Ultrasound Obstet Gynecol.2015;45(6):657-63. 25. Dolk H, Loane M, Garne E; European Surveillance of Congenital Anomalies (EUROCAT) Working Group. Congenital heart defects in Europe: prevalence and perinatal mortality, 2000 to 2005. Circulation. 2011;123(8):841-9.
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38.
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tachyarrhythmias: a 10-year single centre experience. Ann Pediatr Cardiol. 2018;11(1):34-9. Eliasson H, Sonesson SE, Sharland G, et al. Isolated atrioventricular block in the fetus: a retrospective, multinational, multicentric study of 175 patients. Circulation. 2011;124(18):1919-26. Jaeggi ET, Fouron JC, Silverman ED, et al. Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation. 2004;110(12):1542-8. McElhinney DB, Tworetzky W, Lock JE. Current status of fetal cardiac intervention. Circulation. 2010;121(10): 1256-63. Levine JC, Tworetzky W. Intervention for severe aortic stenosis in the fetus: altering the progression of left-sided heart disease. Prog Pediatr Cardiol. 2006;22(1):71-8. Tulzer G, Gardiner H. Cardiac interventions in the fetus: potential for right-sided lesions. Prog Pediatr Cardiol. 2006;22(1):79-83. Marshall AC, Levine J, Morash D, et al. Results of in utero atrial septoplasty in fetuses with hypoplastic left heart syndrome. Prenat Diagn. 2008;28(11):1023-8. Donofrio MT, Moon-Grady AJ, Hornberger LK, et al for the American Heart Association Adults with Congenital Heart Disease Joint Committee of the Council on Cardiovascular Disease in the Young and Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Council on Cardiovascular and Stroke Nursing. Diagnosis and treatment of fetal cardiac disease: a scientific statement from the American Heart Association. Circulation. 2014;129(21):2183-242. Hunter S, Heads A, Wylie J, et al. Prenatal diagnosis of congenital heart disease in the northern region of England: benefits of a training programme for obstetric sonographers. Heart. 2000; 84(3):294-8. Donaghue D, Rychik J. The fetal heart program : a multidisciplinary practice model for the fetus with congenital heart disease. Prog Pediatr Cardiol. 2006;22: 129-33.
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35 Fetal Echocardiography: Current Status and Role in Management of Congenital Heart Defects
26. Levey A, Glickstein JS, Kleinman CS, et al. The impact of prenatal diagnosis of complex congenital heart disease on neonatal outcomes. Pediatr Cardiol. 2010;31(5):587-97. 27. Tararbit K , Bui TT, L elong N, et al. Clinical and socioeconomic predictors of pregnancy termination for fetuses with congenital heart defects: a populationbased evaluation. Prenat Diagn. 2013;33(2):179-86. 28. Copel JA, Pilu G, Green J, et al. Fetal echocardiographic screening for congenital heart disease: the importance of the four-chamber view. Am J Obstet Gynecol. 1987;157(3):648-55. 29. Manual for first trimester medical termination of pregnancy. New Delhi: Technical Operations Division, Ministry of Health and Family Welfare, Government of India, Nirman Bhawan; 1971. 30. Reddy NS, Kappanayil M, Balachandran R, al. Benedict Raj, R. Krishna Kumar. Preoperative determinants of outcomes of infant heart surgery in a limited-resource setting. Semin Thorac Cardiovasc Surg. 2015;27(3):331-8. 31. Jouannic JM, Gavard L, Fermont L, et al. Sensitivity and specificity of prenatal features of physiological shunts to predict neonatal clinical status in transposition of the great arteries. Circulation. 2004;110(13):1743-6. 32. Bonnet D, Coltri A, Butera G, et al. Detection of transposition of the great arteries in fetuses reduces neonatal morbidity and mortality. Circulation. 1999;99(7):916-8. 33. Tworetzky W, McElhinney DB, Reddy VM, et al. Improved surgical outcome after fetal diagnosis of hypoplastic left heart syndrome. Circulation. 2001;103(9):1269-73. 34. Tzifa A, Barker C, Tibby SM, et al. Prenatal diagnosis of pulmonary atresia: impact on clinical presentation and early outcome. Arch Dis Child Fetal Neonatal Ed. 2007;92(3):F199-203. 35. Changlani TD, Jose A, Sudhakar A, et al. Outcomes of infants with prenatally diagnosed congenital heart disease delivered in a tertiary-care pediatric cardiac facility. Indian Pediatr. 2015;52(10):852-6. 36. Perles Z, Gavri S, Rein AJJT. Tachyarrythmias in the fetus: state-of-the-art diagnosis and treatment. Prog Pediatr Cardiol. 2006;22:95-107. 37. Karmegeraj B, Namdeo S, Sudhakar A, et al. Clinical presentation, management and post natal outcomes of fetal
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Advances in CT Angiography CHAPTER 36 for Congenital Heart Disease Arun Sharma, Gurpreet S Gulati
INTRODUCTION Computed tomography (CT) imaging of congenital heart disease (CHD) requires an in-depth understanding of the core teaching elements of both cardiology and radiology, with a focused step-wise approach to image interpretation in the clinical context. Echocardiography remains the initial investigation of choice for patients with CHD. Beyond echocardiography, the choice of further imaging needs to be individualized, based upon the clinical question, patient’s condition, imaging expertise, and availability. While magnetic resonance imaging (MRI) is currently preferred for CHD evaluation due to its multiparametric approach and lack of exposure to ionizing radiation or potentially nephrotoxic contrast, CT offers unique benefits for this patient group due to its speed, need for minimal sedation, and ability to provide information on structures not well evaluated with MRI.
CHALLENGES TO CARDIAC IMAGING Noninvasive imaging evaluation of the heart is technically challenging as it is complicated by the off-axis rotation of the heart, and motion artifacts due to cardiac, respiratory, and diaphragmatic movements. In addition, heart hemodynamics change rapidly during different phases of cardiac and respiratory cycle, adding to the difficulty for optimal imaging evaluation. These challenges are compounded by the presence of wide variation in the densities of surrounding tissues, resulting in an adverse impact on the tissue contrast.
TECHNICAL IMPROVEMENTS IN CARDIAC CT Initial CT scanners were limited for cardiac evaluation due to poor temporal and spatial resolution, and long scan times. Many technical improvements in CT technology have come up in recent years, allowing sub-millimeter isotropic spatial resolution, improved temporal resolution (up to 66 msec) and rapid coverage of large anatomic volumes.1-4 With latest multislice (256 and 320 slice) and dual source CT scanners, it is possible to have a spatial resolution of less than 0.4 mm and gantry rotation time of 82 msec or less. This is particularly important in evaluation of small cardiovascular structures, even at the
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high heart rates encountered in a pediatric population. Latest high-pitch scan and volumetric scanners provide full coverage of pediatric thorax in less than a second or a single heartbeat, nearly freezing respiratory motion.5,6 It virtually eliminates the need for beta-blockers and sedation, or anesthesia in these patients. Moreover, retrospective-gated scans may provide quantification of ventricular function with adequate accuracy. Technical advancements in CT equipment have also been successful in reducing radiation exposure by influencing many factors including tube current and voltage, slice thickness, over-lap, scan range, pitch, and ECG-gating. 7,8 Besides, prospective gating with iterative reconstruction in selected patients allows for even greater reduction in radiation doses while maintaining diagnostic image quality.
CHOOSING THE OPTIMAL IMAGING MODALITY IN CHD Echocardiography Echocardiography remains the initial investigation of choice for majority of CHD patients. It optimally visualizes most of the intracardiac anatomy and provides functional information. Mitral valve flow patterns help in detecting abnormalities in left ventricular filling in many diseases. ECHO is, however, limited in accurately quantifying single or right ventricular size and systolic function. Besides, it is often difficult to adequately assess complex systemic or pulmonary venous anatomy, distal pulmonary arteries, and cavopulmonary anastomoses in patients with single ventricle physiology. Moreover, older or operated patients may have suboptimal windows for ECHO assessment.
Catheter Angiography Catheter angiography remains the gold standard investigation for assessing pressure difference across a vessel or cardiac chamber. Moreover, it is the only method to determine pulmonary artery pressure and pulmonary vascular resistance accurately, which play an important role in decision making for surgery. However, it is invasive and provides only luminal details with 2-dimensional
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Cardiovascular MRI In recent years, MRI has become an essential component of CHD evaluation complimentary to ECHO.9,10 It serves as a problem-solving tool in the evaluation of preoperative and postoperative cardiovascular anatomy and for certain postoperative complications. It characterizes cardiac structures very well (improved tissue differentiation with higher signal and contrast to noise ratio) and provides functional assessment with additional advantage of perfusion and viability imaging. However, higher cost, limited availability, long acquisition time, and operator dependency have limited the widespread use of MRI. Moreover, MRI may be limited due to poorer spatial resolution, presence of image degrading artifacts from implanted metal, such as intravascular stents and embolization coils, pacemakers and greater need for general anesthesia in younger children.
Cardiovascular CT Due to newer generation multislice CT scanners, it has now become possible to image the heart with more accuracy in shorter time.2,3 Shorter acquisition times (4–5 seconds vis-à-vis an hour in MRI) and higher spatial resolution have made CT the investigation of choice for assessment of children with arrhythmia or in situations where purely anatomic information is required beyond an ECHO. It also scores over MRI in imaging evaluation of critically ill and uncooperative pediatric patients. Simultaneous assessment of the airway, lungs, and skeletal anatomy also helps in mapping optimal treatment strategy. Cardiovascular CT is now recommended as an adjunct to echocardiography when cardiac MRI is contraindicated or considered high risk and is unlikely to provide optimal quality images to answer a specific clinical question.
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There are several generally accepted clinical indications of CT in these patients, for which the benefits of imaging outweigh the risks. These are discussed in brief below.
Situs Evaluation The CT allows accurate assessment of situs with detailed information on bronchial branching pattern, atrial sidedness, and relationship of abdominal viscera. Sequential segmental approach allows accurate identification of situs abnormalities and intracardiac lesions, in addition to depiction of associated extracardiac lesions (Figures 1A to D).
Great Vessel Anatomy The pulmonary arteries, pulmonary veins, and aortic arch may be inadequately characterized at echocardiography, necessitating further assessment with CT. Marked morphologic variability in the source and arborization pattern of the pulmonary blood supply is seen in CHDs. Confluent, good sized pulmonary arteries are associated with successful surgical outcome, whereas small arteries would need augmentation procedures to improve pulmonary blood flow (Figure 1A). Isolated stenosis or absence of pulmonary artery, presence of pulmonary artery sling and anomalous arterial supply such as seen in scimitar syndrome with sequestration are all well seen on CT.11-16
Coronary Arteries Coronary anomalies are common in patients with CHD, and precise delineation prior to surgical intervention is often indicated, as it may alter the surgical course. Any interventions on right ventricular outflow tract should be preceded by unambiguous definition of coronary artery anatomy for uneventful surgical management. Coronary artery origin and course (Figures 1D and 2), ostial narrowing, dominance, angulations from the aortic root, coronary artery fistula, and presence and length of intramural course can be well seen on CT.17-20
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Figures 1A to D: CT angiography images in a patient with tetralogy of Fallot shows confluent small pulmonary arteries (broken arrows in A), subaortic ventricular septal defect (* in C), multiple significant aortopulmonary collaterals (arrowheads in B) with normal coronaries (arrows in D)
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assessment. With the advent of recent improvements in cross-sectional imaging, catheter angiography is no longer required for the diagnosis and management of most forms of CHD and is generally reserved for patients requiring invasive hemodynamic evaluation or endovascular treatment.
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Figure 2: CT angiography image shows high take off of right coronary artery (arrow) from ascending aorta in a patient with congenital heart disease
Aortopulmonary Collaterals The aortopulmonary collaterals (APCs) are usually seen in association with cyanotic congenital heart diseases such as tetralogy of Fallot (TOF) or pulmonary atresia (Figure 1B). They may serve as an additive or the only source of blood supply in these cases, depending upon the status of native pulmonary arterial supply. These are fragile vessels and may rupture easily. Moreover, they flood the surgical field and may become major source of gaseous microemboli. Postoperatively, they represent a common cause of persistent pleural effusions. The CT provides detailed information about the site of origin, number, size (exact diameter, areas of stenosis, or aneurysm), course, and the areas of the lungs they supply, which may offer an efficient road map for safe and successful selective embolization.
Systemic and Pulmonary Veins It accurately delineates systemic venous anomalies, which may be important for patients undergoing univentricular repair. These may include persistent left superior vena cava (SVC), retro-aortic innominate vein, interruption of the inferior vena cava, or double SVC (Figure 3A). The exact type of anomalous pulmonary venous return, site of drainage, and presence of anatomic obstruction (Figure 3B) are well seen on CT.21,22 Another potential indication includes pacemaker-dependent patients, who are referred for cardiac resynchronization therapy (CRT). Evaluation of coronary
sinus and coronary venous anatomy on CT can help determine the procedural approach for electrophysiology (EP) device lead placement in these patients.23
Aortic Arch Anomalies and Airway Compression Aortic arch anomalies may be seen associated with CHDs. Right aortic arch with mirror image branching is strongly associated with CHDs in more than 98% of cases, including TOF, truncus arteriosus, tricuspid atresia, and transposition of great arteries. Detailed evaluation of aortic arch anatomy is important for planning surgical or endovascular treatment option, as the presence and pattern of arch variants and anomalies may influence the surgical incision, cardiopulmonary bypass cannulation, and/or interventional approach. The CT has been shown to accurately visualize congenital aortic anomalies such as double aortic arch, aortic coarctation (Figures 4A and B), interrupted aortic arch, and circumflex aorta.24 Dominance of aortic arch, length of atretic segment, origins of aortic arch vessels, and associated airway compression are well seen on CT.
Evaluation of Ventricular Size and Function Though cardiac MRI remains the gold standard technique for cardiac function assessment, cardiac CT with retrospective ECG-gating can be utilized to obtain
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Figures 3A and B: CT angiography image shows double superior vena cava (* in A) in patient with tetralogy of Fallot. CT angiography image from different patient shows obstructed (arrow in B) total anomalous pulmonary venous drainage with common channel (arrowhead in B) draining into dilated portal vein (* in B)
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B Figures 4A and B: CT angiography images show postductal coarctation (arrow in A) with multiple collaterals (arrowheads in B) from descending thoracic aorta
accurate ventricular assessments comparable to cine magnetic resonance (CMR). 25,26 Ventricular dilatation, myocardial thinning and hypodensity, presence or absence of intracardiac thrombus, and regional wall motion abnormalities can all be seen on CT.
Postoperative Evaluation The CT can be used in the assessment of patients operated for CHD (Figures 5A and B) who may have a variety of treatment-related complications. It can evaluate systemic and pulmonary venous baffle obstruction and may help 305
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Figures 5A and B: CT angiography image shows patent modified left Blalock-Taussig shunt (arrow in A). Occluded modified right Blalock-Taussig shunt (arrow in B) is seen in a different patient with congenital heart disease
in evaluating right ventricle (RV) size and function. 27 Baffle leaks are, however, difficult to optimally visualize on CT, unless there is differential opacification showing a negative or positive contrast jet between the atria. Complications of CHD surgery, such as coronary ostial stenosis, neopulmonary artery and branch pulmonary artery stenosis, and neoaortic root stenosis, and dilatation or insufficiency can also be well seen on CT. Shunt obstruction (Figure 5B), thrombus in Fonton circuit, and kinks in reimplanted coronary arteries can also be well seen on CT.28-30 It is particularly useful for evaluation of the aortic arch after endovascular intervention to clearly demonstrate pseudoaneurysm, aortic wall injury, or recurrent arch obstruction, which may be seen in these patients.
sternotomy should be carefully seen and reported for consideration of peripheral bypass at the time of sternal entry.31,32
Associated Findings (Pre-and Postoperative)
Newer CT technologies are constantly evolving, thus widening the scope of cardiac CT from traditional coronary artery assessment to complete depiction of intracardiac morphology, function, perfusion, postoperative complications, and follow-up in addition to the depiction of extracardiac details. Judicious use of CT is recommended in selected patients with CHD such as those where anatomic information mandates the choice and type of surgery. Knowledge of cardiovascular anatomy, physiology, and various surgical techniques is important with a step-wise, segmental approach for optimal interpretation of imaging appearances.
The CT is able to provide rapid comprehensive assessment of lungs, airways, and skeletal anatomy (Figures 6A and B). The CT quickly displays evidence of a variety of CHDrelated complications (both pre- and postoperative) and numerous other medical conditions such as pulmonary embolism, pneumonia, pleural and pericardial effusion, and pneumothorax. The CT can be useful before a reoperation to assess altered anatomic features related to previous surgery. Proximity of the coronary arteries and cardiac structures to the posterior sternum prior to repeat
LIMITATIONS The CT imaging has some inherent limitations such as poor myocardial tissue characterization, inability to quantify valve regurgitation (with multiple regurgitant lesions or shunt), need for iodinated contrast, and exposure to ionizing radiation. Moreover, breath holding is still needed for images acquired over several heart beats such as for functional imaging and detailed coronary artery imaging at high heart rates.
CONCLUSION
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Figures 6A and B: CT angiography images in lung window shows presence of multiple nodular lesions with areas of cavitation (arrow in A) suggestive of septic emboli in a patient of tetralogy of Fallot. Left lung hypoplasia (arrowheads in B) with small left bronchus (arrow in B) is seen in another patient with congenital heart disease
REFERENCES 1. Dillman JR, Hernandez RJ. Role of CT in the evaluation of congenital cardiovascular disease in children. AJR Am J Roentgenol. 2009;192(5):1219-31. 2. Goo HW, Park IS, Ko JK, et al. Computed tomography for the diagnosis of congenital heart disease in pediatric and adult patients. Int J Cardiovasc Imaging. 2005;21(2):347-65. 3. Danad I, Fayad ZA, Willemink MJ, et al. Recent Advances in Cardiac Computed Tomography: Dual Energy, Spectral and Molecular CT Imaging. JACC Cardiovasc Imaging. 2015;8(6):710–23. 4. Siegel MJ. Cardiac CTA: congenital heart disease. Pediatr Radiol. 2008;38(Suppl 2):S200-4. 5. Han BK, Lindberg J, Grant K, et al. Accuracy and safety of high pitch computed tomography imaging in young children with complex congenital heart disease. Am J Cardiol. 2011;107(10):1541-6. 6. Flohr TG, Leng S, Yu L, et al. Dual-source spiral CT with pitch up to 3.2 and 75 ms temporal resolution: image reconstruction and assessment of image quality. Med Phys. 2009;36(12):5641-53. 7. Siegel MJ, Schmidt B, Bradley D, et al. Radiation dose and image quality in pediatric CT: effect of technical factors and phantom size and shape. Radiology. 2004;233(2):515-22. 8. Huang MP, Liang CH, Zhao ZJ, et al. Evaluation of image quality and radiation dose at prospective ECG-triggered axial 256-slice multi-detector CT in infants with congenital heart disease. Pediatr Radiol. 2011;41(7):858-66. 9. Crean A. Cardiovascular MR and CT in congenital heart disease. Heart. 2007;93(12):1637-47. 10. Chan FP. MR and CT imaging of the pediatric patient with structural heart disease. Semin Thorac Cardiovasc Surg. 2008;20(4):393-9.
11. Balci TA, Koc ZP, Kirkil G, et al. Isolated left pulmonary artery agenesis: a case report. Mol Imaging Radionucl Ther. 2012;21(2):80-3. 12. Hernanz-Schulman M. Vascular rings: a practical approach to imaging diagnosis. Pediatr Radiol. 2005;35(10):961-79. 13. Haest RJ, van den Berg CJ, Goei R, et al. Scimitar syndrome; an unusual congenital abnormality occasionally seen in adults. Int J Cardiovasc Imaging. 2006;22(3-4):565-8. 14. Yu H, Li HM, Liu SY, et al. Diagnosis of arterial sequestration using multidetector CT angiography. Eur J Radiol. 2010;76(2):274-8. 15. Maeda E, Akahane M, Kato N, et al.Assessment of major aortopulmonary collateral arteries with multidetector-row computed tomography. Radiat Med. 2006;24(5):378-83. 16. Greil GF, Schoebinger M, Kuettner A, et al. Imaging of aortopulmonary collateral arteries withhigh-resolution multidetector CT. Pediatr Radiol. 2006;36(6):502-9. 17. Yu FF, Lu B, Gao Y, et al. Congenital anomalies of coronary arteries in complex congenital heart disease: diagnosis and analysis with dual-source CT. J Cardiovasc Comput Tomogr. 2013;7(6):383-90. 18. Machida H, Tanaka I, Fukui R, et al. Current and novel imaging techniques in coronary CT. Radiographics. 2015; 35(4):991-1010. 19. Stein PD, Beemath A, Kayali F, et al. Multidetector computed tomography for the diagnosis of coronary artery disease: a systematic review. Am J Med. 2006;119(3):203-16. 20. Deibler AR, Kuzo RS, Vohringer M, et al. Imaging of congenital coronary anomalies with multislice computed tomography. Mayo Clin Proc. 2004;79(8):1017-23. 21. Bonelli-Sica JM, de la Mora-Cervantes R, Diaz-Zamudio M, et al. Dual-source 256-MDCT for diagnosis of anomalous pulmonary venous drainage in pediatric population. AJR Am J Roentgenol. 2013;200(2):W163-9.
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22. Oh KH, Choo KS, Lim SJ, et al. Multidetector CT evaluation of total anomalous pulmonary venous connections: comparison with echocardiography. Pediatr Radiol. 2009;39(9):950-4. 23. N i a z i I , D h a l a A , C h o u d h u r i I , e t a l . C a r d i a c Resynchronization Therapy in Patients with Challenging Anatomy Due to Venous Anomalies or Adult Congenital Heart Disease. Pacing Clin Electrophysiol. 2014;37(9): 1181-8. 24. Brown ML, Burkhart HM, Connolly HM, et al. Coarctation of the aorta: lifelong surveillance is mandatory following surgical repair. J Am Coll Cardiol. 2013;62(11):1020-5. 25. Brodoefel H, Kramer U, Reimann A, et al. Dual-source CT with improved temporal resolution in assessment of leftventricular function: a pilot study. AJR Am J Roentgenol.2007;189(5):1064-70. 26. Guo YK , Gao HL , Zhang XC , et al. Accurac y and reproducibility of assessing right ventricular function with 64-section multi-detector row CT: comparison with magnetic resonance imaging. Int J Cardiol. 2010;139(3): 254-62.
27. Raman SV, Cook SC, McCarthy B, et al. Usefulness of multidetector row computed tomography to quantify right ventricular size and function in adults with either tetralogy of Fallot or transposition of the great arteries. Am J Cardiol. 2005;95(5):683-6. 28. Piggott KD, Nykanen DG, Smith S. Computed tomography angiography successfully used to diagnose postoperative systemic-pulmonary artery shunt narrowing. Case Rep Cardiol. 2011;2011:802643. 29. Grewal J, Al Hussein M, Feldstein J, et al.Evaluation of silent thrombus after the Fontan operation. Congenit Heart Dis. 2013;8:40-7. 30. Lee SY, Baek JS, Kim GB, et al. Clinical significance of thrombosis in an intracardiac blind pouch after a Fontan operation. Pediatr Cardiol. 2012;33:42-8. 31. Russell JL, LeBlanc JG, Sett SS,et al. Risks of repeat sternotomy in pediatric cardiac operations. Ann Thorac Surg. 1998;66(5):1575-8. 32. Adibi A, Mohajer K, Plotnik A, et al. Role of CT and MRI prior to redo sternotomy in paediatric patients with congenital heart disease. Clin Radiol. 2014;69(6):574-80.
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Best Use of Cardiac MRI in CHAPTER 37 Congenital Heart Disease Mahesh Kappanayil, Rajesh Kannan
INTRODUCTION Congenital heart diseases (CHD) are the most common structural birth defects among humans, and the reported incidence of moderate to severe CHD is between 4–7 per 1000 live births. The incidence is much higher (50–75 per 1000 live births) if one includes minor lesions like bicuspid aortic valves, atrial septal aneurysms, tiny muscular ventricular septal defects (VSD), etc.1,2 The range and complexity of lesions in the spectrum of CHD can be extremely varied, from minor defects to heterotaxy syndromes with complex intracardiac abnormalities. What makes CHD assessment and management particularly challenging is the fact that these structural malformations go hand-in-hand with a wide range of physiological and hemodynamic consequences. Management principles, timing of treatment, and outcomes depend on precise understanding of both anatomical and physiological aspects. While some CHD present early and may require repair/palliation in newborn period or infancy, others may require intervention later in life; some may go undetected/unrepaired and present much later with complications. Many forms of CHD require multiple staged procedures (e.g. single ventricular physiology, surgeries requiring prosthetic conduits or valves, etc.); most require long-term follow-up for various events occurring in their natural history. Cardiovascular imaging is crucial to understanding CHD, planning its management, and for long-term follow-up. Challenges and requirements from the imaging are different at different stages. The fundamental, most commonly used modalities for cardiovascular imaging include echocardiography and angiocardiography. Ech o ca rd i o g rap hy i s n o n - i nva si ve, sa f e a n d inexpensive, and provides substantial anatomic and hemodynamic information. Echocardiogram has good spatial and temporal resolution, but is limited by acoustic windows, poor signal/noise ratio, geometric assumptions and limited ability to assess extracardiac structures. Cardiac catheterization and angiocardiography is invasive, and involves exposure to ionizing radiation—but offers ability to obtain excellent hemodynamic information pertaining to pressures
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and shunt quantification, and also an opportunity for intervention. But angiographic imaging is limited to specific planes, and catheter-derived shunt/resistance calculations rely on mathematical assumptions. Advanced radiological imaging tools—multi-detector cardiac computed tomography (MDCT) and cardiac magnetic resonance imaging (CMRI) have recently found increasing role in evaluation of CHD. CT provides volumetric imaging datasets with high spatial resolution, allowing multi-planar visualization, reconstructions and precise 3-dimensional understanding of cardiovascular structures—including extracardiac structures. However, it involves exposure to ionizing radiation, and has limited ability to provide hemodynamic information.
CARDIAC MRI Cardiac magnetic resonance imaging (CMRI) is rapidly gaining importance as a powerful, versatile and multidimensional imaging tool for comprehensive assessment of CHD. Based on the phenomenon of nuclear magnetic resonance (NMR)—this technique uses the NMR signal emitted by molecules of body tissues (hyodrogen atoms) upon application of an external radiofrequency (RF) energy while within a high magnetic field—to generate images. The contrast between different tissues is determined by the rate at which excited atoms return to the equilibrium state. By changing the parameters on the scanner this effect is used to create contrast between different types of body tissue. Unlike CT, CMRI is not a single homogenous modality, rather it comprises of multiple NMR-based techniques or “pulse sequences”, which provide different forms of morphological and physiological information. Pulse sequences are different software programs that encode magnitude and timing of RF pulses emitted by the MR scanner, switching of the magnetic field gradient, and data acquisition, each one tailored for a specific purpose. Each CMR study, typically, is comprised of a set of different sequences that are chosen to answer the specific study questions of the particular case.
Basic CMRI Sequences CMRI sequences are broadly classified into ‘bright-blood’ and ‘dark blood’ sequences.3
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Bright-blood sequences: Also called gradient recalled sequences (GRE), shows fast flowing blood as bright or high intensity, and the surrounding tissue appears dark. Cine GRE sequences can be used to produce moving images (much like 2D echocardiographic images that cardiologists are used to seeing) by stitching together different phases of the cardiac cycle. These sequences allow excellent anatomical delineation of intracardiac and vascular anatomy. The cine sequence allows excellent dynamic visualization, as well as computation of cardiac functions—due to excellent temporal resolution (Figure 1). Dark-blood or black blood sequences: Fast flowing blood appears dark or low intensity. Static black blood images allow excellent anatomic delineation of cardiac chambers and vascular structures. The technique is particularly useful to differentiate between the vessel wall and inner lumen, and intracardiac masses from normal structures. Tissue contrast in MRI is related to signal intensity differences, which are mainly determined by the proton density, T1 and T2 relaxation time differences, flow and motion effects, and magnetic susceptibility, as they are related to the pulse sequence applied. In general, tissue
characteristics and pathologic changes are generally more pronounced on black blood images. Signal intensity on GRE images largely reflects differences in proton density; these images inherently show lower tissue contrast. A newer pulse sequence known as steady state free precession (SSFP) has been applied to cardiac cine studies, leading to greater contrast between myocardium and blood pool (Figure 1). Imaging data can be acquired in any plane, allowing infinite options. Imaging planes are decided according to the needs of the case, and optimized against the time required for the acquisitions.
Other Pulse Sequences Phase contrast MRI (PC-MRI): A pulse sequence with velocity encoding of the signal intensities—gradient pulses induce shifts in moving protons, directly proportional to their velocity along direction of gradient. PC-MRI allows accurate estimation of flow velocity profiles across any valvular or vascular structure. This is among the most valuable hemodynamic assessment tools in CMRI, allowing accurate flow quantifications (Figure 2).4,5
Figure 1: Shows a frozen frame from cine SSFP ventricular short axis stack. This is a “bright blood” pulse sequence. The short axis stack is used for calculating end-diastolic and end-systolic ventricular volumes and determining the ejection fraction. The sequence gives excellent dynamic assessment of anatomy and function
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MR angiography (MRA): Mainly for assessment of the blood vessels. Contrast-enhanced MRA is a standard 3-dimensional spoiled gradient echo sequence with intravenous injection of gadolinium contrast, enhancing anatomic visualization. Non-contrast 3-dimensional segmented SSFP sequence (‘whole heart’) can be used for evaluating intracardiac anatomy and the coronaries. MRA thus provides volumetric imaging data (like CT) which can be post-processed through multiplanar visualization and 3-dimensional volume reconstructions (Figure 3). Myocardial perfusion imaging: Magnetization-prepared gradient echo sequences which allow differentiation between non-ischemic and ischemic myocardial segments. Ischemic segments appear dark (perfusion defects) as compared to normal segments, soon after injection of contrast agent (first pass). Stress perfusion studies (using adenosine infusion) allow assessment of reversible ischemia. Myocardial delayed enhancement (MDE) sequence: Inversion recovery gradient echo sequence taken 10–15 minutes after injecting contrast–allows myocardial scars and infarcts to be identified by their bright appearance as compared to normal myocardium, due to retention of contrast in the scarred/fibrotic regions. Other sequences that can be applied where needed, include myocardial tissue tagging for myocardial wall motion calculations and strain analysis, T2* for myocardial iron assessment. Thus, CMRI is a bouquet of multiple techniques that can be used in versatile ways and in case-specific combinations, to answer a host of study questions relevant to CHD: Morphology (cine SSFP, black blood, MRA) Ventricular functions (cine SSFP) Blood flow (PC-MRI) Myocardial ischemia (perfusion sequence)
Figure 3: Shows a frozen frame from SSFP sequence in a patient with double outlet right ventricle (DORV). The sequence has been prescribed in a plane that clearly shows the left ventricle (LV) to Aorta (AO) pathway, the ventricular septal defect (vsd), and the relationship between the right ventricle (RV) and pulmonary artery (PA). Conal septum (cs) can be seen intruding in the LV-AO pathway
Myocardial scarring and fibrosis (MDE) Myocardial wall motion, myocardial strain. Goals of imaging need to be clearly defined prior to the scan, and sequences need to be planned and optimized on case-to-case basis. Specialized reporting software platforms are used to store and post-process the imaging data—to calculate ventricular volumes and functions, calculate blood flows, generate graphic representations of the data (e.g. blood-flow versus time) and for multi-planar viewing and reconstruction.
Best Use of Cardiac MRI in Congenital Heart Disease
Figure 2: Shows phase contrast MRI (PC-MRI) image prescribed in axial plane. PC-MRI sequence is used for assessing flows across vascular/valvular structures
Specific Advantages of CMR in CHD Evaluation
Noninvasive and devoid of radiation exposure (as compared to CT and angiocardiography)—therefore suitable for multiple, serial evaluations. Powerful tool that is independent of imaging windows (acoustic windows limit the imaging abilities of echocardiography). This becomes particularly important as acoustic windows become increasingly difficult with age and growth. Adolescents and adults with CHD, particularly those with complex lesions, are prime examples (Figure 4). Allows a combination of morphological and physiological assessment in a single comprehensive study. Functional assessment tools provide unique and powerful ways to assess physiology. Contouring of endocardial borders and derivation of end-diastolic and end-diastolic volumes irrespective of the cardiac-chamber geometry allows accurate and reproducible assessment of volumes and function. Short axis or axial stacks (SSFP) are typically used for assessing ventricular volumes and systolic 311
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as well as that of all ancillary equipment has to be ensured. Difficult in patients with claustrophobia or poor cooperation—necessitating general anesthesia. Monitor ing dur ing scans, and access dur ing emergencies is challenging. Therefore, may not be ideal for critically ill or unstable patients. Potential risk of gadolinium-induced nephrogenic systemic fibrosis in patients with end-stage renal failure.6
Specific Applications in Congenital Heart Disease Figure 4: Shows 3-dimensional rendering on the cardiac and extracardiac anatomy in a case of complex heart disease following Glenn (superior vena cava to right pulmonary artery) shunt. Multiple veno venous collaterals can be seen
functions (Figure 1). While echocardiogram is well validated for calculating left ventricular volumes and functions, it is highly inadequate when it comes to assessing the right ventricle (RV) or complex ventricle anatomies. CMRI is the modality of choice for assessment of the RV as well as all types of complex ventricular morphologies (including single-ventricles) irrespective of geometry or spatial orientation. PC-MRI is the gold standard for assessment of blood flow. Determining flow data across structures representing pulmonary and systemic blood flow gives accurate estimate of Qp:Qs, independent of the mathematical assumptions used in cardiac catheterization. PC-MRI is the gold standard for calculating regurgitation fractions across valves. It also allows assessment of very specific flow information, e.g. differential blood flows in branch pulmonary arteries, flows through aortopulmonary collaterals, pulmonary venous flows, etc. Used in combination, these tools for CMRI functional assessment can provide unique and deep insight into physiology accurately and non-invasively.
Disadvantages of CMRI
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CMR facilities are not widely available in resourcelimited environments: — Expensive hardware and software — Expertise and training required for performing and interpreting CHD-CMR. Relatively expensive, particularly in comparison to echocardiography. Does not provide pressure data (as opposed to cardiac catheterization). Technically challenging with long scan times. MRI-compatibility and MRI-safety of patient’s prothetics, artificial valves, stents and pacemakers,
Postoperative assessment of tetralogy of Fallot: CMRI is the modality of choice for serial assessment in this subset of patients. Following TOF repair, CMRI can be used to obtain comprehensive information on the following: (1) biventricular volumes and mass; (2) biventricular function (stroke volume, ejection fraction, regional wall motion abnormalities); (3) accurate quantification of flows – residual shunts, valve regurgitation, differential pulmonary artery flows (Figure 5); (4) description of anatomy of the RVOT, branch pulmonary arteries, aortic root, ascending aorta, aortopulmonary collaterals; (5) assessment of myocardial viability and scar tissue; (6) coronary arteries. CMRI is indicated for routine surveillance, beginning the second decade and the frequency of evaluation is dictated by the baseline condition. Data has emerged that shows that CMR-derived ventricular volumes and functions help in risk-stratification by predicting risk for heart failure, sustained ventricular tachycardia and SCD.7-10 Current guidelines on pulmonary valve implantation are based on CMR-derived data. Comprehensive assessment of complex CHD, especially in older patients: — Heterotaxy syndromes – wide range of viscerocardiac abnormalities. — Multiple extracardiac abnormalities. — Complex venoatrial, atrioventricular, interventricular and ventriculo-arterial relationships, e.g. double-outlet right ventricle (DORV ), congenitally corrected transposition of great arteries (CCTGA), anatomically corrected malposition of great arteries (ACMGA), superioinferior ventricular relationships, criss-cross atrioventricular connections. Decision-making for single-ventricle versus biventricular repair in complex lesions.11 — Adequacy of ventricular volumes for biventricular repair: Accurate estimation of ventricular volumes (SSFP) irrespective of the shape, size or lie of the cardiac chambers aids decision-making regarding suitability for 2-ventricle (2V) repair. Calculated
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Figure 5: Representative images from CMRI assessment of post-tetralogy of Fallot (TOF) repair—SSFP image of the right ventricular outflow tract, and PC-MRI-derived flow-time graphs for calculating regurgitation fractions across the pulmonary arteries
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volumes can be compared against normative values. Chambers can be contoured according to the anticipated lie of the VSD patches or tunnels to estimate post-surgical volumes. — Routability of ventricular septal defects for intraventricular tunneling in DORVs: SSFP images provide dynamic assessment of the pathways, allowing anticipation of surgical challenges (Figure 4). — Need for conduits: 3D anatomical understanding of intracardiac anatomy allows accurate prediction of the need for right-ventricle-to-pulmonary artery conduits in complex repairs. — Coronary anatomy (especially the origins and proximal course) can be well understood on 3D SSFP (whole heart) sequences and MRA. Physiological and blood-flow assessment for decisionmaking in complex lesions : CMRI can provide vital hemodynamic information using PC-MRI sequences—Qp:Qs, valve regurgitation fractions and differential flows in vessels. — Qp:Qs is traditionally calculated using oxymetry data obtained during cardiac catheterization. This technique is prone to errors due to assumption of oxygen consumption and technical issues with sampling. Estimations are also likely to be erroneous when there are multiple sources of pulmonary blood flow, e.g. antegrade pulmonary flows + flow through aortopulmonary collaterals + flows via Blalock Taussig or Glenn shunts. PC-
—
—
CMRI can be used to calculate the total effective pulmonary blood flow in these situations by calculating the pulmonary venous return from each lung segment.12 CMRI allows internal cross validation of hemodynamic data by comparing different means of deriving a desired physiological value, e.g. pulmonary blood flow can be calculated using PC-MRI on the main pulmonary artery (MPA), or as a sum of the flows in both branch PAs, and/or factoring-in the flows through surgical shunts and collaterals, or as a sum of the flow-return through each pulmonary vein. Similarly, systemic venous return may be calculated using PC-MRI derived flows in ascending aorta, or by the sum total of flows in inferior vena cava (IVC) and superior vena cava (SVC). SSFP ventricular contouring derived ventricular outputs can also be compared against the flows entering each great vessel. Thus, CMR provides a unique way to acquire and validate vital information on blood flows, aiding decisionmaking. Combining invasive pressure data (e.g. internal jugular vein cannulation in post-Glenn patient) with CMRI-derived anatomic and physiological information greatly augments the overall understanding and aids clinical decisions. Need for routine pre-Fontan cardiac catheterization can be eliminated in most patients using this technique.
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Figure 6: 3-D printed models of complex cardiac lesions, created using CMRI-derived volumetric data
CMR is likely to become the modality of choice in the long-term follow-up and serial evaluation for the large majority of complex surgical repairs including post arterial switch operation, DORV-repair, repair of anomalous left coronary artery from pulmonary artery (ALCAPA), Senning’s operation, double-switch operation and single-ventricle palliations. Volumetric imaging datasets (3D MRA, 3D SSFP) are used for 3D rendering, giving excellent 3-dimensional spatial understanding. Latest technological advancements now allow creation of 3D printed prototypes of complex cardiac anatomies for surgical planning (Figure 6).13
CONCLUSION Different modalities of cardiac imaging have their own strengths and weaknesses. Choice of modality depends upon the specific clinical questions that need to be answered, weighed-in against multiple other factors that include cost, accessibility, safety and accuracy. In most cases, multiple modalities need to be used in an efficient manner, complimenting each other. T h e ro l e o f C M R I i n C H D - i ma g i n g i s l i k e l y to exponentially grow in the future, complimenting, and at times even replacing some other modalities in specific circumstances. With advances in computational technology, the already versatile range of CMR sequences is likely to expand further in application, accuracy and efficiency. With increasing access, reducing costs,
greater safety and lesser scan times—CMR is likely to be increasingly adopted for CHD-care even in resourcelimited environments.
REFERENCES 1. Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39(12):1890-900. 2. Fyler DC, Buckley LP, Hellenbrand WE, et al. Report of the New England Regional Infant Cardiac Program. Pediatrics. 1980;65(Suppl.):377-460. 3. Biglands JD, Radjenovicand A, Ridgway JP. Cardiovascular magnetic resonance physics for clinicians: Part II. J Cardiovasc Magn Reson. 2012;14:14-66. 4. Meier D, Meier S, Bosiger P. Quantitative flow measurements on phantom and on blood vessels with MR. Magn Reson Med. 1988;8:25-34. 5. Rebergen SA, Niezen RA, Helbing WA, et al. Cine gradientecho MR imaging and MR velocity mapping in the evaluation of congenital heart disease. Radiographics. 1996;16(3):467-81. 6. Perazella MA, Reilly RF. Nephrogenic systemic fibrosis: recommendations for gadolinium-based contrast use in patients with kidney disease. Semin Dial. 2008;21(2):171–3. 7. G e v a T. R e p a i re d Te t ra l o g y o f Fa l l o t : t h e ro l e s of cardiovascular magnetic resonance in evaluating pathophysiology and for pulmonary valve replacement decision support. J Cardiovasc Magn Reson. 2011;20:13:9. doi: 10.1186/1532-429X-13-9. 8. Geva T, Sandweiss BM, Gauvreau K, et al. Factors associated with impaired clinical status in long-term survivors of tetralogy of Fallot repair evaluated by magnetic resonance imaging. J Am Coll Cardiol. 2004;43(6):1068-74.
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towards single-ventricle repair. Interact Cardiovasc Thorac Surg. 2014;18(3):266-71. 12. Kappanayil M, Kannan R, Kumar RK. Understanding the physiology of complex congenital heart disease using cardiac magnetic resonance imaging. Annals of Pediatric Cardiology. 2011;4:177-82. 13. Kappanayil M, Koneti NR, Kannan R, et al. Threedimensional-printed cardiac prototypes aid surgical decision-making and preoperative planning in selected cases of complex congenital heart diseases : Early experience and proof of concept in a resource-limited environment. Ann Pediatr Cardiol. 2017;10(2):117-25.
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9. Knauth AL, Gauvreau K, Powell AJ, et al. Ventricular size and function assessed by cardiac MRI predict major adverse clinical outcomes late after tetralogy of Fallot repair. Heart. 2008;94(2):211-6. 10. Valente AM, Gauvreau K , Babu-Narayan SV, et al. Ventricular size and function measured by cardiac MRI improve prediction of major adverse clinical outcomes independent of prolonged QRS duration in patients with repaired tetralogy of Fallot (abstr). Circulation. 2011. 11. Kottayil BP, Sunil GS, Kappanayil M, et al. Two-ventricle repair for complex congenital heart defects palliated
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Acyanotic Congenital Heart Disease Natural History of Ventricular Septal Defect
Sakshi Sachdeva, Shyam S Kothari Ventricular Septal Defect with Aortic Regurgitation
Manoj Kumar Rohit, Kanabar Kewal Imaging of Atrial Septal Defect
Kshitij Sheth, Bharat Dalvi Lutembacher’s Syndrome
Bhanu Duggal, Yash Shrivastava, Pintu Sharma Which Device for which Patent Ductus Arteriosus?
IB Vijayalakshmi Aneurysms of the Sinuses of Valsalva
Kewal C Goswami, Sivasubramanian Ramakrishnan, Siddharthan Deepti Coarctation of Aorta in Adults: Diagnosis and Current Management Strategies
PV Suresh
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Natural History of Ventricular CHAPTER 38 Septal Defect Sakshi Sachdeva, Shyam S Kothari
NATURAL HISTORY OF VENTRICULAR SEPTAL DEFECT Appreciation of the natural history of ventricular septal defect (VSD) is a prerequisite for appropriate management of children born with this defect. The VSD is the most common congenital heart defect (CHD) and isolated VSD constitutes about 30% of the total congenital heart defects (CHD).1 In general, CHD occurs in about 0.8–1% of live births throughout the world uniformly with marginal differences such as higher incidence of subarterial VSDs in the oriental regions.2,3 This article deals with the natural history of isolated VSDs and does not include VSD in other congenital defects such as tetralogy of Fallot, etc. where a malaligned VSD is seen which is in fact a space and not a defect in the septum; thus such malaligned VSDs never close spontaneously. It is important to follow a common nomenclature in order to maintain uniformity in communication; thus nowadays, VSDs are classified as: subarterial; perimembranous; inlet; and muscular VSDs.4 Muscular
A
VSDs are further classified into anterior, posterior, mid, apical, or outlet muscular depending on their location in the trabecular septum (Figures 1A and B). The VSDs can be classified as small, moderate, and large depending upon their size in comparison to diameter of aortic valve.5 The defects which are less than one-third the size of aortic valve are small VSDs; those more than two-thirds of aortic valve diameter are large defects; while those between one-third and two-thirds of aortic valve diameter are moderate defects. Depending upon the pressure gradient across the defect, they are labeled as nonrestrictive if gradient is ≤20 mm Hg; moderately restrictive defects have 20–40 mm Hg pressure gradient across them; and restrictive defects have >40 mm Hg gradient. Perimembranous defects account for 80% of all VSDs, followed by muscular defects with 5%. Subarterial VSDs form 5–10% of all defects, and inlet VSDs account for 20 mm Hg across coarctation segment suggests hemodynamically significant obstruction and necessitates intervention. The pressure gradient may be diminished in the setting of left ventricular dysfunction and low cardiac output. The gradient is also underestimated in the presence of associated patent ductus arteriosus, other left-sided obstructive lesions such as mitral stenosis or aortic stenosis. The pressure gradient may be completely absent in the presence of significant collaterals decompressing aorta proximal to the coarctation. Thus, measured coarctation gradient must be assessed in the context of the patient’s overall anatomy and physiology.
INDICATIONS OF INTERVENTION The most widely accepted indication for intervention in adolescents and adults is the presence of systemic
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B
Figures 4A and B: (A) MRI images of a 16-year-old male with focal coarctation of aorta with poststenotic dilatation of aorta; (B) MRI image of the same patient with stent in situ across the coarctoplasty segment
Figure 5: CT scan 3 D reconstruction showing coarctation of aorta, focal segment of coarctation seen distal to left subclavian artery
arterial hypertension, with an upper and lower extremity systolic blood pressure difference >20 mg.18 In 2008, ACC/ AHA guidelines for adults19 with congenital heart disease recommended intervention for CoA in the following settings: a. Peak-to-peak coarctation gradient >20 mg; which is the difference in peak pressure proximal and beyond the narrowed segment. (Level of evidence: C). b. Peak-to-peak coarctation gradient 140/90 mm Hg in adults),
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Coarctation of Aorta in Adults: Diagnosis and Current Management Strategies
A
Figure 6: Sagittal multiplanar reconstruction (MPR) image post coarctation stenting with some beam hardening artifacts
abnormal exercise blood pressure response, or significant left ventricular hypertrophy. ii. Class IIa recommendation indicates intervention should be considered in hypertensive patients with more than 50% aortic narrowing relative to the aortic diameter at the level of the diaphragm (as seen on MRI, CT scan, or invasive angiography), regardless of the pressure gradient. iii. Class IIb recommendation indicates intervention may be considered in patients with more than 50% aortic narrowing relative to the aortic diameter at the level of the diaphragm (as seen on MRI, CT scan, or invasive angiography), regardless of the pressure gradient and the presence of hypertension.
Recommendations for Interventional and Surgical Treatment of Coarctation of the Aorta in Adults19 1. Choice of percutaneous catheter intervention versus surgical repair of native discrete coarctation should
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be determined by consultation with a team of Adult Congenital Heart Disease (ACHD) cardiologists, interventionalists, and surgeons at an ACHD center (Level of Evidence: C) 2. Percutaneous catheter intervention is indicated for recurrent, discrete coarctation and a peak-to-peak gradient of at least 20 mm Hg. (Level of Evidence: B) 3. Surgeons with training and expertise in CHD should perform operations for previously repaired coarctation and the following indications:) a. Long recoarctation segment. (Level of Evidence: B) b. Concomitant hypoplasia of the aortic arch. (Level of Evidence: B).
Class IIb Stent placement for long-segment CoA may be considered, but the usefulness is not well established, and the long-term efficacy and safety are unknown. (Level of Evidence: C).
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1. Balloon coarctoplasty for recurrent coarctation of Aorta: In a recent study of patients who underwent surgical correction for CoA at mean age of 10 years, the cumulative 40 years survival was 79%.21 Recoarctation was seen in 16% of survivors. Balloon dilatation of coarctation segment can be performed using antegrade or retrograde approaches depending on clinician preferences. Balloon coarctoplasty for the treatment of recurrent CoA has been accepted as treatment of choice, based on assumption that the scar tissue is resistant to rupture or aneurysm formation.22 Histological reports have revealed that the acute increase in lumen size and reduction in systolic pressure gradients due to balloon coarctoplasty are due to tears in the lumen of aorta. These are generally confined to intimal and medial layer, rarely can be transmedial. The transmedial tears are associated with aneurysm formation and occasionally aortic dissection. 23 Mortality rates among adult patient undergoing balloon coarctoplasty being 1%.24 2. Balloon coarctoplasty for native coarctation of aorta: This may be a preferred option in children. However, in adults due to tough aortic wall balloon dilatation is not recommended. Recoarctation develops in 6–19% in adults with balloon coarctoplasty for native CoA.25 McCrindle et al.26 reported the recurrence rate of approximately 7%, with a further 7% of patients having a suboptimal primary outcome. Thus, for localized discrete narrowing, balloon angioplasty is an acceptable alternative to surgical repair as a primary intervention but is less suitable for long-segment or tortuous forms of CoA. 3. Stent implantation: The stents are being increasingly used for the treatment of CoA in adults
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(Figures 7A to F). Stenting works by stretching and scaffolding rather than tearing the aorta as in the case of balloon coarctoplasty. As a result, there are lesser complications with aneurysm formation and restenosis.27 In 1991, O’Laughlin et al reported the first use of Palmaz iliac artery stent 28 to reduce pressure gradient in coarctation segment in thoracic aorta of a 12-year-old boy previously treated with balloon angioplasty. Subsequently, larger scale studies showed optimal results with significant reduction in pressure gradient in stent group compared to balloon coarctoplasty. A recent report of intermediate outcomes from Coarctation of Aorta Stent Trial (COAST)29 demonstrated that after the placement of Cheatham–Platinum bare metal stents in patients older than 8 years of age, at 2 years follow-up, 13% required repeat catheterization for stent dilatation, but none needed surgical management. Stent fractures were seen in 22% of patients, however, none had adverse outcomes. Overall the results are promising. At present, transcatheter stenting of CoA is indicated in adults with native or recurrent coarctation of aorta, or in those with diffuse lesions where balloon dilatation results in higher risk aneurysmal dilatation, or in older adults with long segment coarctation with modestly compromised aortic wall elasticity as an alternative to insertion of interposition graft or patch.
Surgical Treatment Strategies Surgical repair of coarctation of the aorta was first reported in 1945 by Crafoord and Nylin,30 who described the technique of resection and end-to-end anastomosis. In most centers, this procedure remains the surgical treatment of choice for patients with a discrete coarctation. An extended end-to-end anastomosis using a broader longitudinal incision across the proximal aorta improves the effectiveness of this operation in infants with hypoplasia of the isthmus or transverse arch. Prosthetic patch aortoplasty was the second surgical technique described for coarctation repair, by Vosschulte31 in 1961. Compared with coarctation resection, patch aortoplasty has the advantages of requiring less extensive aortic mobilization, preserving intercostal arteries, and avoiding a circumferential suture line. Patch aortoplasty also can be used for long-segment coarctation. Jump graft or a prosthetic graft may be used in patients with long segment CoA with compromised aortic wall elasticity. The disadvantages of this technique include the use of prosthetic material and a relatively high incidence of late aortic aneurysm formation.
Outcomes and Late Complications Patients without a significant residual systolic gradient (140 mm Hg. Following coarctation repair, there was an improvement in systolic blood pressure in all patients with decrease in the requirement of antihypertensive agents. The prevalence of systemic hypertension postcoarctation repair ranges from 25–65%, 49 the mechanism of hypertension being unclear, probably related to abnormal vascular compliance or increased baroreceptor sensitivity. There are limited data on the efficacy of different classes of antihypertensive medications in hypertensive patients following CoA repair. A study of 128 young adults with hypertension after CoA repair reported better control of hypertension with Candesartan over Metoprolol with fewer side effects. 50 The 2008 ACC/AHA guidelines for management of CoA in adults recommended use of beta blocker, angiotensin–converting enzyme inhibitor or angiotensin II receptor blocker as first-line therapy, with a preference of one agent over another dependant on presence of aortic root dilatation or aortic regurgitation.19
Recommendations for Key Issues to Evaluate and Follow-up19 Class I 1. Lifelong cardiology follow-up is recommended for all patients with aortic coarctation (repaired or not), including an evaluation by or consultation with a cardiologist with expertise in ACHD. (Level of Evidence: C). 2. Patients who have had surgical repair of coarctation at the aorta or percutaneous intervention for coarctation of the aorta should have at least yearly follow-up. (Level of Evidence: C). 3. Even if the coarctation repair appears to be satisfactory, late postoperative thoracic aortic imaging should be performed to assess for aortic dilatation or aneurysm formation. (Level of Evidence: B). 4. Patients should be observed closely for the appearance or reappearance of resting or exercise-induced systemic arterial hypertension, which should be treated aggressively after recoarctation is excluded. (Level of Evidence: B). 5. Evaluation of the coarctation repair site by MRI/CT should be performed at intervals of 5 years or less, depending on the specific anatomic findings before and after repair. (Level of Evidence:C).
Class IIb Routine exercise testing may be performed at intervals determined by consultationwith the regional ACHD center. (Level of Evidence: C).
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Exercise and athletics:19 Significant residual or unrepaired coarctation, associated BAV with AS, or a dilated aortic root warrants prohibition of contact sports, isometric
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or heavy weight lifting, and sudden stop-start sports. It would be prudent to have a cardiology consultation, stress testing, and an echocardiogram before permitting low- to moderate-level dynamic sports or light-weight lifting. Reproduction : 19 Pregnanc y in coarctation of the aorta continues to be a source of concern, but major cardiovascular complications are infrequent. An assessment of the hemodynamic status, severity of coarctation, and associated lesions, particularly BAV, AS, or a significantly dilated root, should be undertaken before pregnancy for proper planning and advice. The potential for aortic dissection remains, although it is quite small unless the aorta is dilated significantly. Endocarditis prophylaxis:19 Patients with uncomplicated native coarctation or uncomplicated, recurrent coarctation that is successfully repaired do not require endocarditis prophylaxis unless there is a prior history of endocarditis or a conduit has been inserted or if surgical repair or stenting has been performed less than 6 months previously.
REFERENCES 1. Samanek M, Slavik Z, Zborilova B, et al. Prevalence treatment and outcome of heart diseases in live born children: a prospective analysis of 91823 live born children. Pediatr Cardiol. 1989;10(4):205-11. 2. Grech V. Diagnostic and surgical trends, and epidemiology of coarctation of aorta in a population based study. Int J Cardiol. 1999;68(2):197-202. 3. van der Linde De, Konnings EE, Slager MA, et al. Birth prevalence of congenital heart diseases worldwide a systematic review and meta analysis. J Am Coll Cardiol. 2002;39(12):1890-900. 4. Nadas AS, Fyler DC. Pediatric Cardiology. 3rd edn. Philadeplhia: Saunders; 1972. 5. Keith JD, Rowe RD, Vlad P. Heart Disease in Infancy and Childhood. 3rd ed. New York: MacMillan Publishers Limited; 1978. 6. Adams FH, Emmanouildes GC, Riemenschneider TA. Moss’ Heart Disease in Infants, Children and Adolescents. 4th edn. Baltimore , New York: Williams & Wilkins; 1989. 7. Jurkut R, Daraban AM, Lorber A, et al. Coarctation of Aorta in adults, what is the best treatment? J Med Life. 2011;4(2):189-95. 8. Kaushal S, Backer CL, Patel JN, et al. Coarctation of the aorta: midterm outcomes of resection with extended endto-end anastomosis. Ann Thoraic Surg. 2009;88(6):1932-8. 9. Tanous D, Benson LN, Horlick EM. Coarctation of the aorta: evaluation and management. Curr Opin Cardiol. 2009;24(6):509-15. 10. Moss Aj, Allen HD. Moss and Adams Heart diseases in infants children and adolescents, including fetus and adults, 7th edn. Philadelphia: Wolters Kluwer health/ Lippinkot William and Willkins; 2008. 11. Anderson RH, Lenox CC, Zuberbuhler JR. Morphology of ventricular septal defect associated with coarctation of aorta. Br Heart J. 1983;50(2):176-81.
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Anomalies (VACA) Registry Investigators. J Am Coll Cardiol. 1996;7:1810-7. Magee A, Rosenthal E, Qureshi SA, et al. Stent implantation for aortic recoarctation. Heart. 1995;129:1220-1. O’ Laughlin MP, Perry SB, Lock JE, et al. Use of endovascular stents in congenital heart disease. Circulation. 1998;3(6): 1923-39. Meadows J, Minahan M, Mc Elhinney DB, et al. Intermediate outcome in prospective, multicentre coarctation of aorta stent trial (COAST). Circulation. 2015;131(19):1656-64. Crafoord C, Nylin G. Congenital coarctation of the aorta and its surgical treatment. J Thorac Surg. 1945;14:347-52. Vosschulte K. Surgical correction of coarctation of the aorta by an “isthmusplastic” operation. Thorax. 1961;16(4):338-45. Graham TP Jr, Driscoll DJ, Gersony WM, et al. 36th Bethesda Conference: Eligibility recommendations for competitive athletes with cardiovascular abnormalities. Task Force 2: Congenital heart disease. J Am Coll Cardiol. 2005;45:1326-33. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease. J Am Coll Cardiol. 2008;52(23):143-263. Maron BJ, Humphries JO, Rowe RD, et al. Prognosis of surgically corrected coarctation of the aorta: a 20-year postoperative appraisal. Circulation. 1973;47(1):119-26. Toro-Salazar OH, Steinberger J, Thomas W, et al. Long-term follow-up of patients after coarctation of the aorta repair. Am J Cardiol. 2002;89(5):541-7. Brown ML, Burkhart HM, Connolly HM, et al. Coarctation of the aorta: lifelong surveillance is mandatory following surgical repair. J Am Coll Cardiol. 2013;62(11):1020-5. Bromberg BI, Beekman RH, Rocchini AP, et al. Aortic aneurysm after patch aortoplasty repair of coarctation: a prospective analysis of prevalence, screening tests and risks. J Am Coll Cardiol. 1989;14:734-41. del Nido P, Williams WG, Wilson GJ, et al. Synthetic patch angioplasty for repair of coarctation of the aorta: experience with aneurysm formation. Circulation. 1986;74(3 Pt 2):32-6. Clarkson PM, Brandt PW, Barratt-Boyes BG, et al. Prosthetic repair of coarctation of the aorta with particular reference to dacron onlay patch grafts and late aneurysm formation. Am J Cardiol. 1985;56:342-6. Cramer JW, Ginde S, Bartz PJ, et al. Aortic aneurysms remain a significant source of morbidity and mortality after use of Dacron patch aortoplasty to repair coarctation of the aorta: results from a single center. Pediatr Cardiol. 2013;34(2):296-301. Mendelsohn AM, Crowley DC, Lindauer A, et al. Rapid progression of aortic aneurysms after patch aortoplasty repair of coarctation of the aorta. J Am Coll Cardiol. 1992;20:381-5. Mendelshon AM, Lloyd TR, Crowley DC, et al. Late follow-up of balloon angioplasty in children with a native coarctation of the aorta. Am J Cardiol. 1994;74:696-700. Fletcher SE, Nihill MR, Grifka RG, et al. Balloon angioplasty of native coarctation of the aorta: mid-term follow-up and prognostic factors. J Am Coll Cardiol. 1995;25(3):730-4. Fawzy ME, Fathala A, Osman A, et al. Twenty-two years of follow-up results of balloon angioplasty for discreet native
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44 Coarctation of Aorta in Adults: Diagnosis and Current Management Strategies
12. Moene RJ, Gittenberger-de Groot AC, OppenheimerDekker A, et al. Anatomic characteristics of ventricular septal defect associated with coarctation of the aorta. Am J Cardiol. 1987;59(9):952-5. 13. Shone JD, Sellers RD, Anderson RC, et al. The development complex of “parachute mitral valve,” supravalvar ring of left atrium, subaortic stenosis and coarctation of the aorta. Am J Cardiol. 1963;11:714-25. 14. Parks WJ, Ngo TD, Plauth WH Jr, et al. Incidence of aneurysm formation after Dacron patch aortoplasty repair for coarctation of the aorta: long-term results and assessment utilizing magnetic resonance angiography with three-dimensional surface rendering. J Am Coll Cardiol. 1995;26:266-71. 15. Tsai SF, Trivedi M, Boettner B, et al. Usefulness of screening cardiovascular magnetic resonance imaging to detect aortic abnormalities after repair of coarctation of the aorta. Am J Cardiol. 2011;107:297- 301. 16. Didier D, Saint- Martin C, Lapierre C, et al. Coarctation of aorta pre and post operative evaluation with MRI And MR angiography, correlation with echocardiography and surgery. Int J Cardiovasc imaging. 2006;22(3-4):457-75. 17. Rosenthal E, Bell A. Optimal imaging after Coarctation Stenting. Heart. 2010;96(15):1169-71. 18. Marshall AC, Perry SB, Keane JF, et al. Early results and medium-term follow-up of stent implantation for mild residual or recurrent aortic coarctation. Am Heart J. 2000;139(6):1054-60. 19. Warnes CA, Williams RG, et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: Executive Summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines for the management of adults with congenital heart disease). Circulation. 2008;118(23):2395-451. 20. Erbel R, Aboyans V, Boileau C, et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). EUR Heart J. 2014;35(41):2873-926. 21. Toro–Salazar OH, Steinberg J, Thomas W, et al. Long term follow-up of patients after coarctation of aorta repair. Am J Cardiol. 2002;89(5):541-7. 22. Gibbs JL. Treatment options for coarctation of aorta. Heart. 2000;84:11-3. 23. Lock JE, Casteneda-Zunega WR, Bass JL, et al. Balloon dilatation of excised aortic coarctations. Radiology. 1982;143(3):689-91. 24. Hellenbrand WE, Allen HD, Golinko RJ, et al. Balloon angiplasty for Aortic recoartation: results of valvuloplasty and angioplasty of congenital anomalies registry. Am J Cardiology. 1990;65(11):793-7. 25. Tyagi S, Arora R, Kaul UA, et al. Balloon coartoplasty of native coarctation of aorta in adolescents and young. Am Heart J. 1992;123(3):674-80. 26. McCrindle BW, et al. Acute results of balloon angioplasty of native coarctation vs recurrent aortic obstruction and equivalent. Valvuloplasty and Angioplasty of Congenital
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coarctation of the aorta in adolescents and adults. Am Heart J. 2008;156(5):910–7. 45. Harris KC, Du W, Cowley CG, et al. Congenital Cardiac Intervention Study Consortium (CCISC). A prospective observational multicenter study of balloon angioplasty for the treatment of native and recurrent coarctation of the aorta. Catheter Cardiovasc Interv. 2014;83(7):1116-23. 46. Silversides CK, Kiess M, Beauchesne L, et al. Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart disease: outflow tract obstruction, coarctation of the aorta, tetralogy of Fallot, Ebstein anomaly and Marfan’s syndrome. Can J Cardiol. 2010;26(3):80-97.
47. Wells WJ, Prendergast TW, Berdjis F, et al. Repair of Coarctation of Aorta in Adults: the fate of systolic hypertension. Ann Thoracic Surg. 1996;61(4):1168-71. 48. Bhat MA, Neelakandhan KS, Unnikrishnan M, et al. Fate of Hypertension after repair repair of coarctation of aorta in adults. Br J Surg. 2001;88(4):536-8. 49. Canniffe C, Ou P, Walsh K, et al. Hypertension after repair of coarctation; systematic review. Int J Cardiol. 2013;167(6): 2456-61. 50. Giordano U, Cifra B, Giannico S, et al. Midterm results and therapeutic management, for patients suffering hypertension after surgical repair of aortic coarctation. Cardiol Young. 2009;19(5):451-5.
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Cyanotic Congenital Heart Disease Approach to Cyanosis in Newborn
Anita Saxena Cyanosis in Adults
Raghavan Subramanyan, R Saileela Eisenmenger Syndrome: An Update
Sylvia Colaco, Prashant Bobhate Adults with Repaired Tetralogy of Fallot
Snehal Kulkarni Single Ventricle Pathway: Simplified
Nageswara Rao Koneti, Vinoth Doraiswamy Fontan Circulation: Simplified
Jay Relan, Saurabh Kumar Gupta Ebstein’s Anomaly: What’s New?
Jayaranganath M, Usha MK Total Anomalous Pulmonary Venous Connection: An Overview
Sivasubramanian Ramakrishnan, Arvind Balaji, Kewal C Goswami
S E C T I O N
Pulmonary Arteriovenous Malformations
Edwin Francis, Annu Jose, Bijesh Viswambaran Systemic Effects of Cyanosis
Neeraj Awasthy, Naveen Kumar
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Approach to Cyanosis CHAPTER 45 in Newborn Anita Saxena
INTRODUCTION Cyanosis in the newborn is a frequently encountered problem. The term cyanosis is derived from the Greek word kuaneos meaning dark blue, referring to the bluish discoloration of the skin, nailbeds, or mucous membranes. Cyanosis is classified into central and peripheral cyanosis. If cyanosis is limited to the extremities, it is referred to as peripheral cyanosis or acrocyanosis. This is relatively common in young infants, and is generally a physiologic finding due to the large arteriovenous oxygen difference that results during slow flow through peripheral capillary beds. In contrast to acrocyanosis, central cyanosis is present throughout the body, and is evident in the mucous membranes and tongue. Central cyanosis indicates the presence of potentially serious and life-threatening disease, and requires immediate evaluation. The clinician will need to rapidly consider respiratory and central nervous systems, and hematologic, cardiac, and metabolic causes.1 Cyanosis is dependent on the absolute concentration of the reduced hemoglobin and not on the ratio of reduced hemoglobin to oxyhemoglobin. With careful observation, cyanosis may become apparent when the deoxygenated hemoglobin content is as little as 3 g/dL. Therefore, infants with polycythemia may exhibit cyanosis at relatively high arterial saturations, while it is more difficult to discern cyanosis in a severely anemic infant unless the oxygen saturation is extremely low. In general, the relatively high hemoglobin of the normal infant tends to facilitate the recognition of cyanosis. The ratio of fetal to adult hemoglobin varies from infant to infant, and the proportions of each hemoglobin affect the oxygen saturation resulting at any given PaO2. Thus, if a child has mostly adult hemoglobin, central cyanosis (arterial saturation 75–85%) will be observed when the PaO2 falls below 45 mm Hg. In contrast, if the baby has mostly fetal hemoglobin, central cyanosis may not be observed until the PaO2 drops well below 30 mm Hg. Thus, infants with a high proportion of fetal hemoglobin may have a serious reduction in oxygenation before cyanosis is clinically apparent (Figure 1).
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Figure 1: Effect of fetal vs. adult hemoglobin on oxygen dissociation curve. A saturation of 80% indicates a PaO2 of 45 mm Hg in an adult, but much lower value for a neonate (PaO2 3 Wood units × m2 for biventricular physiology.4,5 The most severe form of pulmonary arterial hypertension (PAH) related to CHD is called Eisenmenger syndrome (ES). In 1897, Victor Eisenmenger described postmortem findings of ventricular septal defect in an adult patient who died of cyanosis and dyspnea on exertion.6 However, the exact pathophysiology was only described six decades later by Paul Wood who defined ES as ‘pulmonary hypertension at systemic level, due to a high pulmonary vascular resistance (>800 dynes/cm5 or >10 Wood unit × m2), with reversed or bidirectional shunt through any large communication between the two circulations.’7
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CLASSIFICATION In the clinical classification of pulmonary hypertension (PH) proposed at Dana Point in 2009 and revised at the National Institute for Health and Care (NICE) in 2013 (Table 1); PH associated with all CHD was clubbed in Group I. 16 The rationale for the same is the similar histological findings of plexiform lesions on light microscopy. However, the Dana Point classification with NICE modification do not always readily apply to PHVD
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CHAPTER
Table 1: Updated clinical classification of pulmonary hypertension (NICE 2013)
47
1. Pulmonary arterial hypertension Idiopathic PAH
1.2
Heritable PAH
Eisenmenger Syndrome: An Update
1.1
1.2.1 BMPR2 1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3 1.2.3 Unknown 1.3
Drug and toxin induced
1.4
Associated with:
1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis 1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1’’ Persistent pulmonary hypertension of the newborn (PPHN) 2. Pulmonary hypertension due to left heart disease 2.1
Left ventricular systolic dysfunction
2.2
Left ventricular diastolic dysfunction
2.3
Valvular disease
2.4
Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
3. Pulmonary hypertension due to lung diseases and/or hypoxia 3.1
Chronic obstructive pulmonary disease
3.2
Interstitial lung disease
3.3
Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4
Sleep-disordered breathing
3.5
Alveolar hypoventilation disorders
3.6
Chronic exposure to high altitude
3.7
Developmental lung diseases
4. Chronic thromboembolic pulmonary hypertension (CTEPH) 5. Pulmonary hypertension with unclear multifactorial mechanisms 5.1
Hematologic disorders: Chronic hemolytic anemia, myeloproliferative disorders, splenectomy
5.2
Systemic disorders: Sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
5.3
Metabolic disorders: Glycogen storage disease, Gaucher disease, thyroiddisorders
5.4
Others: Tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
associated with CHD. Arterial and venous hypertension are arbitrarily separated in the clinical classification, it has been demonstrated that these frequently coexist in PHVD associated with CHD.17 Also, the proliferating endothelial cells in PHVD associated with CHD are of polyclonal origin as opposed to monoclonal in idiopathic/hereditary PAH.18 This has led to development of numerous subclassifications in pediatric PH and PHVD associated with CHD (Tables 2 to 4).5
vasodilators and constrictors ultimately leading to unfavorable vascular remodeling.19 Four clinical variables have been suggested in influencing the development of pulmonary hypertensive vascular disease in patients with CHD.20 1. Age of the patient 2. Type of cardiac lesion 3. Genetic and epigenetic factors 4. Environmental factors and comorbidities.
PATHOPHYSIOLOGY
Age
Increase in pulmonary blood flow (PBF) and pressure induce endothelial cell dysfunction, abnormal shear stress, circumferential wall stretch and imbalance between
The duration of shunt flow should be directly proportional to the chance of developing irreversible disease. Rabinovitch et al. demonstrated that even advance 385
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Table 2: Anatomic-pathophysiologic classification of congenital systemic-to-pulmonary shunts associated with pulmonary arterial hypertension
Cyanotic Congenital Heart Disease
7
Type
Description
1.
Type
1.1
Simple tricuspid shunt
1.1.1
Atrial septal defect (ASD)
1.1.1.1
Ostium secundum
1.1.1.2
Sinus venosus
1.1.1.3
Ostium primum
1.1.2
Total or partial unobstructed anomalous pulmonary venous return
1.2
Simple post-tricuspid shunts
1.2.1
Ventricular septal defect (VSD)
1.2.3
Patent ductus arteriosus
1.3
Combined shunts (describe combination and define predominant defect)
1.4
Complex congenital heart disease
1.4.1
Complete atrioventricular canal defect
1.4.2
Truncus arteriosus
1.4.3
Single ventricle physiology with unobstructed pulmonary blood flow
1.4.4
Transposition of great arteries with VSD (without pulmonary stenosis) and/or patent ductus arteriosus
1.4.5
Other
2.
Dimension (specify for each defect if >1 congenital heart defect)
2.1
Hemodynamic (specify Qp/Qs)
2.1.1
Restrictive (pressure gradient across the defect)
2.1.2
Nonrestrictive
2.2
Anatomic
2.2.1
Small to moderate (ASD ≤ 2.0 cm and VSD≤ 1.0 cm)
2.2.2
Large (ASD> 2.0 cm and VSD > 1.0 cm)
3.
Direction of shunt
3.1 3.2 3.3
Predominantly systemic to pulmonary Predominantly pulmonary to systemic Bidirectional
4.
Associated cardiac and extracardiac abnormalities
5.
Repair status
5.1
Unoperated
5.2
Palliated (specify type of operation, age of surgery)
5.3
Repaired (specify type of operation, age of surgery)
pulmonary vascular changes could be reversed with cessation of precipitating factors. However; there are a certain group of patients who develop PHVD much earlier than the cut off criteria of 2 years as described by Rabinovitch et al. Environmental factors such as high altitude, genetic and epigenetic factors such as the presence of Down’s syndrome increase the likelihood of developing PVHD earlier than previously described.21
Types of Cardiac Lesion
386
The wide spectrum of CHD presents a unique perspective to development of PHVD. Not all CHDs have the same propensity to develop PHVD. Patients with post-tricuspid shunt, with increase in both flow and pressure develop PHVD earlier that patients with pretricuspid shunt.
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Pretricuspid shunts result in volume overload on the pulmonary circulation without an immediate increase in pulmonary artery pressures. The development of PHVD in pretricuspid shunt is determined by the size of the defect, right ventricular compliance as well as the presence of left ventricular dysfunction and left heart disease.3 Moreover, only 2% of the patients with pretricuspid shunt progress to have ES.8 The presence of PHVD in adults with simple pretricuspid shunt should initiate investigation into other probable causes of PAH. Even in patients with posttricuspid shunt, complex lesions such as transposition of great vessels with a ventricular septal defect or a truncus arteriousus develop PHVD earlier than simpler lesions such as ventricular septal defect (VSD), patent ductus arteriosus (PDA), and aortopulmonary window.
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CHAPTER
Table 3: Clinical classification of congenital systemic-to-pulmonary shunts associated to PAH Includes all systemic-to-pulmonary shunts resulting from large defects and leading to a severe increase in PVR and a reversed (pulmonary-to-systemic) or bidirectional shunt; cyanosis, erythrocytosis, and multiple organ involvement are present
B. PAH associated with systemic-topulmonary shunts
Includes moderate-to-large defects; PVR is mildly to moderately increased, systemic-topulmonary shunt is still prevalent, and no cyanosis is present at rest
C. PAH with small defects
Small defects (usually ventricular septal defects 2.0 in end-systole. 3. Multiple deep intertrabecular recesses communicating with the ventricular cavity, as visualized on color Doppler interrogation (Figures 3A and B). 4. Systolic thickness of compacted myocardium 8 mm. Contrast enhanced echocardiography facilitates the identification of noncompacted myocardium when conventional echocardiographic images are poor or inconclusive. CMR is particularly helpful in distinction of the two layers—compacted outer (epicardial) layer and the noncompacted inner (endocardial) layer and precise measurement of the two segments and the ratio. Grothoff et al. 17 studied the value of CMR-derived parameters to distinguish left ventricular non-compaction cardiomyopathy from other cardiomyopathies and controls. The investigators established quantitative CMR diagnostic criteria that facilitate differentiation o f n o n c o mp a c t i o n ca rd i o myo p at hy f ro m o t h e r cardiomyopathies. The LV non-compacted myocardial mass index, total LV myocardial mass index (LV MMI), and the percentage of LV non-compacted myocardium were calculated.
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CHAPTER
57
B
Figures 3A and B: (A) Two-dimensional echocardiography profiling apical 4 chamber view demonstrates the noncompacted myocardium at left ventricular apex with multiple deep intertrabecular recesses; (B) Color Doppler interrogation demonstrating blood flow in the recesses
The four basic criteria for dioagnosis of noncompaction cardiomyopathy include: 1. Noncompacted LV myocardial mass >25%. 2. Total non-compacted LV myocardial mass index 15 g/m2. 3. Noncompacted/compacted myocardium ratio ≥ 3:1 in at least one of the segments 1–3, 7–16, excluding the apical segment 17 and segments 4–6 of 17-segment model. 4. The ratio of noncompacted/compacted myocardium ≥2:1 in segments 4 to 6 of 17-segment model. The diagnostic performance will be enhanced if CMR criteria are combined together and utilized for the diagnosis.
RESTRICTIVE CARDIOMYOPATHY RCM should be considered in the presence of heart failure symtoms with a nondilated, nonhypertrophied LV with preserved contractility but abnormal diastolic function and dilated atria. Echocardiography is the preferred imaging modality for assessing the morphological and functional characteristics of RCM. 1. Electro cardiograhy: It may show nonspecific abnormalities and include either large P waves indicating enlarged atria or atrial fibrillation may be present. ST-T wave abnormalities, premature atrial and ventricular beats, atrioventricular (AV) block, and intraventricular conduction delay may be noticed. 2. Chest radiograph: It is usually characterized by significant atrial enlargement with pulmonary venous congestion and pleural effusions. Endomyocardial calcium may be found which is characteristic of endomyocardial fibrosis. Sometimes radiological cardiac enlargement may be absent. 3. Echocardiogram : Echocardiogram is the most commonly performed and most useful imaging modality in the evaluation and management of patients suspected to have RCM. An integrated approach with combination of 2DE, M mode, Doppler evaluation and color Doppler imaging gives a comprehensive
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description of cardiac involvement with detailed structural and hemodynamic assessment. Novel echo techniques like tissue velocity imaging and speckle tracking which analyze strain and strain rate provide information regarding ventricular myocardial properties and can detect the disease in its early course. These techniques also help in differentiating RCM from chronic constrictive pericarditis. The characteristic echocardiographic features of RCM include: I. Two-dimensional echocardiographic features: 1. Normal or small ventricular cavity size with generally preserved or mildly reduced systolic ventricular function (Figures 4A and B). 2. Biatrial enlargement (Figure 4B). 3. In RCM, wall thickness is typically normal, though it may be increased with certain infiltrative processes (e.g. amyloidosis) or storage disease (e.g. Fabry disease). 4. Raised right atrial pressures as evidenced by dilated inferior vena cava. 5. Valve thickening, interatrial septal thickening or pericardial effusion may be present and are suggestive of cardiac amyloidosis. 6. LV/RV apical obliteration is seen in endomyocardial fibrosis. 7. RV free wall dimple is seen in RV endomyocardial fibrosis. 8. Autocontrast may be seen in atria or inferior vena cava. II. Doppler echocardiography: Abnormal diastolic function, frequently with a restrictive LV filling pattern as evidenced by: 1. Increased early diastolic filling velocity (E). 2. Decreased atrial filling velocity (A). 3. E/A ≥ 1.5. 4. Decreased deceleration time (Edt) 150 msec. 5. Decreased isovolumic relaxation time (IVRT). 6. Significant decrease in the ratio of Systolic (S) and diastolic (D) wave velocities in pulmonary venous flow, i.e. S/D ratio.
Noninvasive Evaluation of Suspected Heart Muscle Disease
A
471
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Cardiomyopathy
8
A
B
Figures 4A and B: (A) Parasternal long axis view shows thickened interventricular septum and posterior wall with sparkling appearance of myocardium, dilated LA and small posterior pericardial effusion; (B) Apical 4 chamber view shows normal size LV and RV, dilated atria, thickened and sparkling interventricular septum
7. Augmented atrial reversal velocity in the pulmonary venous flow. 8. Pulmonary arterial hypertension which can be evaluated by tricuspid regurgitation jet velocity providing right ventricular systolic pressure (RVSP) or pulmonary regurgitation velocity providing pulmonary arterial mean pressure and pulmonary arterial diastolic pressure. III. Tissue velocity imaging 1. Markedly reduced mitral annular tissue velocities: Early diastolic medial mitral annular tissue velocity e’ and late diastolic medial mitral annular tissue velocity a’ and systolic medial mitral annular tissue velocity s’ are all significantly reduced. 2. Evaluation of segmental myocardial tissue velocities of LV and RV show significantly reduced segmental myocardial tissue velocities. Tissue velocity imaging identifies the subclinical ventricular dysfunction even before the reduction in ejection fraction occurs. It also helps in distinguishing RCM from constrictive pericarditis, with a mitral annular diastolic velocity e’ ≤8 cm/s, a good discriminator for restrictive physiology while constrictive pericarditis is characterized by normal or elevated mitral annular tissue velocities. IV. 2D speckle tracking echocardiography: Strain and strain rate imaging 1. Markedly reduced global strain rate of left and right ventricle. 2. Specific longitudinal strain rate pattern like reduced longitudinal strain rate with relative apical sparing as seen in amyloidosis.
Cardiac Computerized Tomography (CCT)
472
It is especially helpful in excluding constrictive pericarditis which is a very deceptive mimic of restrictive cardiomyopathy. Evidence of pericardial thickening and
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calcification on CCT favor constrictive pericarditis, though not conclusive.
Cardiac Magnetic Resonance Imaging (CMR) CMR helps in the identification or exclusion of various causes of RCM. LGE enables identification of myocardial fibrosis, scar, necrosis, or infiltration. Characteristic patterns of LGE help the diagnosis of certain characteristic disease processes. LGE in left atrium/interatrial septum/valves and global LV distribution along with classical gadolinium dynamics are diagnostic of cardiac amyloidosis.LV inferolateral LGE is typical of Fabry’s disease. In sarcoidosis, there is often patchy enhancement, involving basal septum and basal inferolateral wall, frequently not consistent with any coronary artery territory. Myocardial iron overload can be assessed by cardiac T2 measurements. In addition, CMR-based tissue tracking can be used to differentiate restrictive cardiomyopathy from constrictive pericarditis. Nuclear imaging has a potential clinical role in two forms of RCM: amyloidosis and sarcoidosis.
IDIOPATHIC RESTRICTIVE CARDIOMYOPATHY Echocardiographic features are those of restrictive physiology usually with preserved LV systolic function, dilated atria, without ventricular hypertrophy or dilatation. Longitudinal function of LV may be decreased as brought out by strain rate imaging. The right ventricle may be involved. There is no ‘pathognomonic’ echocardiographic pattern diagnostic of idiopathic RCM.18 CMR with LGE enables identification of infiltrative myocardial disease, and is useful for ruling out a particular cause of RCM.
CARDIAC AMYLOIDOSIS Amyloidosis is a systemic disorder characterized by extracellular deposition of insoluble fibrillar protein in the
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complexes on ECG are commonly seen in patients with AL amyloidosis and less frequent finding in other forms of amyloidosis. Echocardiography is the preferred noninvasive diagnostic imaging modality for the evaluation of cardiac amyloidosis. The characteristic features include increased ventricular wall thickness with “granular sparkling” appearance of the myocardium, valvular thickening with regurgitation, interatrial septal thickening , normal or decreased LV cavity size, dilated atria, and small to moderate pericardial effusion. Tissue velocity imaging, myocardial strain and strain rate imaging are more sensitive. Strain rate imaging reveals markedly reduced global strain—both longitudinal and radial strains of LV. 19 But the global strain may be reduced in other cardiomyopathies also. Phelan et al. 20 have reported characteristic regional patterns in longitudinal strain (LS) using two-dimensional speckle-tracking echocardiography with regional variations in LS from base to apex along with relative apical sparing. A relative ‘apical sparing’ pattern of LS is an easily recognizable, accurate and reproducible method of differentiating cardiac amyloidosis from other causes of LV hypertrophy (Figures 5A and B). This classic regional pattern of LS can be easily identified on strain polar maps or ‘‘Bull’s eye’’ plots. It typically displays marked decrease in LS in the basal- and mid-wall segments with relative apical sparring of LS and is typically called ‘cherry on the top’ (Figure 5C). In HCM,
A
B
C
Figures 5A to C: (A) Strain rate imaging in apical 4 chamber view shows reduced longitudinal peak systolic strain; (B) Strain rate imaging in apical 2 chamber view also shows reduced longitudinal peak systolic strain of basal and mid segments. Typically note that the mid and basal segments have low strain rate as compared to the apical segments in the apical 4 chamber and 2 chamber views and also apical segments in 2 chamber view show normal strain of 20%. This is the characteristic relative ‘apical sparing’ pattern of longitudinal strain which is diagnostic of cardiac amyloidosis; (C) Global longitudinal strain with Bull’s eye plot shows apical sparing pattern typically called as ‘cherry on the top’
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57 Noninvasive Evaluation of Suspected Heart Muscle Disease
interstitial space in various organs like liver, kidney, heart, bowel, nerves, skin, and tongue. Cardiac amyloidosis is the commonest cause of RCM. The three most common types of amyloidosis, defined by their precursor proteins, are light-chain (AL) amyloidosis, familial or senile transthyretin related (ATTR) amyloidosis, and secondary amyloid A (AA) amyloidosis. The frequency and severity of cardiac involvement varies among various types of amyloidosis. Cardiac amyloidosis must be suspected when systemic features are present and patient has symptoms of congestive heart failure. The diagnosis of cardiac amyloidosis is established by echocardiographic or CMR evidence of amyloidosis and histologic confirmation of amyloid in noncardiac tissue. Endomyocardial biopsy is the gold standard for the diagnosis of cardiac amyloidosis. The various electrocardiographic abnormalities in patients with cardiac amyloidosis include Low voltage complexes, large P waves due to biatrial enlargement, pseudoinfarction pattern, conduction abnormalities—Intraventricular conduction delays or blocks like incomplete right bundle branch block or left anterior fascicular block may be present, arrhythmia atrial fibrillation—in advanced stage or fragmented QRS complexes are also frequently seen. Low voltage complexes on ECG in a patient with preserved LV systolic function and LV hypertrophy by echocardiography should raise the clinical suspicion of cardiac amyloid. Low voltage
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there is preferential decrease in longitudinal strain at the site of greatest hypertrophy. This characteristic pattern of apical sparing in cardiac amyloidosis was integrated into a relative apical LS formula as: Relative apical LS = average apical LS/(average of basal + mid LS) A score of 1 was associated with very high sensitivity and specificity of 93% and 82% respectively for the diagnosis of cardiac amyloidosis.
CARDIAC MAGNETIC RESONANCE IMAGING The anatomical features diagnostic of cardiac amyloid on CMR cine imaging are biatrial enlargement, thickened LV wall, reduced long-axis shortening, and pleural or pericardial effusion. Cardiac amyloidosis depicts a characteristic pattern of LGE—diffuse circumferential subendocardial enhancement with diffuse LV subendocardial or transmural enhancement (Figure 6) or bilateral septal subendocardial LGE, which may also involve the RV and atrial walls. This characteristic pattern of global transmural or diffuse subendocardial LGE facilitates diagnosis of the disease in the early stage when significant increase in LV wall thickness is not present and it correlates with disease severity 20. Light chain (AL) amyloidosis and hereditary transthyretin-associated (ATTR) amyloidosis can be distinguished with the help of
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specific CMR features. ATTR amyloidosis was associated with significantly higher LV mass index, higher LV volumes, and lower LVEF compared with AL amyloidosis. Myocardial and blood pool gadolinium kinetics and uptake are unusual and typical for cardiac amyloidosis. Pleural and pericardial effusions were more common in cardiac AL amyloidosis.In cardiac ATTR amyloidosis, LGE was more extensive, with a higher prevalence of trans mural LV LGE as well as of RV LGE.21
NUCLEAR IMAGING IN CARDIAC AMYLOIDOSIS Phosphonate-based tracers, including 99m Tc pyrophosphate (Tc-PYP) and 99mTc-3,3 diphosphono-1,2 propanodicarboxylic acid (99mTc-DPD) Tc-DPD, have been reported to localize amyloid in the heart 99mTc-DPD scintigraphy is useful in differentiating ATTR amyloidosis from AL amyloidosis. 99mTc-DPD uptake could be characterized as moderate to severe with left ventricular or biventricular distribution in all patients with ATTR amyloidosis (Figure 7), and absent or mild and diffusely distributed in AL amyloidosis.22
CARDIAC SARCOIDOSIS It is a systemic inflammatory disorder characterized by noncaseating granulomas in lungs, spleen, lymph nodes, skin, liver, parotid glands and heart. Cardiac involvement
Figure 6: CMR with late gadolinium enhancement images depicting diffuse transmural enhancement of LV (as indicated by arrow) a diagnostic feature of cardiac amyloidosis
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is patchy with the most common locations of granulomas found in the left ventricular free wall and basal ventricular septum, frequently affecting the conducting system.
ELECTROCARDIOGRAM An electrocardiogram (ECG) should be performed in every patient with sarcoidosis (systemic or cardiac) to detect subtle or overt conduction or repolarization abnormalities. Many patients may have splintered QRS complexes, atrioventricular or intraventricular conduction abnormalities. Ventricular tachycardia, complete heart block, bundle branch blocks or first degree heart block occur very frequently in patients with sarcoidosis. In patients with suspected or known cardiac sarcoidosis 24-hour ECG monitoring should be performed to document and define subclinical rhythm disturbances that may be missed on ECGs, to aid risk estimation of sudden death.
ECHOCARDIOGRAPHY Echocardiography is basic imaging modality for the evaluation of cardiac sarcoidosis as it provides useful information regarding the LV systolic and diastolic function as well as the RV function. Characteristic echocardiographic findings are: 1. Systolic function of the ventricles may be normal initially but it is usually severely impaired late in the course of the disease when it usually comes to clinical attention due to symptoms of heart failure. 2. Global hypokinesia of LV or regional wall motion abnormalities not consistent with vascular territory. 3. Focal thinning, hyperechogenicity or scarring of myocardium, usually basal septum is affected while apex is spared (Figures 8A to C). 4. LV wall focal hypertrophy with localized thickening 13 mm (due to granulomatous expansion). 5. Pulmonary involvement is frequently noted with resultant pulmonary arterial hypertension or right heart failure.
6. LV aneurysms. 7. Valvular regurgitation.
CARDIAC MAGNETIC RESONANCE CMR has a valuable role in the diagnosis of cardiac sarcoidosis. It can detect both the active inflammatory phase as well as the chronic phase of fibrosis and scarring of cardiac sarcoidosis. CMR is currently the technique of choice in the evaluation of sarcoidosis. CMR imaging reveals dilated LV with diffuse hypokinesis with LV wall thinning and LV dysfunction.CMR uses T2-weighted imaging and early gadolinium images to detect acute inflammation (edema). T1-weighted (cine) imaging illustrates wall motion abnormalities, hypertrophy due to possible infiltrative disease, wall thinning, or heart failure. LGE assesses fibrosis or scar and may represent chronic rather than active disease. 23 Typical patterns of enhancement on CMR are non-vascular in territory, mid-myocardial, and sub-epicardial, although many patients have patterns in a coronary distribution with subendocardial involvement similar to myocardial infarction.
Noninvasive Evaluation of Suspected Heart Muscle Disease
Figure 7: Radionuclide imaging with 18F-fluorodeoxyglucose (FDG ): PET CT scan images in a patient with cardiac amyloidosis. It revealed tracer uptake in thickened LV and RV myocardium. Patchy low grade uptake is seen in thickened wall of dilated RA
POSITRON EMISSION TOMOGRAPHY (PET) 18F-fluorodeoxyglucose [(18F)FDG] PET detects active phase of cardiac sarcoidosis with high sensitivity. FDG PET is more sensitive than gallium-67 scintigraphy, thallium-201, or technicium-99m single-photon emission computed tomography (SPECT).24 It can also be combined with myocardial perfusion imaging to detect fibrogranulomatous replacement. However, PET is non-specific for sarcoidosis as uptake of 18F-FDG is seen in other inflammatory myocardial diseases also, e.g. myocarditis, cardiac amyloidosis, infection, cardiac tuberculosis, and myocardial metastases causing focal (18F)FDG uptake. The imaging protocol includes gated cardiac (18F)FDG andwhole body images.25 A cardiac perfusion scan could be combined to compare [18F] FDG-PET and perfusion patterns. Serial (18F)FDG-PET/ 475
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Figures 8A to C: (A) Parasternal long axis view shows dilated LA and LV with hyperechoic and thinned out basal anterior septum; (B) Parasternal short axis view of LV at the level of papillary muscles shows dilated LV with thinning of inferior and anterior septum; (C) Apical 4 chamber view show dilated all 4 cardiac chambers with focal thinning and hyperechogenicity of basal and mid inferior septum. This focal thinning and hyperechogenicity is not consistent with any vascular territory and is diagnostic of cardiac sarcoidosis.
CT imaging is useful to assess the response to therapies. Decreased (18F)FDG uptake in cardiac lesions following therapy has been reported in case of corticosteroid treatment as well as immunosuppressive therapies. Thus PET can be used in assessing the disease progression and also the response to the therapy.
ANDERSON-FABRY DISEASE Anderson-Fabry disease is X-linked glycolipid storage disease caused by deficient activity of alpha galactosidase A enzyme. Clinical manifestations include cutaneous, corneal, cardiac, renal, and neurologic manifestations. Cardiovascular manifestations of Fabry disease include hypertension, left ventricular hypertrophy, conduction abnormalities, valvular regurgitation, coronary artery disease, and dilation of aortic root.26 The right ventricle is also often hypertrophied. Among the affected individuals female patients are more likely to present the cardiac variant of the disease.
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1. Unexplained left ventricular hypertrophy is the most characteristic finding. Concentric hypertrophy is the most frequent manifestation, asymmetric septal hypertrophy or eccentric hypertrophy can also occur. Rarely LV outflow obstruction may also occur. RV hypertrophy may also be seen. 2. In some cases the basal inferolateral wall becomes thin and may exhibit hypokinesia due to myocardial fibrosis and STE shows reduced longitudinal strain in this segment. 3. The valves may be thickened with subsequent mitral, aortic or tricuspid regurgitation. The regurgitant lesions are usually mild. 4. Usually LVEF will be preserved but STE demonstrates reduced strain rate. 5. Binary appearance of the myocardium on 2DE occurs as a result of a thickened hyperechogenic
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Figure 9: Cardiac magnetic resonance imaging in a patient with Fabry disease shows scarring of the basal inferolateral segment
endocardial layer subtended by a hypoechogenic layer. Binary appearance reflects endomyocardial glycosphingolipids compartmentalization. However, the binary appearance has a low sensitivity of 15–35% and specificity of 73–80% for the diagnosis of Fabry disease.27 6. Aortic dimensions can be measured by 2DE and aortic root dilatation may be diagnosed
CARDIAC MAGNETIC RESONANCE IMAGING LGE characteristically demonstrates the scarring of basal and mid segments of the anterolateral and inferolateral walls (Figure 9). Basal third of other LV walls may be involved in severe cases. LGE in Fabry disease usually spares the subendocardium, which helps distinguish it from the pattern seen with myocardial infarction.
NUCLEAR IMAGING IN FABRY DISEASE In patients with Fabry disease presenting with angina stress myocardial perfusion imaging reveals reversible defects consistent with ischemia, often accompanied by fixed defects. These findings generally occur without significant obstructive coronary disease and appear to be due to small vessel coronary disease with replacement fibrosis surrounding severely stenosed intramural arteries.
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ENDOMYOCARDIAL FIBROSIS AND LÖFFLER’S ENDOCARDITIS
ECHOCARDIOGRAPHY The characteristic echocardiographic features of endomyocardial fibrosis include: Endomyocardial thickening with apical obliteration due to thrombus formation without any regional wall motion abnormality. Endocardial calcium is seen as hyperechogenicity lining the apical endocardium. Rarely focal involvement of other segments of LV can be seen. Biatrial enlargement. Mitral or tricuspid leaflet involvement with tethering of the leaflet and regurgitation. Doppler echocardiography can show diastolic dysfunction often a restrictive left ventricular filling pattern. Pericardial effusion may be present. Preserved LV systolic function (including the apex). Tissue velocity imaging reveals significantly reduced segmental tissue velocities of LV and RV. Thrombi may be found in left atrium or right atrium or both or the left atrial appendage or the right atrial appendage. RV free wall dimple may be present in RV endomyocardial fibrosis.
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CMR often provides additional diagnostic information due to its ability to detect subendocardial fibrosis and its greater sensitivity for ventricular thrombus detection. LGE imaging is capable of detecting myocardial fibrosis and inflammation. Overlying thrombus is identifiable as a low signal mass on the delayed enhancement images, which does not deform on tagged images. A characteristic three-layered image can be seen: a hypointense inner rim of thrombus adjacent to an hyperenhancement of endocardium compared with the rest of the myocardium. Despite the convincing diagnostic information available from the noninvasive imaging modalities endomyocardial biopsy remains the diagnostic gold standard.30
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by structural and functional abnormalities of the right ventricle. It is characterized by the fibrofatty replacement of RV myocardium which eventually leads to progressive RV dysfunction and life-threatening ventricular arrhythmias. LV involvement has also been reported in later stages of the disease. The electrocardiographic diagnostic criteria of ARVD include Epsilon wave—electric potentials after the end of the QRS complex—a major diagnostic criterion and T wave inversions in V1 through V3, a minor diagnostic criterion, but most common ECG abnormality. Transthoracic echocardiography (TTE) is the basic first line imaging modality in the evaluation of a patient with suspicion of ARVD. The echocardiographic features of diagnostic ARVD are:31 RV dilation and hypokinesia Dilatation of the right ventricular outflow tract ≥32 mm on the parasternal long-axis view or ≥36 mm on parasternal short axis view – a major criterion for diagnosis of ARVD Increased reflectivity of the moderator band Prominent apical trabeculae Focal aneurysms or sacculations of RV. Off-axis images should be obtained for appropriate visualization of all segments of the RV free wall and identification of localized RV aneurysms Akinesis-dyskinesis of the inferobasal segment RV function can be assessed by the estimation of the RV fractional area change (FAC) from the Apical 4-chamber and it is decreased in individuals with ARVD. FAC ≤ 33% is a major criterion TDI derived tricuspid annular peak systolic velocity (TAPSV) and M-mode derived tricuspid annular plane systolic excursion (TAPSE) also are utilized in the assessment of RV function.
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Endomyocardial fibrosis (EMF) occurs due to endocardial involvement with deposition of fibrous tissue in the endomyocardium, endocardial calcification of LV or RV or both, leading to restrictive physiology. It is endemic in certain geographical areas like Asia, subtropical Africa and South America. EMF is a form of restrictive, cardioobliterative cardiomyopathy characterized by fibrotic thickening and obliteration of either of the ventricles or both with selective involvement of the ventricular apices and inflow region, sparing the outflow tract. The cardiac involvement in EMF follows three stages: 28 (1) Acute necrotic stage, (2) Intermediate phase—thrombotic stage and (3) Fibrotic stage. Löffler’s endocarditis represents the third stage. It was first described in 1936 by Wilhelm Löffler. He referred to it as ‘fibroplastic parietal endocarditis with blood eosinophilia’.29. It is a manifestation of hypereosinophilia and morphologic abnormalities of eosinophils have been noted in patients with Löffler’s endocarditis. The most characteristic cardiac abnormality in hypereosinophilic syndrome is fibrosis and scarring of the ventricular apex with resultant restrictive physiology. About 50 to 60% of patients with hypereosinophilic syndrome show cardiovascular manifestation. The patients with Loffler’s endocarditis present with symptoms of heart failure, intracardiac thrombus, myocardial ischemia or arrhythmias and rarely pericarditis.
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Myocardial performance index or Tei index is another reliable parameter for assessment of RV function. Newer echocardiographic techniques like 3D TTE and strain rate imaging of RV are now gaining popularity for the assessment of RV function. 3D TTE is an emerging tool for accurate estimation of RV volumes and RV ejection fraction. Strain rate imaging provides assessment of global and regional RV function. But both the techniques require expertise and there is a steep learning curve. CMR represents the preferred imaging modality in the diagnosis of ARVD and it gives accurate and comprehensive assessment of RV morphology—RV wall motion abnormalities: Akinesia and dyskinesia and focal aneurysms and RV function.32 The CMR finding of regional RV akinesia or dyskinesia or dyssynchronous RV contraction along with RV dilatation with indexed RV end-diastolic volume (EDV) ≥110 mL/m2 in males or ≥ 100 ml/m2 in females or RV ejection fraction ≤40% constitutes one of the major diagnostic criterion of ARVD. Other CMR findings associated with ARVD include RV wall thinning, RV outflow tract enlargement, trabecular disarray, fibrofatty replacement, ventricular dilation, and global or regional systolic dysfunction.
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Reversible cardiomyopathies are associated with a temporary reduction in contractile function leading to reversible heart failure which improves when the root etiological factor is addressed. The two mechanisms responsible for reversible myocyte dysfunction are : acute inflammatory activation in which cytokines depress myocyte function, and toxic effects in which there is impairment of intracellular energetics. There are many etiological factors that can result in severe structural and functional dysregulation 33. The various forms of reversible cardiomyopthies are Inflammatory or infectious cardiomyopthy: Cardiac sarcoidosis, viral myocarditis, sepsis Metabolic: Thyroid disease–induced cardiomyopathy, hypocalcemia induced lv dysfunction Sympathoexcitation-induced: Takotsubo cardiomyopathy/catechol cardiomyopathy Cardiomyopathy of chronic diseases: Cirrhosis, obesity, and uremia Arrhythmogenic cardiomyopathy Autoimmune-mediated peripartum cardiomyopathy Cardiomyopathy related to toxins: Alcohol, chemotherapeutic drugs Nutritional deficiencies: Thiamine deficiency The clinical scenario will indicate the etiology of reversible cardiomyopathy. Echocardigraphy assists in the diagnosis of LV systolic or diastolic dysfunction. In few instances additional imaging modalities like CMR or PET will be required for confirmation of the etiology.
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Reversible cardiomyopathies have been shown to have a transient impact on the heart. Significant improvement in cardiac function is seen if these reversible cardiomyopathies are diagnosed promptly and treated appropriately.
CHEMOTHERAPY AND RADIATION-INDUCED CARDIOMYOPATHY Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. A baseline echocariographic evaluation of LV assessment, including LVEF measurement, is mandatory before the initiation of chemotherapy or radiotherapy. Chemocardiotoxicity can manifest as impairment of myocardial systolic function with resultant congestive heart failure during or immediately after the initial infusion, although acute cardiotoxicity occurs very rarely. Cessation of therapy usually improves myocardial function, though this depends on the cumulative dose experienced by patients. Early cardiotoxicity can occur within 12 months of treatment and late cardiotoxicity can occur beyond 12 months. The concomitant use of trastuzumab has been shown to potentiate the cardiotoxic effects of anthracyclines. Besides causing dilated cardiomyopathy, anthracyclines can also cause endomyocardial fibrosis and diastolic dysfunction with restrictive filling pattern. Radiotherapy carries a very risk of diastolic cardiac failure. Chemocardiotoxicity can occur many years after the chemotherapy and does not correlate with the dose.34 The regular monitoring of heart function during chemotherapy is of major importance for early detection of cardiotoxicity. Three-dimensional echocardiography has been validated as the accurate echocardiographic modality for the calculation of LV ejection fraction. Strain rate imaging has the ability to detect LV systolic dysfunction even before the decline in LVEF. Strain and strain rate imaging identify abnormalities in myocardial mechanics early during cardiotoxicity, allowing the prediction of later overt systolic dysfunction. These parameters are useful in identifying the patients treated with chemotherapy who could benefit from alternate therapies, and thus reduce the incidence of cardiotoxicity. Relative decline in global longitudinal strain 15% is indicates subclinical left ventricular dysfunction and should prompt modification in chemotherapy dosage and initiation of cardioprotective drugs.35 Exercise and pharmacologic stress testing has been studied as a way to unmask subclinical abnormalities of LV function induced by chemotherapeutic agents.36
CONCLUSION Echocardiography will remain the main screening method in routine evaluation of cardiomyopathies. Novel echocardiographic techniques of 3D echocardiography and strain assessment supplement traditional
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ACKNOWLEDGMENTS Authors are thankful to Management of CARE HOSPITALS, BANJARA HILLS, HYDERABAD; Dr . Johann, Mr. Shiva for providing MDCT and CMR images.
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10. Bozkurt B, Colvin M, Cook J, et al. Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart Association. Circulation. 2016 ;134(23):e579-e646. 11. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28:139. 12. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;58(25):e212-60. 13. Nagueh SF, Bierig SM, Budoff MJ, et al. American Society of Echocardiography Clinical Recommendations for Multimodality Cardiovascular Imaging of Patients with Hypertrophic Cardiomyopathy. J Am Soc Echocardiogr. 2011;24(5):473-98. 14. Robinson A, Kramer CM. Imaging in Hypertrophic Cardiomyopathy. JACC Cardiovasc Imaging. 2016;9:1392-402. 15. Chan RH, Maron BJ, Olivotto I, et al. Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation. 2014;130(6):484-95. 16. Jenni R, Oechslin E, Schneider J, et al. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart. 2001;86(6):666–71. 17. Grothoff M, Pachowsky M, Hoffmann J, et al. Value of cardiovascular MR in diagnosing left ventricular noncompaction cardiomyopathy and in discriminating between other cardiomyopathies. Eur Radiol. 2012; 22(12):2699–709. 18. Habib G, Bucciarelli-Ducci C, Alida LP, et al. Imaging in Restrictive Cardiomyopathies: An EACVI expert consensus document In collaboration with the “Working Group on myocardial and pericardial diseases” of the European Society of Cardiology Endorsed by The Indian Academy of Echocardiography. Eur Heart J Cardiovasc Imaging. 2017; 18(10):1090–121. 19. Phelan D, Collier P, Thavendiranathan P, et al. Relative ‘‘apical sparing’’ of longitudinal strain using 2-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart. 2012;98(19):1442-8. 20. Syed IS, Glockner JF, Feng D, et al. Role of cardiac magnetic resonance imaging in the detection of cardiac amyloidosis. JACC Cardiovasc Imaging. 2010;3:155-64. 21. Dungu JN, Valencia O, Pinney JH, et al. CMR-based differentiation of AL and ATTR cardiac amyloidosis. JACC Cardiovasc Imaging. 2014;7:133-42.
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2D echocardiographic examination and provide important information regarding etiology, cardiac mechanics, and prognosis in patients with cardiomyopathy. CMR indeed represents a standard method in diagnosis of ARVD and certain restrictive cardiomyopathies (particularly cardiac amyloidosis), myocarditis or persisting suspicion for hypertrophic cardiomyopathy with in conclusive echocardiography. Most important role of cardiovascular CT in cardiomyopathies is distinguishing ischemic heart disease from DCM, and RCM from constrictive pericarditis. PET imaging provides an effective method of assessing myocardial perfusion and inflammation. It plays an important role in distinguishing cardiac sarcoidosis from other causes of cardiomyopathy and monitoring response of immunosuppressive therapy in patients with cardiac sarcoidosis.
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22. de Haro-del Moral FJ, Sánchez-Lajusticia A, Gómez-Bueno M, et al. Role of cardiac scintigraphy with ⁹⁹mTc-DPD in the differentiation of cardiac amyloidosis subtype. Rev Esp Cardiol (Engl Ed). 2012;65(5):440-6. 23. Sharma S. Cardiac imaging in myocardial sarcoidosis and other cardiomyopathies. Curr Opin Pulm Med. 2009; 15(5):507-12. 24. Ishimaru S, Tsujino I, Tsukamoto E, et al. Combination of 18F-fluoro-2-deoxyglucose positron emission tomography and magnetic resonance imaging in assessing cardiac sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2005;22(3):234-5. 25. Skali H, Schulman AR, Dorbala S. (18)F-FDG PET/CT for the assessment of myocardial sarcoidosis. Curr Cardiol Rep. 2013;15(5):352. 26. Nagueh SF. Fabry disease: Clinical features, diagnosis, and management of cardiac disease. Uptodate; 2018. 27. Kounas S, Demetrescu C, Pantazis AA, et al. The binary endocardial appearance is a poor discriminator of Anderson-Fabry disease from familial hypertrophic cardiomyopathy. J Am Coll Cardiol. 2008; 51(21):2058-61. 28. Brockington IF, Olsen EG. Löffler’s endocarditis and Davies’ endomyocardial fibrosis. Am Heart J. 1973;85: 308-22.
29. Löffler W. Endocarditis parietalis fibroplastica mit bluteosinophilie. Ein eigenartiges Krankheitsbild. Schweiz Med Wochenschr. 1936;66:817-20. 30. ten Oever J, Theunissen LJ, Tick LW, et al. Cardiac involvement in hypereosinophilic syndrome. Neth J Med. 2011; 69(5): 240-4. 31. Te Riele ASJM, Tandri H, Sanborn DM, et al. Noninvasive Multimodality Imaging in ARVD/C. J Am Coll Cardiol Imaging. 2015;8(5):597–611. 32. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/ dysplasia: proposed modification of the task force criteria. Circulation. 2010;121(13):1533-41. 33. Morris PD, Robinson T, Channer KS. Reversible heart failure: toxins, tachycardiomyopathy and mitochondrial abnormalities. Postgrad Med J. 2012;88(1046):706-12. 34. Khawaja MZ, Cafferkey C, Rajani R, et al. Cardiac complications and manifestations of chemotherapy for cancer. Heart. 2014;100(14): 1133-40. 35. Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in highrisk patients by angiotensin-converting enzyme inhibitors. Circulation. 2006;114(23):2474-81. 36. Cottin Y, L’Huillier I, Casasnovas O, et al. Dobutamine stress echocardiography identifies anthracycline cardiotoxicity. Eur J Echocardiogr. 2000;1(3):180-3.
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Curable Forms of Ventricular CHAPTER 58 Dysfunction Tamiruddin A Danwade, Calambur Narasimhan
INTRODUCTION Ventricular dysfunction with subsequent heart failure (HF) constitutes the final common pathway for a number of cardiac disorders. Coronary artery disease (CAD) or ischemic heart disease is the dominant cause of HF. Other conditions which commonly lead to ventricular dysfunction and HF include hypertension, diabetes mellitus (DM), valvular heart disease, myocarditis, and cardiomyopathies. Progressive HF decreases the quality of life and increases morbidity and mortality of patients suffering from it. Incremental cost of hospitalizations, and the expenses due to drugs, devices and other interventions results in significant economic burden to the society. In this chapter, we will review some of the reversible causes of ventricular dysfunction (Table 1) their pathophysiology, and management in brief. These conditions should probably be separated from cardiomyopathies and described as distinct entities.
ISCHEMIC CARDIOMYOPATHY (CORONARY ARTERY DISEASE) Coronary atherosclerosis is a common cause of ventricular dysfunction, comprising 50–75% of patients with ventricular dysfunction and HF. 1-3 Although the term ‘ischemic cardiomyopathy’ has been used to describe ischemic myocardial dysfunction, this is not supported by the recent American Heart Association (AHA) or European Society of Cardiology (ESC) cardiomyopathy classification systems. In some patients, persistent ventricular dysfunction follows transient ischemia, even after the restoration of coronary flow (myocardial stunning). Hibernating myocardium on the other hand is a state of persistently impaired ventricular dysfunction at rest due to chronically reduced coronary blood flow. This can result in HF and can be partially or completely restored to normal either by improving blood flow or by reducing oxygen demand. Several tools, such as low-dose Dobutamine
Table 1: Curable forms of ventricular dysfunction* Common causes zz zz zz zz zz zz zz zz
zz zz zz zz
zz zz zz zz
zz zz
Coronary artery disease: Hibernating myocardium Hypertensive heart disease Diabetic cardiomyopathy Valvular Heart disease Obstructive sleep apnea Tachycardiomyopathy (TCMP): Incessant tachycardias (both supraventricular and ventricular tachycardias), frequent premature ventricular contractions (PVCs) Drugs:** Chemotherapeutics agents (Anthracyclines, trastuzumab, cyclophosphamide), phenothiazines, clozapine, tricyclic antidepressants, lithium, interleukins, 5-fluorouracil, antitubercular drugs, ionotropes, glitazones Addictions: Alcohol, cocaine, amphetamines, etc. Critical illness cardiomyopathy Peripartum cardiomyopathy Endocrine abnormalities: Hypothyroidism. hyperthyroidism, Hypoparathyroidism (hypocalcemia induced), growth hormone and/or insulin-like growth factor 1 deficiency or excess, pheochromocytoma, Conn’s syndrome Nutritional deficiencies: Thiamine, selenium, carnitine Takotsubo cardiomyopathy Infections: Viral myocarditis, Lyme’s disease, tuberculosis, Chagas disease, fungal infections, etc. Autoimmune diseases: Systemic lupus erythomatosis (SLE), rheumatoid arthritis, Wegener’s granulomatosis, giant cell myocarditis, sarcoidosis Accessory pathway-induced cardiomyopathy: Conduction through accessory pathway causing dyssynchrony and cardiomyopathy Uremic heart disease
Note: * Although we tried to present a list of curable forms of ventricular dysfunction, some conditions may have been missed. **Any drug used in clinical practice can cause myocarditis (immune-mediated)
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C Figures 1A to C: Showing myocardial perfusion and metabolism studies with (A) Short-axis; (B) Horizontal-axis; (C) Vertical-long-axis slices. Top rows in each A, B and C are a SPECT MIBI scan (perfusion) images and the bottom rows are 18-F FDG PET scan (metabolism) images. There is significant perfusion mismatch demonstrating hibernating myocardium in the LAD territory Abbreviations: LAD, left anterior descending artery; SPECT, single-photon emission computed tomography; 18-F FDG PET-18, fluoro-2deoxyglucose positron emission tomography
stress echocardiography (DSE) and contrast-enhanced cardiac MRI, are helpful in identifying hibernating myocardium. Positron emission tomography (PET) has shown that regions with abnormal wall motion, which are metabolically active, can improve after revascularization (Figures 1A to C).4 Occult CAD is not an uncommon cause of dilated cardiomyopathy (DCM), it accounts for about 7% of otherwise unexplained cases.5 Significant coronary artery stenosis causing ischemia in a large area of myocardium can present as ventricular dysfunction (with or without overt HF), and revascularization results in partial or complete restoration of the contractile function of this hibernating myocardium, and resolution of HF.
HYPERTENSIVE HEART DISEASE In persons with hypertension, ventricular relaxation abnormalities are common. It is often accompanied by left ventricular hypertrophy (LVH), coexistent CAD aging
and structural abnormalities, such as fibrosis along with LVH, contribute to the development of HF with preserved ejection fraction (EF). Systolic dysfunction usually follows. The mechanisms by which hypertension can cause ventricular dysfunction and HF are depicted in Figure 2. Early left ventricular (LV) diastolic dyssynchrony may be associated with LV remodeling and contribute to LV diastolic dysfunction. The level of this dysfunction appears to correlate with increasing severity of hypertension. Abnormal early diastolic strain rate of the left ventricle may be an independent factor contributing to the dysfunction.7 Aggressive treatment of hypertension early in the course of the disease may reverse the diastolic as well as systolic dysfunction. In general, patients with hypertension and HF with systolic dysfunction should be treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor antagonist. Along with this, a beta-blocker and a mineralocorticoid-receptor antagonist may be added if there is no contraindication. This results in improvement of their EF and reduction in
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morbidity [stroke and chronic kidney disease (CKD)] and mortality. These agents have been shown to reduce LVH and may be preferred agents in this subset of patients.8-12 The α-blockers, such as prazosin and doxazosin, are to be avoided as the risk of HF increases with their use.13
DIABETES MELLITUS Heart failure is reported to be the ‘frequent, forgotten, and often fatal complication of diabetes’.14 The role of elevated blood sugar in the causation of various cardiovascular diseases has been investigated by several researchers.15-17 DM can cause structural and functional abnormalities of the myocardium independent of atherosclerotic CAD resulting in adverse cardiovascular events. 18 Chronic hyperglycemia in DM results in nonenzymatic glycation of tissue macromolecules, such as proteins, lipids, and deoxyribonucleic acid (DNA) to form advanced glycated end products. 19 Such products accumulate in myocardium and subsequent fibrosis and microangiopathy leads to structural changes.18,20,21 In the diabetic heart, there is an increase in apoptosis leading to increased collagen deposition in a diffuse manner as a result of replacement fibrosis and connective tissue proliferation. Ultimately, there is decreased ventricular compliance.22 Left ventricular diastolic dysfunction has been proposed to be the first stage of the putative ‘diabetic cardiomyopathy’ which subsequently leads to systolic dysfunction. 23 There are several mechanisms leading to HF among patients with DM,24 which are beyond the scope of this review. Control of hyperglycemia in early stages of the disease can reverse the ventricular dysfunction. Choice of antidiabetic medications seems to be important. While all of them control the blood sugars, only some prevent or reverse the cardiac abnormalities. Metformin does not have adverse cardiovascular effects and decreases
Curable Forms of Ventricular Dysfunction
Figure 2: The pathways in the progression from hypertension to ventricular dysfunction and heart failure 1. Hypertension leading to concentric LVH. 2. Hypertension without LVH leading to decrease in LVEF with interval MI. 3. Hypertension without LVH progressing to decrease in LVEF without interval MI. 4. Hypertension with LVH progressing to decrease in LVEF with interval MI. 5. Hypertension with LVH progressing to decrease in LVEF without interval MI. 6. Patients with concentric LVH developing heart failure with a preserved LVEF. 7. Patients with decreased LVEF developing symptomatic heart failure6 Abbreviations: LVH, left ventricular hypertrophy; LVEF, left ventricular ejection fraction; MI, myocardial infarction
cardiovascular events in diabetic population.25-27 There are a growing number of trials assessing important favorable cardiovascular health outcomes in patients taking sodium-glucose cotransporter-2 (SGLT2) inhibitors. 28,29 Peroxisome proliferator-activated receptor (PPAR) agonists significantly increase the risk of HF30,31 and the risk of HF are intermediate with dipeptidyl peptidase-4 (DPP-4) inhibitors.32
VALVULAR HEART DISEASE Valvular heart diseases, such as aortic stenosis, mitral regurgitation, and pulmonary stenosis, can cause ventricular dysfunction either due to pressure and/or volume overload. These patients are managed initially with medical treatment. If valve surgery or interventions are performed in timely fashion, then ventricular dysfunction is reversible in some cases.33
ALCOHOLIC CARDIOMYOPATHY Chronic alcohol intake in significant quantity may lead to biventricular dysfunction. Criteria for diagnosing alcoholic cardiomyopathy (ACM) include: (a) DCM phenotype, (b) Absence of other known and detectable causes of DCM, and (c) Long history of heavy alcohol intake. The toxic effect is observed when daily alcohol consumption is over 80 g (three or more standard-sized drinks per day) lasting 5 years or more before the onset or diagnosis.34-36 Thiamine deficiency (beriberi) is no longer confused with this entity; the former fully responds to thiamine administration, whereas the latter does not.37 Although the evidence is limited, genetic factors may predispose to ACM.38 Abstinence from alcohol is the most important aspect of management; but ACM patients, who reduced their alcohol intake to moderate levels, exhibited similar cardiac function recovery as abstainers.39 483
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COCAINE Cocaine abuse generally leads to coronary ischemia; but, sometimes, it can lead to development of cardiomyopathy although the mechanism is not well understood. Cocaine abuse should be suspected when a young person presents with cardiomegaly and otherwise unexplained HF. Direct toxic effect, cocaine-induced hyperadrenergic state, and in parenteral cocaine abusers, concomitant infective endocarditis are possible mechanisms. Complete reversal of the myocardial dysfunction usually follows abstinence.40,41
MEDICATIONS
Lyme Disease
Drugs can cause cardiomyopathy (see Table 1), significant improvement can occur after discontinuation. The most extensively studied example is anthracyclineinduced cardiomyopathy. Trastuzumab is another chemotherapeutic agent associated with frequent cardiotoxicity particularly in patients also treated with an anthracycline plus cyclophosphamide.42 Early discontinuation of the culprit medication and supportive treatment reverses ventricular dysfunction.
Lyme disease is usually manifested as a conduction abnormality, but cardiac muscle dysfunction can also occur; it is usually self-limited and mild, leading to transient cardiomegaly or pericardial effusion on echocardiogram or chest radiograph. However, occasional patients develop symptomatic myocarditis and DCM. Patients with Lyme carditis are treated with antibiotics to prevent later complications of Lyme disease and to shorten the duration of the cardiac manifestations.48
INFECTIOUS CARDIOMYOPATHY
Myocardial Tuberculosis
A variety of infectious organisms can lead to myocarditis and ventricular dysfunction.
Although rare, myocardial tuberculosis can cause significant cardiovascular abnormalities, such as unexplained VT, atrioventricular blocks, and cardiomyopathy, and even sudden death. This is discussed in greater detail under granulomatous myocarditis.
Viral Cardiomyopathy The most common cause of myocarditis is viral infection, and this can lead to development of DCM. Causative viruses include parvovirus B19, human herpesvirus 6, coxsackievirus, influenza virus, adenovirus, echovirus, cytomegalovirus, and human immunodeficiency virus (HIV).43 The degree of viremia is limited by the initial immune response early during infection and protects against myocarditis. But, if this response is not sufficient, the virus may not be eliminated, and myocyte injury may ensue via one or two mechanisms: (a) Receptor-mediated entry of the virus into cardiac myocytes causing direct cytotoxicity, and (b) An adverse autoimmune response induced by persisting viral genomic fragments that may not be capable of replicating as intact virus. If there is early recovery from the viral infection, then ventricular dysfunction reverses. Management of myocarditis includes general nonspecific measures, such as HF therapy, treatment of arrhythmias according to current guidelines, and if required anticoagulation. The efficacy of antiviral, immunosuppressive, and intravenous immune-globulin therapies are being investigated in these patients.44-46
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America. Clinically, it presents as acute myocarditis, cardiac enlargement, tachycardia, and nonspecific electrocardiogram abnormalities including right bundle branch block and premature ventricular contractions and left ventricular apical aneurysms that are pathognomonic for this disease. Antitrypanosomal therapy is useful to treat patients with early chronic Chagas disease (CD). In patients with advanced DCM, the focus of management is supportive care for HF, arrhythmia, and thromboembolism since antitrypanosomal therapy is unlikely to be effective in reversing established myocardial disease.47
Trace Elements Trace elements play an important role in myocardial metabolism and their excess, e.g. cobalt, arsenic or deficiency like selenium can lead to development in a reversible form of DCM that is very similar to an idiopathic cardiomyopathy.49-54
Peripartum Cardiomyopathy Presenting in late pregnancy and the early postpartum period, peripartum cardiomyopathy (PPCM) is a rare cause (0.1% of all pregnancies) of DCM. Despite many attempts to uncover a distinct etiology of PPCM, the cause remains unknown and may be multifactorial. Alterations in prolactin processing may contribute to the angiogenic imbalance, which can lead to development of PPCM.55 Diagnosis requires exclusion of other causes of cardiomyopathy. A variety of definitions have been proposed for this disorder.56 The LV may not be dilated, but the EF (EF) is always reduced below 45%.56 Ventricular dysfunction recovers over a period. But recurrence rates in subsequent pregnancies are very high.
Chagas Disease
Autoimmune Disorders
Protozoa Trypanosoma cruzi is the causative organism; it is the most common cause of DCM in Central and South
The DCM can be caused by autoimmunity, 57 and the presence of autoantibodies may identify family members
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Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) commonly involves the heart. Valvular, pericardial, coronary disease or myocarditis can develop. Myocarditis can present with resting tachycardia disproportionate to body temperature, electrocardiographic abnormalities (such as ST-T wave abnormalities), and unexplained cardiomegaly. Immunosuppressive therapy occasionally leads to improved myocardial function in this setting.
Celiac Disease As many as 5% of patients with autoimmune myocarditis or idiopathic DCM can be caused by celiac disease, which is often clinically unsuspected.59,60 The disease can be subclinical presenting only as iron deficiency anemia refractory to iron replacement.59 Cardiac function improves following a gluten-free diet with or without immunosuppressive therapy. It is premature to screen all patients with otherwise unexplained cardiomyopathy for celiac disease. Still, it is reasonable to elicit history of gastrointestinal complaints or refractory iron deficiency.
factor-1 (IGF-1) can also cause reversible forms of DCM.64,65
Nutritional Deficiencies Deficiencies in thiamine, selenium, and carnitine have been reported to produce ventricular dysfunction and replacement therapy is curative.66,67 Thiamine is very important in normal oxidative phosphorylation and myocardial energy production. Its deficiency initially presents as a high output state secondary to vasodilation; this is followed by depression of myocardial function and the development of a low-output state.66 Selenium (Se) deficiency causes increased free radicals that are toxic to cardiac myocytes due to decrease in the activity of glutathione peroxide. The development endemic cardiomyopathy that affects children and women of childbearing age in areas of China known as Keshan disease has been linked to Se deficiency. 68 Keshan disease is associated with local diets, which are nearly devoid of Se in these geographical areas. Carnitine deficiency results in lipid accumulation in the myocyte cytoplasm due to impaired oxidation of fatty acids. This can be reversed by carnitine supplements.
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Obstructive Sleep Apnea Obstructive sleep apnea can contribute to the impairment of left ventricular dysfunction. A history of snoring, daytime somnolence, and obesity should alert the clinician to the diagnosis. Effective therapy, as with nasal continuous positive airway pressure during sleep, can lead to a significant improvement in left ventricular dysfunction.69
Endocrine Dysfunction
Tachycardiomyopathies
Thyroid dysfunction, excess sympathetic activity in pheochromocytoma, and rarely Cushing’s syndrome and growth hormone (GH) excess or deficiency can cause cardiac dysfunction, which can usually be reversed by correction of the endocrine disorder.61-64 The exact mechanisms of thyroid dysfunction leading to DCM are not known. Preload, afterload, heart rate, and contractility of heart are altered by thyroid hormone each of which may contribute to cardiac dysfunction. Experiments have also shown that excess triiodothyronine (T3) causes myocyte hypertrophy and changes in specific protein synthesis.61 Excess sympathomimetic amines in pheochromocytoma leads to focal direct myocyte injury followed by inflammation, downregulation of beta-receptors, ultimately leading to net reduction of viable myofibrils.62 As many as 10% of patients with newly diagnosed acromegaly have HF due to high cardiac output. 63 Deficiency of growth hormone or interleukin growth
In routine clinical practice, arrhythmias are a common cause of cardiomyopathy which is potentially reversible but often overlooked. Practically, any kind of incessant tachycardia can lead to tachycardiomyopathies (TCMP) including: atrial tachycardia (AT), atrial fibrillation (AF), atrial flutter, atrioventricular re-entrant tachycardia, atrioventricular nodal re-entrant tachycardia, junctional ectopic tachycardia, ventricular tachycardia (VT), frequent premature ventricular contractions (PVCs) and right ventricular pacing.70-84 When patients present with tachyarrhythmia and unexplained DCMP, it may be difficult to know whether HF is the cause or effect of tachycardia. 85 Thus, while managing these cases, we should focus on treatment of HF and control of arrhythmia. The presence of tachycardia may limit the therapy for HF. In cases like atrial tachycardia, radiofrequency catheter ablation (RFCA) should be considered early, as it has a curative potential and is associated with high success rate (Figures 3A and B).
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of patients with DCM who are at a greater risk of developing cardiomyopathy. Several cardiac autoantibodies have been identified which target a variety of antigens. The following are some of the examples: beta-1 adrenoceptor, alpha-myosin heavy chain, beta-myosin heavy chain, myosin light chain, and troponin. All these autoantibodies are sometimes referred to as antiheart antibodies (AHAs). Therapy should be directed towards the underlying disease. Treatment options, such as immunoadsorption, can reverse the ventricular dysfunction.58
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A(I)
B(I)
A(II)
B(II)
Figures 3A and B: (A) 12-lead ECG of a patient who presented with tachycardiomyopathy: A(I) Focal atrial tachycardia. A(II) Sinus rhythm ECG of same patient after radiofrequency ablation of atrial tachycardia; (B) Chest X-ray of same patient B(I) Chest X-ray at the time of presentation B(II) Chest X-ray one week after radiofrequency catheter ablation
Ventricular dysfunction due to TCMP can be cured by catheter ablation.86 There are two categories of TCMP: (a) first where arrhythmia is the cause of cardiomyopathy (arrhythmiainduced) which completely reverses once tachycardia is taken care of, and (b) where arrhythmia exacerbates the underlying ventricular dysfunction in a patient with known myocardial disease (arrhythmia mediated). 82 TCMP as a cause of HF can only be evident once sinus rhythm is restored. The mechanism of myocyte dysfunction in TCMP is not completely defined, but includes oxidative mitochondrial damage, subclinical ischemia and calcium overload.85,87,88 A timely recognition and treatment of culprit arrhythmia is important, in view of potential for complete recovery of ventricular dysfunction.
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Granulomatous myocarditis (GM) mainly comprising of cardiac sarcoidosis (CS) and cardiac tuberculosis (CTB) is prevalent but under-recognized in India. Diagnoses of these entities have more often been made at autopsy highlighting the difficulty in diagnosing.89-93 Cardiomyopathy with or without HF may be one of the initial clinical presentations. Paucity of constitutional symptoms and lack of awareness results in delayed diagnosis. Besides routine clinical evaluation and laboratory tests, cardiac MRI, CT chest and FDG-PET (Fluorine-18 fluoro-2-deoxyglucose positron emission tomography) help in evaluation of GM. The optimal treatment modality for GM with HF is not well defined. Left ventricular function can improve significantly with disease-specific therapy of the
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underlying inflammation along with antiarrhythmic drugs and standard treatment of HF (Figures 4A and B).94-97 Corticosteroids are the first line of therapy in sarcoidosis. However, methotrexate can be used as a steroid sparing agent for long-term suppression of ongoing inflammation. Similarly, in CTB, left ventricular function and HF can improve with antitubercular therapy and short course of steroids.98
Accessory Pathway-induced Cardiomyopathy In the current era, any symptomatic patient with HF and left bundle branch block (LBBB) (QRS ≥150 ms) in sinus rhythm on guideline-directed medical therapy (GDMT) is considered for cardiac resynchronization therapy (CRT).99However, it is prudent to evaluate such patients for the underlying etiology before implanting CRT. Accessory pathways cause pre-excitation of small part of the ventricular myocardium. Incessant tachyarrhythmia in patients with Wolff–Parkinson–White (WPW) syndrome can result in TCMP. However, the possibility of accessory pathway-induced dysynchrony must not be ignored. Patients with right-sided accessory pathways (type B WPW syndrome) have wide QRS pattern similar to LBBB which can cause LV dyssynchrony-induced cardiomyopathy. Such patients have a gratifying outcome following radiofrequency ablation (RFA).100-104 In general, the indication of RFCA in patients with WPW syndrome is frequent episodes of tachycardia with or without medical therapy.105 However, in some patients, RFA is performed not for tachyarrhythmias but to restore LV synchrony and normalize the LV function, as a treatment for HF (Figures 5A and B).
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A
B(II)
Figures 4A and B: (A) FDG-PET CT of a patient who presented with heart failure showing diffuse heterogeneous uptake in LV with maximum uptake in apicolateral segment; (B) 12-lead ECG of same patient B(I) Baseline ECG at the time of presentation showing LBBB. B(II) ECG six months after disease specific therapy (immunosuppressant) showing normalization of LBBB Abbreviations: LBBB, left bundle branch block; FDG-PET CT, fluorine-18 fluoro-2-deoxyglucose positron emission tomography and computed tomography; LV, Left ventricle.
A(I)
A(II)
B(I)
B(II)
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B(I)
Figures 5A and B: 1. 12-lead ECG of a patient who presented with WPW syndrome with LV dysfunction: A(I) Showing LBBB type of preexcitation (type B WPW syndrome); A(II) ECG after radiofrequency catheter ablation of pathway (B) Fluoroscopy (AP view) of the same patient. B(I) White arrow showing ablation catheter at the site of RFCA. B(II) Contrast injection (white arrow) at the site of successful catheter ablation for accessory pathway, which is right atrial appendage Abbreviations: AP, anteroposterior; LV, left ventricle; RFCA, radiofrequency catheter ablation; LBBB, left bundle branch block; WPW, Wolff– Parkinson–White
Left Apical Ballooning Syndrome The left apical ballooning syndrome, or Takotsubo cardiomyopathy, is characterized by transient hypocontractility of the mid and apical segments of the LV associated with hyperkinesis of the basal walls. This leads
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to a balloon-like appearance of the distal ventricular walls in systole. It mimics acute coronary syndrome in the absence of CAD or spasm. It is most prevalent in older women exposed to emotional or physical stressors. This can present atypically such as reversed and right
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ventricular Takotsubo and global hypokinesis. 106,107 It is generally associated with increased levels of circulating catecholamines, especially epinephrine. Sometimes, it does not follow obvious physical or emotional stress; superadded, it may carry significant early and late serious complication risks. Concomitant subcritical CAD may be present; and cardiovascular risk factors can be present.107 Primary Takotsubo cardiomyopathy is frequently related to emotional stress, is largely reversible, and carries a good prognosis compared to secondary forms which have higher event rate.108 They do not share the chronic morphologic LV abnormalities and remodeling that characterize DCM.
Uremic Cardiomyopathy Chronic renal diseases can get complicated by developing uremic cardiomyopathy and is considered a risk factor for morbidity and mortality.109 Approximately 50% of deaths in patients with CKD occurs due to CAD, LV hypertrophy and congestive HF. Proper etiology is unclear but uremic toxins, renin-angiotensin-aldosterone system activation, sympathetic nervous system activation, anemia, calcium phosphate imbalance, and inflammation are emerging as factors involved in the pathogenesis of cardiac disease in CKD.110, 111 Frequent hemodialysis (nocturnal home hemodialysis, short daily hemodialysis, and peritoneal dialysis) optimizes the ultrafiltration rate with minimal reductions in intravascular volume and cooling the dialysate as compared with conventional hemodialysis (3 days per week); this reduces dialysis-induced myocardial stunning and intradialysis hypotension. Uremic cardiomyopathy can be reversed after kidney transplantation and it confers a significant survival advantage over hemodialysis.112 Early diagnosis of uremic cardiomyopathy contributes to risk stratification and decisions about proper type of dialysis therapy.113
CONCLUSION Clinical evaluation patients of ventricular dysfunction with or without HF should include assessment for underlying causes. These conditions may either cause HF or aggravate it. Treatment of these correctable factors helps to reverse the syndrome of ventricular dysfunction and HF.
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56. Sliwa K, Hilfiker-Kleiner D, Petrie MC, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy. Eur J Heart Fail. 2010;12(8):767-78. 57. Yoshikawa T, Baba A , Nagatomo Y. Autoimmune mechanisms underlying dilated cardiomyopathy. Circ J. 2009;73(4):602-7. 58. Müller J, Wallukat G, Dandel M, et al. Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy. Circulation. 2000;101(4):385-91. 59. Frustaci A, Cuoco L, Chimenti C, et al. Celiac disease associated with autoimmune myocarditis. Circulation. 2002;105(22):2611-8. 60. Curione M, Barbato M, De Biase L, et al. Prevalence of coeliac disease in idiopathic dilated cardiomyopathy. Lancet. 1999;354(9174):222-3. 61. Kantharia BK, Richards HB, Battaglia J. Reversible dilated cardiomyopathy: an unusual case of thyrotoxicosis. Am Heart J. 1995;129(5):1030-2. 62. Sa rd e s a i S H , Mou ra nt A J, Si vat ha n d o n Y, e t a l . Phaeochromocytoma and catecholamine induced cardiomyopathy presenting as heart failure. Br Heart J. 1990;63(4):234-7. 63. Damjanovic SS, Neskovic AN, Petakov MS, et al. High output heart failure in patients with newly diagnosed acromegaly. Am J Med.2002;112(8):610-6. 64. Frustaci A, Perrone GA, Gentiloni N, et al. Reversible dilated cardiomyopathy due to growth hormone deficiency. Am J Clin Pathol.1992;97(4):503-11. 65. Vasan RS, Sullivan LM, D’Agostino RB, et al. Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Ann Intern Med. 2003;139(8):642-8. 66. Abelmann WH, Lorell BH. The challenge of cardiomyopathy. J Am Coll Cardiol. 1989;13(6):1219-39. 67. Abelmann WH. Cardiomyopathies and inflammatory disorders. Curr Opin Cardiol. 1992;7:417. 68. Observations on effect of sodium selenite in prevention of Keshan disease. Chin Med J (Engl). 1979; 92(7):471-6. 69. Malone S, Liu PP, Holloway R, et al. Obstructive sleep apnoea in patients with dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet. 1991; 338(8781):1480-4. 70. Nia AM, Gassanov N, Dahlem KM, et al. Diagnostic accuracy of NT-proBNP ratio (BNP-R) for early diagnosis of tachycardia-mediated cardiomyopathy: a pilot study. Clin Res Cardiol. 2011;100(10):887–96. 71. Allen HW. Auricular fibrillation. Cal State J Med. 1913;11:435–40. 72. Fujino T, Yamashita T, Suzuki S, et al. Characteristics of congestive heart failure accompanied by atrial fibrillation with special reference to tachycardiainduced cardiomyopathy. Circ J.2007;71(6):936–40. 73. Pizzale S, Lemery R, Green MS, et al. Frequency and predictors of tachycardia-induced cardiomyopathy in patients with persistent atrial flutter. Can J Cardiol. 2009;25(8):469–72.
74. Furushima H, Chinushi M, Sugiura H, et al. Radiofrequency catheter ablation for incessant atrioventricular nodal reentrant tachycardia normalized H- V block associated with tachycardia-induced cardiomyopathy. J Electrocardiol. 2004;37(4):315–9. 75. Medi C, Kalman JM, Haqqani H, et al. Tachycardiamediated cardiomyopathy secondary to focal atrial tachycardia: long-term outcome after catheter ablation. J Am Coll Cardiol. 2009;53(19):1791–7. 76. Bensler JM, Frank CM, Razavi M, et al. Tachycardiamediated cardiomyopathy and the permanent form of junctional reciprocating tachycardia. Tex Heart Inst J. 2010;37(6):695–8. 77. S cheinman MM, Basu D, Hollenb erg M, et al . Electrophysiologic studies in patients with persistent atrial tachycardia. Circulation. 1974;50(2):266–73. 78. Bertil Olsson S, Blomström P, Sabel KG, et al. Incessant ectopic atrial tachycardia: successful surgical treatment with regression of dilated cardiomyopathy picture. Am J Cardiol.1984;53(10):1465–6. 79. Gillette PC, Smith RT, Garson A Jr, et al. Chronic supraventricular tachycardia. A curable cause of congestive cardiomyopathy. JAMA.1985;253(3):391–2. 80. Gillette PC, Wampler DG, Garson A Jr, et al. Treatment of atrial automatic tachycardia by ablation procedures. J Am Coll Cardiol.1985;6(2):405–9. 81. Penela D, Van Huls Van Taxis C, Aguinaga L, et al. Neurohormonal, structural, and functional recovery pattern after premature ventricular complex ablation is independent of structural heart disease status in patients with depressed left ventricular ejection fraction: a prospective multicenter study. J Am Coll Cardiol. 2013;62(13):1195–202. 82. Gopinathannair R, Etheridge SP, Marchlinski FE, Arrhythmia-induced cardiomyopathies: mechanisms, recognition, and management. J Am Coll Cardiol. 2015;66(15):1714–28. 83. Martin CA, Lambiase PD. Pathophysiology, diagnosis a n d t re a t m e n t o f t a c h y c a rd i o my o p a t hy . He a r t . 2017;103(19):1543-52. 84. Dhawan R, Gopinathannair R. Arrhythmia-induced cardiomyopathy: prevalent, under-recognized, reversible. J Atr Fibrillation. 2017;10(3):1776. 85. Bhushan M, Asirvatham SJ. The conundrum of ventricular arrhythmia and cardiomyopathy: which abnormality came first? Curr Heart Fail Rep. 2009;6(1):7–13. 86. Hanumandla A, Kaur D, Shah M, et al. Epicardial ablation of focal atrial tachycardia arising from left atrial appendage in children. Indian Pacing Electrophysiol J. 2014;14(4):199202. 87. Morris PD, Robinson T, Channer KS. Reversible heart failure: toxins, tachycardiomyopathy and mitochondrial abnormalities. Postgrad Med J. 2012;88(1046):706-12. 88. Ansari A, Maron BJ, Berntson DG. Drug-induced toxic myocarditis. Tex Heart Inst J. 2003;30(1):76-9. 89. Roberts WC, McAllister HA Jr, Ferrans VJ. Sarcoidosis of the heart. A clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11). Am J Med. 1977;63(1):86-108.
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103.
104.
105.
106. 107.
108.
109.
110.
111.
112.
113.
cardiac resynchronization therapy in a patient with dilated cardiomyopathy. Europace. 2009;11(1):121-3. Udink ten Cate FE, Kruessell MA, Wagner K, et al. Dilated cardiomyopathy in children with ventricular preexcitation: the location of the accessory pathway is predictive of this association. J Electrocardiol. 2010;43(2):146-54. Nakabayashi K, Sugiura R, Mizuno Y, et al. Successful catheter ablation as a substitute for cardiac resynchronization therapy in patient with an accessory pathway-induced cardiomyopathy. Intern Med. 2017;56(16):2165-9. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/ AHA/ HRS Guideline for the management of adult patients with supraventricular tachycardia: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2016;67(13):e27-115. Sharkey SW, Maron BJ. Epidemiology and clinical profile of Takotsubo cardiomyopathy. Circ J.2014;78(9):2119-28. Pelliccia F, Parodi G, Greco C, et al. Comorbidities frequency in Takotsubo syndrome: an international collaborative systematic review including 1109 patients. Am J Med. 2015;128(6):654.e11-9. D e s a i S K , Sh i n b a n e J, Da s J R , e t a l . Ta k o t s u b o cardiomyopathy: clinical characteristics and outcomes. Rev Cardiovasc Med. 2015;16(4):244-52. Alhaj E, Alhaj N, Rahman I, t al. Uremic cardiomyopathy: an underdiagnosed disease. Congest Heart Fail. 2013;19(4):E40-5. Chinnappa S, Hothi SS, Tan LB. Is uremic cardiomyopathy a direct consequence of chronic kidney disease? Expert Rev Cardiovasc Ther. 2014;12(2):127-30. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk : epidemiology, mechanisms, and prevention. Lancet. 2013;382(9889):339-52. Zolty R, Hynes PJ, Vittorio TJ. Severe left ventricular systolic dysfunction may reverse with renal transplantation: uremic cardiomyopathy and cardiorenal syndrome. Am J Transplant. 2008;8(11):2219-24. Hassanin N, Alkemary A. Early detection of subclinical u re m i c ca rd i o myo p at hy u s i ng t w o - d i m e n s i o na l speckle tracking echocardiography. Echocardiography. 2016;33(4):527-36.
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58 Curable Forms of Ventricular Dysfunction
90. Duke C, Rosenthal E. Sudden death caused by cardiac sarcoidosis in childhood. J Cardiovasc Electrophysiol. 2002;13(9):939-42. 91. Veinot JP, Johnston B. Cardiac sarcoidosis--an occult cause of sudden death: a case report and literature review. J Forensic Sci. 1998;43(3):715-7. 92. Wallis PJ, Branfoot AC, Emerson PA. Sudden death due to myocardial tuberculosis. Thorax.1984;39(2):155-6. 93. Rose AG. Cardiac tuberculosis. A study of 19 patients. Arch Pathol Lab Med. 1987;111(5):422–6. 94. Banba K, Kusano KF, Nakamura K, Morita H, Ogawa A, Ohtsuka F, et al. Relationship between arrhythmogenesis and disease activity in cardiac sarcoidosis. Heart Rhythm. 2007;4(10):1292-9. 95. Soejima K, Yada H. The work-up and management of patients with apparent or subcl inical cardiac sarcoidosis: with emphasis on the associated heart rhythm abnormalities. J Cardiovasc Electrophysiol. 2009;20(5):57883. 96. Terasaki F, Ishizaka N. Deterioration of cardiac function during the progression of cardiac sarcoidosis: diagnosis and treatment. Intern Med. 2014;53(15):1595-605. 97. Padala SK, Peaslee S, Sidhu MS, Steckman DA, Judson MA. Impact of early initiation of corticosteroid therapy on cardiac function and rhythm in patients with cardiac sarcoidosis. Int J Cardiol. 2017;227:565-70. 98. Mohan A, Thachil A, Sundar G, Sastry BK, Hasan A, Sridevi C, et al. Ventricular tachycardia and tuberculous lymphadenopathy: sign of myocardial tuberculosis? J Am Coll Cardiol. 2015;65(2):218-20. 99. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed). 2016;69(12):1167. 100. Fazio G, Mongiovi’ M, Sutera L, et al. Segmental dyskinesia in Wolff-Parkinson-White syndrome: a possible cause of dilatative cardiomyopathy. Int J Cardiol.2008;123(2):e31-4. 101. Tomaske M, Janousek J, Rázek V, et al. Adverse effects of Wolff-Parkinson-White syndrome with right septal or posteroseptal accessory pathways on cardiac function. Europace. 2008;10(2):181-9. 102. Iwasaku T, Hirooka K, Taniguchi T, et al. Successful catheter ablation to accessory atrioventricular pathway as
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CHAPTER 59 Myocarditis: An Update Neeraj Pandit, Mohit Bhutani
INTRODUCTION
CLASSIFICATION OF MYOCARDITIS
Myocarditis is an inflammatory disease of heart muscle diagnosed by established histological, immunological and immunohistochemical criteria.1,2 It has infectious and noninfectious etiology. It usually presents with nonspecific symptoms and signs. Myocarditis may have a fulminant course with high morbidity and mortality or may present with chronic course of left ventricular dysfunction (LVD), dilated cardiomyopathy (DCM), chronic heart failure, conduction disturbances, ventricular arrhythmias, and sudden death. Due to these varied presentations and outcomes, a high degree of suspicion early in the course of disease is essential for the clinical diagnosis of myocarditis. The incidence of biopsy proven myocarditis in adults with nonischemic DCM is reported to be 3–16% in the Western literature. However, there is paucity of data from our country.
Myocarditis can be of various types based on etiology, histology (lymphocytes, eosinophils, giant cells, granulomatous, etc.), immunohistology and clinical status (acute, fulminant or chronic). Viral myocarditis has histological evidence of inflammatory infiltrates in the myocardium as per Dallas criteria associated with positive viral polymerase chain reaction (PCR). Autoimmune myocarditis has histological evidence of myocarditis with negative viral PCR with or without serum cardiac autoantibodies. There can also be a clinical scenario with histological evidence of myocarditis, positive viral PCR and positive serum cardiac autoantibodies. Patients presenting with acute onset and fulminant clinical course with development of recurrent ventricular tachycardia, high-grade atrioventricular block or failure to show response to optimum heart failure treatment may be suffering from giant cell myocarditis. This subgroup has poor prognosis. Early endomyocardial biopsy (EMB) can help in the histological diagnosis and guide appropriate therapy. Cardiac sarcoidosis is suspected in patient presenting with chronic heart failure, dilated cardiomyopathy, new onset ventricular arrhythmia, and high-grade atrioventricular block not responding to conventional treatment.
ETIOPATHOGENESIS The most common cause of myocarditis is due to various infectious agents. Hypersensitivity or toxic reaction to drugs and autoimmune mechanism also initiate the process of myocardial inflammation in a susceptible host.3 Table 1 enumerates some of the common etiological agents in the pathogenesis of myocarditis. The progression from acute tissue injury to chronic dilated cardiomyopathy passes through three phases (Figure 1).4,5 In the rodent model and isolated cell system studies of molecular basis of myocardial inflammation, virus enters myocardial cells through specific receptors and coreceptors. The virus after gaining entry into the cell has cytopathic effect in the initial weeks post infection. An innate humoral and cellular immune response consisting of macrophages, CD4+ and CD8+ T lymphocytes is started through toll-like receptors and pattern recognition receptors in patients with tissue injury to remove the invading infectious agent. However, inflammation may damage cardiac myocytes with the release of hidden antigens from cells (troponins) and generation of autoantibodies. This leads to further myocardial damage, LVD and dilatation. Genetic predisposition may play a role in the development of viral and autoimmune myocarditis in susceptible humans.6
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CLINICAL FEATURES Myocarditis commonly presents with nonspecific symptoms of palpitation, malaise, exertional breathlessness, fatigue, chest pain and syncope. Chest pain may mimic myocardial ischemia but coronary angiography shows normal coronaries.7 Acute fulminant myocarditis has symptoms of acute heart failure, tachyarryhthmia, syncope, and cardiogenic shock. There may be preceding history of viral exanthema or exposure to new drug or toxin. Also, some patients of systemic autoimmune disorder may present with symptoms of myocarditis. In India, rheumatic carditis, tubercular myocarditis and viral infection, such as dengue and chickungunya, as causes of myocarditis are also reported.8-10 A clinicopathological correlation helps in prognosticating and planning line of management including advanced life support and left
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CHAPTER
Table 1: Causes of myocarditis2
59
1. Infectious myocarditis Staphylococcus, Streptococcus, Pneumococcus, Meningococcus, Gonococcus, Salmonella, Corynebacterium diphtheriae, Haemophilus influenzae, Myobacterium (tuberculosis), Mycoplasma pneumoniae, Brucella
Spirochaetal
Borrelia (Lyme disease), Leptospira (Weil disease)
Fungal
Aspergillus, Actinomyces, Blastomyces, Candida, Coccidioides, Cryptococcus, Histoplasma, Mucormycoses, Nocardia, Sporothrix
Protozoal
Trypanosoma cruzi, Toxoplasma gondii, Entamoeba, Leishmania
Parasitic
Trichinella spiralis, Echinococcus granulosus, Taenia solium
Rickettsial
Coxiella burnetti (Q fever), R. rickettsia (Rocky Mountain Spotted fever), R. tsutsugamuschi
Viral
RNA viruses: Cox sackie viruses A and B, echo viruses, polio viruses, influenza A and B viruses, respiratory syncytial virus, mumps virus, measles virus, rubella virus, hepatitis C virus, dengue virus, yellow fever virus, Chikungunya virus, Junin virus, Lassa fever virus, rabies virus, human immunodeficiency virus-1 DNA viruses: Adenoviruses, parvovirus B19, cytomegalovirus, human herpes virus-6, Epstein-Barr virus, varicella-zoster virus, herpes simplex virus, variola virus, vaccinia virus
Myocarditis: An Update
Bacterial
2. Immune-mediated myocarditis Allergens
Tetanus toxoid, vaccines, serum sickness Drugs: Penicillin, cefaclor, colchicine, furosemide, isoniazid, lidocaine, tetracycline, sulfonamides, phenytoin, phenylbutazone, methyldopa, thiazide diuretics, amitriptyline
Alloantigens
Heart transplant rejection
Autoantigens
Infection-negative lymphocytic, infection-negative giant cell Associated with autoimmune or immune-oriented disorders: Systemic lupus erythematosus, rheumatoid arthritis, Churg-Strauss syndrome, Kawasaki’s disease, inflammatory bowel disease, scleroderma, polymyositis, myasthenia gravis, insulin-dependent diabetes mellitus, thyrotoxicosis, sarcoidosis, Wegener’s granulomatosis, rheumatic heart disease (rheumatic fever)
3. Toxic myocarditis Drugs
Amphetamines, anthracyclines, cocaine, cyclophosphamide, ethanol, fluorouracil, lithium, catecholamines, hemetine, interleukin-2, trastuzumab, clozapine
Heavy metals
Copper, iron, lead (rare, more commonly cause intramyocyte accumulation)
Miscellaneous
Scorpion sting, snake and spider bites, bee and wasp stings, carbon monoxide, inhalants, phosphorus, arsenic, sodium azide
Hormones
Phaeochromocytoma, vitamins: beri-beri
Physical agents
Radiation, electric shock
*Reprinted from Carforia ALP, et al. Position statement of the European Society of Cardiology working group of myocardial and pericardial diseases, Eur Heart J. 2013;34:2636-48, with permission from Oxford University Press and the European Society of Cardiology.
INVESTIGATIONS Electrocardiogram
Figure 1: Pathophysiological process of virus myocarditis
ventricular assist devices. In known patients of dilated cardiomyopathy, hypertensive heart disease or chronic heart failure, unexplained deterioration in clinical status despite optimum medical therapy should raise suspicion of associated myocarditis.
The sensitivity of electrocardiogram (ECG) in the diagnosis of myocarditis is low. 2 ECG may show the following abnormalities in acute myocarditis: Sinus tachycardia Generalized ST-T segment elevation/depression, T wave inversion Atrioventricular(AV) block QRS prolongation, left bundle branch block (LBBB), pathological Q waves, ventricular tachycardia, fibrillation, supraventricular tachyarrythmia.11 These ECG findings may indicate poor prognosis.
Echocardiography Two-dimensional echocardiography helps to rule out other causes of cardiac dysfunction like valvular heart disease. It also helps to monitor the progression of disease. There 493
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SECTION
Cardiomyopathy
8
may be biventricular chamber dilatation, global LVD or regional wall motion abnormality. Valvular regurgitation and evidence of pulmonary hypertension may be seen. Increased sphericity of LV with increased volume suggests acute myocarditis.12,13 In fulminant myocarditis, smaller LV cavity size with increased ventricular wall thickness due to edema and decreased contractility is observed. Tissue Doppler and strain rate imaging are the new modalities to assess myocardial function in suspected myocarditis.
Biomarkers Inflammatory markers like C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are elevated. Elevated biomarker of myocardial injury like troponin I is highly specific (89%) but of limited sensitivity (34%). However, it is more sensitive than creatine kinase levels.14 Others like circulatory cytokines and brain natriuretic peptide may also be elevated. However, positive viral serology has limited diagnostic utility. Serum cardiac autoantibodies to cardiac and muscle specific autoantigens have been evaluated in research laboratories but not yet available for commercial use.15
Cardiovascular Magnetic Resonance Imaging Cardiovascular magnetic resonance imaging (CMR) helps in myocardial tissue characterization noninvasively. It can detect inflammation, edema, necrosis and fibrosis within myocardial tissue.16 It should be considered before an EMB in suspected patients of myocarditis who are stable. Var ious imaging s e quence provide different information. 17,18 T2-weighted imaging can detect myocardial edema and tissue hyperemia which is surrogate of inflammation (Figures 2A and B). Contrast imaging with Gadolinium can show early capillary leakage on the basis of T1-weighted early Gadolinium enhancement. Late Gadolinium enhancement (LGE) is diagnostic of myocardial necrosis and fibrosis. LGE in myocarditis can have two types of presentation: 1. Intramural rim-like pattern involving septum 2. Patchy epicardial distribution on lateral LV free wall. An international consensus group on CMR diagnosis of myocarditis have developed certain criteria (Lake Louise criteria). If two of the three criteria are positive, it has sensitivity of 67%, specificity of 91%, positive predictive value 91%, and negative predictive value of 69%.19 However, CMR has some limitations like it is less sensitive in borderline myocarditis, inability to provide information of degree of inflammation and it does not identify specific forms of myocarditis (viral, bacterial, granulomatous or eosinophilic, etc.).4
Endomyocardial Biopsy Endomyocardial biopsy (EMB) is confirmatory in the diagnosis of myocarditis. It helps in identifying the
A
B
Figures 2A and B: Cardiovascular magnetic resonance image. Short-axis cardiac magnetic resonance imaging of a patient with acute myocarditis. (A) T2-weighted image, showing regional edema of the lateral left ventricle predominantly subepicardial involvement (arrow); (B) Late enhancement image, demonstrating high signal intensity in the epicardial region of the lateral wall of the left ventricle (arrow) Source: Used with permission from Oxford University Press
etiology and type of inflammation. At least three biopsy samples (1–2 mm size) should be obtained from either ventricle or biventricular sites.2 Dallas histopathological criteria ares useful to arrive at the diagnosis. It defines active myocarditis as inflammatory infiltrate with necrosis and/or degeneration of adjacent myocytes not typical of ischemic damage.20 However, there is large interobserver variability in pathological interpretation. It does not detect noncellular inflammation and the diagnostic yield is only 10–20%. 21 Therefore, a combination of histopathology, immunohistochemistry and molecular detection of viral genomic sequence in diseased myocardium improves the diagnostic yield. Immunohistological evidence of inflammatory infiltrates is associated with risk of death and need for cardiac transplantation.22 Persistence of viral genome in myocardium has shown to progress to end-stage dilated cardiomyopathy (DCM).23 Therefore, EMB may help to select the mode of therapy in a patient. Biopsy specimen showing specific human leukocyte antigen (HLA) markers with the absence of infectious agent (PCR-negative for viral genome) may be candidate for immunosuppressive therapy.24,25
NATURAL COURSE OF DISEASE Acute myocarditis resolves in 50% cases within 2–4 weeks. Twenty-five percent will develop persistent cardiac dysfunction. Twelve to twenty five percent deteriorate acutely and may not survive or develop end-stage DCM (Figure 3). 2 Survival in giant cell myocarditis is even worse. This subgroup of fulminant progressive myocarditis, especially in children, may be candidates for ventricular assist device, extracorporeal membrane oxygenation (ECMO) and cardiac transplantation.
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CHAPTER
59 Myocarditis: An Update
Figure 3: Evolution of acute viral myocarditis Abbreviation: DCM, dilated cardiomyopathy
Box 1: Current recommendations for immunosuppressive therapy z z
z
z
z
Immunosuppression should be started only after ruling out active infection on EMB by PCR. Based on experience with noncardiac autoimmune disease, consideration of immunosuppression in proven autoimmune (for example, infection negative) forms of myocarditis, should be made if no contraindications to immunosuppression are present, including giant-cell myocarditis, cardiac sarcoidosis, and myocarditis associated with known extracardiac autoimmune disease. Steroid therapy is indicated in cardiac sarcoidosis in the presence of ventricular dysfunction and/or arrhythmia and in some forms of infection negative eosinophilic or toxic myocarditis with heart failure and/or arrhythmia. Immunosuppression can be considered, on an individual basis, in infection negative lymphocytic myocarditis refractory to standard therapy in patients with no contraindications to immunosuppression. Follow-up EMB can be required to guide the intensity and the length of immunosuppression.
Abbreviations: EMB, endomyocardial biopsy; PCR, polymerase chain reaction Source: Reprinted with permission from Oxford University Press and the European Society of Cardiology.
MANAGEMENT Guidelines directed management of heart failure and arrhythmia is recommended. Therapy directed towards specific etiology of myocarditis may be considered. Acute fulminant cases of myocarditis in cardiogenic shock would require extracorporeal membrane oxygenator (ECMO) or ventricular assist device as bridge to recovery or cardiac transplantation. Patients of giant cell myocarditis not responding to optimal medical therapy may be candidates for cardiac transplantation. Immunomodulation therapy directed towards maladaptive immune response against myocardium triggered by viral infection may be potentially beneficial. Intravenous immunoglobulin (IVIG) is useful in antibody-mediated autoimmune disease. In pediatric age group, high-dose IVIG in acute myocarditis has shown improvement in left ventricular function and recovery in patients. However, in adults with biopsy proven myocarditis, benefit of IVIG still needs to be established. Selection of suitable candidates for immunosuppressive therapy is listed in Box 1.
Immunosuppressive Therapy Corticosteroids, azathioprine and cyclosporine have been studied in various combinations in acute autoimmune virus-negative myocarditis with mixed result. The role of corticosteroids in myocarditis due to sarcoidosis is established. Various prospective randomized controlled trials of immunosuppression and immunomodulation therapy is shown in Table 2. Th e n ove l c o n c e p t o f i m mu n oa d s o r p t i o n o f autoantibodies that can cause damage to myocardium, requires testing in a large prospective study.
Antiviral Therapy At present, no antiviral therapy is approved in the management of acute myocarditis. Larger randomized prospective trials are required to establish the role of antiviral treatment for acute myocarditis. Since no definitive guidelines are available to manage myocarditis, a practical algorithm to help decision making is proposed by Pollack et al (Figure 4).4 495
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Randomized, controlled trial of 85 patients with inflammatory, virus-negative DCM to compare prednisone plus azathioprine with placebo
Frustaci, et al29 LVEF at 6 months
A composite of death, heart transplantation, and hospital readmission over 2 years
Randomized, controlled trial of 40 patients with chronic DCM to compare IVIG with placebo
Change in LVEF at 6 months
Randomized, controlled trial of 84 patients with inflammatory DCM (unknown etiology, increased HLA expression on EMB) to compare prednisone plus azathioprine with placebo
Wojnicz, et al28
LVEF at 28 weeks
Gullestad, et al31
Randomized, controlled trial of 111 patients with biopsy-proven myocarditis (unknown etiology) to compare prednisone plus cyclosporin or azathioprine with conventional therapy
Mason, et al27
Improved LVEF at 3 months or reduced LV end-diastolic dimensions
Primary end point
Change in LVEF at 6 months and 12 months
Randomized, controlled trial of 102 patients with a history of idiopathic DCM to compare prednisone with placebo
McNamara, et al30 Randomized, controlled trial of 62 patients with recent-onset unexplained DCM (≤6 months) to compare IVIG with placebo
Design
Parrillo, et al26
Improved LVEF at 6 months in IVIG group (LVEF increased from 26 ± 2% to 31 ± 3%, p 0.79
z
Transesophageal echocardiography (TEE) pericardial thickness > 4 mm
z
Strain: Longitudinal strain preserved and circumferential strain is reduced
Table 3: Echo signs of constrictive pericarditis—Mayo clinic criteria: Diagnostic sensitivity and specificity Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
1
Septal shift
93
69
92
74
2
Inspiratory change in mitral velocity
84
73
92
55
3
Medial e’ >9 cm/sec
83
81
94
57
4
Medial e’/lateral e’ >0. 91
75
85
95
50
5
Hepatic vein diastolic reversal velocity / forward velocity in expiration >0.79
76
88
96
49
6
1 and 3
80
92
97
56
7
1 with 3 or 5
87
91
97
65
8
1 with 3 and 5
64
97
99
42
Abbreviations: PPV, positive predictive value; NPV, negative predictive value
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Figure 5: Algorithm based on Echo for differentiating constrictive and restrictive physiologies Source: Adapted from ASE guidelines for diastolic dysfunction. JASE. April, 2016
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Constrictive Pericarditis and Restrictive Cardiomyopathy: How to Differentiate?
Figure 6: Algorithm for the use of multimodality imaging in differentiating constriction from restriction
CHAPTER
62
519
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SECTION
Table 4: Invasive hemodynamic criteria for constriction—sensitivity and specificity
8
Criteria
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
Cardiomyopathy
Resting hemodynamics 1
LVEDP-RVEDP 1/3
93
46
73
66
3
PASP 1.3 carry 85%, 70% and 76% sensitivity, respectively for diagnosing constrictive pericarditis. Presence of all three criteria is diagnostic of constrictive pericarditis in more than 90% of patients.30,31 Thus, patients with CCP have symptoms and signs of right heart failure disproportionate to left ventricular dysfunction or valvular heart disease. The challenge is to determine whether abnormalities are caused by pericardial restraint, myocardial restriction, or both.30,31
Timing of Operation, Selection of Surgical Approach, Extent of Decortication, Requirement of Cardiopulmonary Bypass and Postoperative Low Cardiac Output Syndrome
528
Pericardiectomy is the only accepted treatment for CCP. Its origin dates back to 1898, when DeLorme first suggested it. However, the German group Rehn and Sauerbruch in 1913 performed successful pericardial resection for CCP through a left anterolateral thoracotomy approach. 32 Other surgical approaches for pericardiectomy include Churchill’s approach, left anterolateral thoracotomy, bilateral anterolateral thoracotomy, median sternotomy (Holman and Willett’s approach) and a U-shaped incision with the base of “U” at the left sternal border (Harrington’s approach).33-34 Despite the experience spanning over 100 years, there is no fool-proof formula in the published literature to decide the optimal approach for a given patient. The literature is rife with descriptions of pericardiectomy by either left anterolateral thoracotomy or median sternotomy. Despite the effectiveness of surgery, there are disparate opinions regarding the role of corticosteroids in treating tuberculous pericarditis, timing of operation, surgical approach, extent of decortication and requirement of cardiopulmonary
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bypass.32-37 The efficacy of pericardiocentesis in preventing CCP in pericardial effusion (serous/or hemorrhagic) has been inadequately investigated. 37 The terms “total”, “complete”, “extensive”, “radical”, “partial”, “subtotal” and “near-total” pericardiectomy have been variably used to describe the procedure, often without precise definition of the limits of pericardial resection.32-37 Published reports attest to the unpredictable and variable pattern of CCP and lend support to radical decortication. In 2005, to define the limit of pericardial resection, total pericardiectomy was defined as wide excision of the pericardium with the phrenic nerves defining the posterior extent, the great vessels including the intrapericardial portion of superior vena cava and superior vena cava—right atrial junction defining the superior extent, and the diaphragmatic surface, including the inferior vena cava—right atrial junction defining the inferior extent of the pericardial resection.6 Constricting layers of the epicardium were removed whenever possible and the atria and venae cavae were decorticated in all cases in this study group. Pericardiectomy was considered partial if both ventricles could not be decorticated completely because of dense myopericardial adhesions or calcification.6 Radical pericardiectomy was defined as removal of the entire pericardium over the anterolateral, diaphragmatic surfaces of left ventricle, portion of pericardium posterior to the phrenic nerve and the left ventricle and the anterior and diaphragmatic surfaces of RV until the atrioventricular groove leaving behind intact left and right phrenic pedicles.6 Secondly, the importance of unrecognized constricting epicardial peel was described by Harrington in 1944 and successful pericardiectomy requires removal of all constricting layers including decortication of the ventricular epicardium.33 In a study, Kolster and associates demonstrated normalization of pressure volume loop as an indicator of operative success of pericardiectomy.38 In 2005, we compared two surgical approaches used for the treatment of CCP, i.e. median sternotomy and conventional left anterolateral thoracotomy in 395 patients. The surgical approach was primarily based on surgeon’s preference and remained uniform.6 However, the median sternotomy approach was preferred in the following conditions: (i) annular CCP, (ii) presence of a gradient between the superior or inferior venae cavae and right atrium of 2 mm Hg or greater, (iii) calcific pericardial patch compressing the RA and right ventricular outflow tract, (iv) extracardiac intrapericardial mass, (v) previous open heart surgery, (vi) circumferential ‘cocoon’ calcification of the pericardium, and (vii) recurrent CCP after partial pericardiectomy.6 We demonstrated that the maximum benefit occurs after total pericardiectomy, which is best achieved through a median sternotomy and is very difficult through a conventional left anterolateral thoracotomy.6,20
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Criterions for Decision-Making on the Timing of Operation and Selection of Surgical Approach for Patients Undergoing Pericardiectomy The clinical course of constrictive pericarditis is usually progressive and it is extremely difficult for the cardiologist to delineate the degree of pericardial constriction and myocardial restriction. The result of pericardiectomy are poor with dominant myocardial involvement and better with dominant constrictive element. Early pericardiectomy is beneficial for patients with a central venous pressure between 12 and 15 mm Hg, RA pressure >24 mm Hg, hepatic dysfunction, renal dysfunction and massive ascites. Survival of patients with CCP following pericardiectomy is higher than without surgery.5,6,19,20,39,40 In our previous study, we compared the outcomes after total versus partial pericardiectomy. Our study demonstrated that total pericardiectomy was associated with lower operative mortality and low cardiac output syndrome, abbreviated hospitalization, and better longterm survival than partial pericardiectomy. Ascites, renal dysfunction, hyperbilirubinemia, high preoperative RA pressure (>24 mm Hg), atrial fibrillation, low ejection fraction (0.40 or less), pericardial calcification, tricuspid regurgitation, mitral regurgitation, partial pericardiectomy, thoracotomy approach and postoperative LCOS negatively affected survival. 6 In this study, the risk of death was 4.5 times higher (95% CI: 2.05 - 9.75) in patients undergoing partial pericardiectomy compared to total pericardiectomy.6 Despite total pericardiectomy, the operative mortality rate was 7.6% in our series and 6% to 19% in several large series published after 1985.2-6,18-20,39,40 Unlike others, there was no correlation with age, tuberculous etiology and
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advanced NYHA symptoms on late survival, presumably because of young patient population and timely institution of chemotherapy and surgery.6,20,39,40 Although the median sternotomy approach allowed a more radical clearance of pericardium overlying the right atrium and venae cavae including the cavo-atrial junctions, these areas usually are of little hemodynamic significance in the majority of patients. Furthermore, it is impossible to excise the portion of the pericardium posterior to the phrenic nerve using this approach.6,20,39,40
Criterions for Decision-Making and Selection of Surgical Approach for Patients Undergoing Radical Pericardiectomy via Left Anterolateral Thoracotomy without Cardiopulmonary Bypass (UKC’S Modification) As enunciated above, the median sternotomy approach was the preferred option of the author (UKC) in the selected heterogenous group of patients undergoing pericardiectomy.6,20 In an effort to decrease the hospital mortality rates and postoperative LCOS, the author proceeded to perform several technical modifications of the conventional left anterolateral thoracotomy approach to achieve further radical excision of the pericardium posterior to the phrenic nerve and diaphragmatic pericardium without utilizing cardiopulmonary bypass.39,40 Thus, there were seven forces driving our decision-making towards improvement of the results after pericardiectomy via modified anterolateral thoracotomy. The desire to obtain improved operative exposure of the RV and RA by developing a new dissection plane between the posterior surface of the sternum and anterior surface of the pericardium. The desire to dissect the pericardium posterior to the phrenic nerve overlying the left atrium and posterolateral surface of the left ventricle. The desire to develop a new cleavage plane between the diaphragmatic pericardium and diaphragm. The desire to minimize cardiac manipulation at the time of dissection by dividing the anterior and posterior pericardial flap in two halves respectively. The desire to minimise postoperative autotransfusion by inserting a peritoneal dialysis catheter before surgical incision and placing it on gravity drainage intraoperatively. The desire to maintain oxygenation and hemodynamic stability during pericardiectomy via left anterolateral thoracotomy by placing an intercostal chest drain on the opposite side in case of right-sided significant pleural effusion. The desire to keep both groins prepared at the time of pericardiectomy via modified left anterolateral thoracotomy in case of inadvertent injury to the cardiac chambers and/or great vessels and urgent institution of cardiopulmonary bypass.
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The institution of cardiopulmonary bypass for effusive or inflammatory pericarditis depends on how the patient tolerates cardiac manipulation. It is justified to use cardiopulmonary bypass in order to facilitate complete pericardiectomy as it has more favorable long-term functional outcome compared to partial pericardiectomy.35 Although routine use of cardiopulmonary bypass to achieve total pericardiectomy is an issue of debate, it requires to be employed in special circumstances, namely (i) inadvertent damage to a cardiac chamber, (ii) concomitant intracardiac surgical procedures, (iii) previous partial pericardiectomy, (iv) presence of calcific pericardial “cocoon” encompassing all cardiac chambers, (v) pericardiectomy following mediastinal irradiation and (vi) coexistent cardiac lesion.6,18-20,35,39,40 However, a left anterolateral thoracotomy was the preferred approach in cases of purulent pericarditis and effusive constrictive pericarditis because of the presence of concomitant pyothorax and the concerns of sternal infection.6,20,39,40
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SURGICAL TECHNIQUES AND RESULTS The step-by-step technical details of the conventional median sternotomy (n = 55) and the authors modification of the left anterolateral thoracotomy (n = 67) to achieve radical pericardiectomy without utilizing cardiopulmonary bypass have been alluded to in our previous publications. 6,20,39,40 The following specific maneuvers (Figures 1 and 2) facilitated performance of radical pericardiectomy via modified left anterolateral thoracotomy: Development of a new cleavage plane between the sternum and the anterior surface of the pericardium using cautery and a right angled deep blade sternal retractor. Extension of the dissection plane beyond the midsternum to the right phrenic pedicle. Development of a new cleavage plane between the diaphragmatic pericardium and diaphragm. Dissection of the pericardium posterior to the left phrenic nerve and division of the posterior pericardium in two halves. Dissection of the pericardium anterior to the phrenic nerve, division of the anterior pericardium in two halves and detachment of the anterior pericardium 1 cm away from the right atrioventricular groove. Using these modifications, radical pericardiectomy was associated with a further reduction of operative mortality as compared to total pericardiectomy of our initial publication (2.9% vs 7.6%) and patients undergoing total pericardiectomy of our second publication (2.9% vs 7.2%). 6,20,39,40 By employing these modifications, we have been able to reduce the incidence of postoperative low cardiac output syndrome (LCOS) from 69% (total pericardiectomy) to 26.8% (radical pericardiectomy).6,20,39,40
Despite improved diagnostic accuracy with echocardiography and computed tomography, aggressive preoperative stabilization, improvements in cardiac anesthesia, perioperative hemodynamic monitoring and advances in surgical techniques over the past 100 years, pericardiectomy for CCP continues to be associated with significant mortality (6-19%).2,3,5,6,8,9,18-20,24-36,39,40
POST-PERICARDIECTOMY LOW CARDIAC OUTPUT SYNDROME The incidence of post-pericardiectomy low cardiac output syndrome is significant and the pathophysiological mechanisms responsible are multifactorial in nature, including myopericardial involvement, immobilization atrophy, abnormal diastolic filling characteristics, incomplete decortication, remodelling of the ventricle, worsening tricuspid regurgitation, postoperative mitral regurgitation due to papillary muscle elongation and massive ascites. 41-45 Several investigators including ourselves have observed that regardless of the operative approach or extent of pericardial resection, a subset of patients with chronic CCP will develop low cardiac output syndrome. The hemodynamic hallmark of CCP is impaired ventricular diastolic compliance. Following pericardiectomy, there are major fluid shifts from extravascular to intravascular compartments (autotransfusion) which results in failure of Frank-Starling mechanism causing acute cardiac dilatation. 6,20 In these patients the use of cardiopulmonary bypass allows to control these fluid shifts and ultrafiltration.35 So, this may be a concept that is not appreciated—the use of cardiopulmonary bypass to avoid cardiac distension.
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Figures 1A to F: (A) Intraoperative views of the steps of left modified anterolateral thoracotomy (UKC’s modification) for radical pericardiectomy. The left pleural cavity is entered through fourth intercostal space; (B) Left lung is retracted posteriorly with a wet sponge for adequate exposure. Left phrenic pedicle is identified; (C and D) Using cautery, a new cleavage plane is created between posterior surface of the sternum and anterior surface of the pericardium; (E) The cleavage plane is extended beyond sternum to identify the right phrenic pedicle; (F) Using cautery, a new dissection plane is developed between the diaphragmatic pericardium and diaphragm
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Figures 2A to F: (A) Using cautery, two full-length parallel incisions are made 5 mm anterior and posterior to the left phrenic pedicle with pulmonary artery (PA) as the superior and diaphragm as the inferior extent of the incision; (B and C) Posterior to the phrenic pedicle, the posterior pericardial flap (PPF) is raised to expose the posterolateral surface of left ventricle (LV) and left atrial appendage (LAA). This flap is further divided into two halves in the center; (D and E) Anterior to the phrenic pedicle, anterior pericardial flap is raised to expose left ventricle, right ventricle and pulmonary artery. This flap is further divided into two halves. The flap is excised 5 mm anterior to the right phrenic pedicle extending to pulmonary artery superiorly and inferior vena cava-right atrium inferiorly; (F) The diaphragmatic pericardium is dissected along the diaphragm to create a flap and excised
There is myo cardial e dema due to rep eate d mechanical compression during surgery which settles slowly over time.6,20,39,40 It is indeed impossible to pinpoint a specific causative factor for low cardiac output syndrome following pericardiectomy. Although elevated right atrial pressure and atrial fibrillation are associated with poor postoperative outcomes, we refrain from adopting an aggressive surgical approach to treat tricuspid regurgitation or atrial fibrillation. If the cardiac output cannot be sustained by the currently available medical treatment, the next strategy may be to assist the failing heart by mechanical circulatory assistance.46,47 Although the use of intra-aortic balloon counterpulsation (IABC) is universal in adults with acute left ventricular dysfunction after myocardial infarction or cardiac surgery, its use in patients undergoing pericardiectomy for chronic CCP remains sporadic.46 Intra-aortic balloon counterpulsation (IABC) facilitates recovery of left ventricular function by decreasing left ventricular end-diastolic and left atrial pressure, thus helping the systemic ventricle and indirectly helping the pulmonary ventricle by the phenomenon of ventricular interdependence.46 The advantage of IABC over left atrialaortic assist devices, axial flow pumps and veno-arterial extracorporeal membrane oxygenation is the ease of application.48,49 The timing and indications of balloon deployment is a matter of judgment. It is certainly indicated in patients
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who suddenly deteriorate after total pericardiectomy and are unresponsive to medical therapy. The other subset include cases of progressive deterioration of ventricular function and unresponsive to inotropic support.46
SPECIFIC DISEASE ENTITIES Effusive-Constrictive Pericarditis Effusive-pericarditis is a unique clinical-hemodynamic syndrome of multifactorial etiology combining elements of effusion/tamponade and constriction. In this disease, there is pericardial effusion, pericardial thickening and impaired diastolic cardiac filling. The reported incidence in patients presenting with pericardial effusions is 1 to 15%. 2,5,8,11 In developing countries, tuberculosis accounts for approximately 70% cases of effusive-constrictive pericarditis. 2,5,8,11 Penetrating trauma, post-open heart surgery, neoplasia, post-irradiation, streptococcal, Salmonella infections and lasa fever infections are other causes of effusiveconstrictive pericarditis.2,5,6,8,11,50 The clinical course is insidious and ranges from a month to a year. The clinical, hemodynamic, radiologic and echocardiographic findings are of those associated with effusion and constriction. Before surgery, the right atrial, right ventricular enddiastolic, pulmonary wedge, and intrapericardial pressures are equally increased with a prominent X-descent on right atrial pressure tracing. After pericardiocentesis, the
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intrapericardial pressure declines but the right atrial, right ventricular end-diastolic and pulmonary wedge pressures remain elevated with a prominent Y-descent and early diastolic dip in right ventricular pressure. Diagnosis is confirmed on pericardial fluid biochemistry and histopathology.
MANAGEMENT There are no guidelines on the management of effusiveconstrictive pericarditis in published English language literature. The possible reasons are diagnostic difficulty, varied etiopathogenesis, evolution patterns and lack of available data.2-6,8-11 Generally, management is according to the specific etiology. Reaching an etiological diagnosis is a real challenge globally. The results of pericardial fluid culture are frequently falsely negative and pericardial biopsy has a higher yield of diagnostic specimens. One therefore has to rely on pericardial tissue biopsy microbiology or cytology.2-6,8,11,50
Treatment Based on Etiology The management of tubercular effusive-constrictive pericarditis has been elaborated under tubercular pericarditis. In idiopathic and postpericardiotomy cases with tamponade and effusive-constrictive physiology anti-inflammatory treatment with corticosteroids and colchicine has been tried to avoid pericardiectomy. Pericardiectomy is ultimately required in many of these patients.2-6,8,11,39,40,50
Treatment Based on Timing of Presentation and Response to Medication The following management algorithm has been proposed by Salami and colleagues. 50 In patients with cardiac tamponade or imminent tamponade the first step would be pericardiocentesis followed by pericardiostomy and pericardial biopsy for bacteriology and histology. Duration of illness is the next guide. Patients without tamponade of more than 1 year duration are advised pericardiostomy and biopsy. These authors recommended trial of medical treatment for 6–8 weeks and operate only when there is persistent evidence of constriction. Presence of pericardial thickening with calcification following pericardiocentesis is an absolute indication for pericardiectomy.50
TUBERCULOUS PERICARDITIS Clinical Presentation
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Clinically, tuberculous pericarditis presents in one of the three forms: pericardial effusion (80%), effusiveconstrictive pericarditis (15%) or as constrictive pericarditis (5%).3-6,9-11
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TUBERCULOUS PERICARDIAL EFFUSION The disease develops insidiously over time with fever, fatigue, night sweats and weight loss. The symptoms and signs include chest pain, cough, breathlessness and right upper abdominal pain. Some patients exhibit evidence of chronic cardiac compression mimicking heart failure. Although there is a marked overlap between the physical signs of pericardial effusion and CCP, the presence of pericardial friction rub and increased cardiac dullness favors a clinical diagnosis of pericardial effusion.51,52
Noncalcific and Calcific Constrictive Pericarditis The first presentation of tuberculous pericarditis may be pericardial constriction withour a prior effusive stage. Symptoms of systemic venous congestion include oedema, abdominal swelling, hepatomegaly and ascites.6,8-11,18-20,51 The incidence of pericardial calcification in tubercular constrictive pericarditis ranges between 5% to 76%.6,8-11,18-20,39,40,51 In our previous study on 395 patients undergoing pericardiectomy between 1985 and 2004, we observed 4.8% incidence of calcified pericardium, of which tubercular constriction comprised 88.9% of cases.6 Usually the maximal pericardial calcification occur over the right atrium and right ventricle, diaphragmatic surface and atrioventricular grooves. Fluid displaced by vigorous LV contraction during resorption of the primary pericardial effusion, preferentially, gravitates towards the right side of the heart where calcium and even bone are slowly deposited in the inspissated fluid.6,8-11,51
Effusive-Constrictive Pericarditis This mixed form of tuberculous pericarditis is a common presentation in India. Clinically, there may be signs of pericardial effusion along with a diastolic knock and early third heart sound. Echocardiography reveals loculated pericardial effusion between thickened pericardial membranes.3-5,50,51
Diagnosis of Tuberculous Pericardial Effusion: A Systematic Approach The chest radiograph shows an enlarged cardiothoracic ratio in almost all cases, features of active pulmonary tuberculosis in 30% and pleural effusion in 40–60% of cases. Echocardiography is an accurate and noninvasive method for the diagnosis of pericardial effusion and constriction.21,22,53,54 CT scan chest demonstrate pericardial effusion along with thickened pericardium and enlarged mediastinal lymph nodes (i.e. enlargement >10 mm with matting and hypodense centers) in almost 100% of cases that resolve on treatment. MRI reveals the extent of pericardial and myocardial involvement.28-30
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Tuberculous Constrictive Pericarditis The diagnosis of pericardial constriction is made on the basis of clinical features and confirmed by investigations including chest radiography, ECG, and echocardiography, CT scan, or MRI. The roles of different investigative modalities for CCP have already been enumerated. The lymphatic drainage of the pericardium is to the anterior and posterior mediastinal and tracheobronchial lymph nodes. The mediastinal node enlargement of tuberculous pericardial effusion is usually detected on CT scan and/or MRI. If CCP remains doubtful, endomyocardial biopsy is useful.10,55
TREATMENT Tuberculous Pericardial Effusion Patients living in tuberculosis-endemic regions, particularly those infected with HIV, a pericardial effusion is considered to be tuberculous in origin in the absence of an alternative etiology. Approximately two-thirds of these patients have a definite diagnosis of tuberculosis according to microbiological or histologic criteria. In the remainder, an adequate response to antituberculosis chemotherapy or other indirect evidence of tuberculous etiology serves as support for the diagnosis. Even in the absence of a diagnosis of tubercular pericarditis, antitubercular treatment should be started in patients from non-endemic areas.3-6,10,51-53,55
Antitubercular Drugs: What is the Optimal Drug Combination, Dosing Frequency and Treatment Duration of Tuberculous Pericarditis? Published literature including our observations over 3 decades suggests that there are no reasons to administer antitubercular drug treatment for tuberculous pericarditis longer than for extrapulmonary tuberculosis.6,8-10,52,55 The WHO guidelines advocate a regimen consisting of isoniazid, rifampicin, pyrazinamide and ethambutol for at least 2 months followed by isoniazid and rifampicin for a period of 4 months (total 6 months of therapy).56 The WHO guidelines suggest that the optimal dosing frequency for new patients with tuberculous pericarditis is daily throughout the course of therapy (strong/high
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grade of evidence of pulmonary TB). Thrice-weekly dosing frequency [2(HRZE) 3 4(HR)3] may be an alternative to the above recommendation, provided that every dose is directly observed and the patient is not living with HIV or living in a HIV-prevalent setting (conditional/high and moderate grade of evidence). Treatment for 9 months or longer gives no better results and has the disadvantages of increased cost and poor compliance. Short-course chemotherapy is also effective in curing TB in HIVinfected patients.55,56 Antituberculosis chemotherapy increases survival dramatically in tuberculous pericarditis. In the preantibiotic era, mortality was 80% to 90%; it ranges currently from 8% to 17% in HIV-negative patients and 17% to 34% in HIV-positive individuals.4,9,10,53-56
Role of Corticosteroids Although adjunctive steroids may have beneficial effects on mortality and morbidity in tuberculous pericardial effusion, published studies have not demonstrated any significant beneficial effect on the reaccumulation of pericardial effusion or progression to constrictive pericarditis.4,5,8-10,52,53,55-57 A systematic meta-analysis reported significant reduction in mortality with corticosteroids when used along with rifampicin containing drug combinations. 58 Despite prompt antitubercular treatment and use of corticosteroids, CCP occurs in 30% to 60% of patients with tubercular pericarditis.4,5,8-10,52,53,55-57 Most of the published guidelines recommend the use of adjunctive oral corticosteroids for the treatment of tuberculous pericarditis. However, the choice of drug (prednisone, prednisolone, methylprednisolone), route (oral, intravenous, and intrapericardial) and dosage is variable.52,53,55,57-59
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64 Surgery for Chronic Constrictive Pericarditis, Tuberculous Pericarditis and Effusive-Constrictive Pericarditis
Accordingly, a “definite” diagnosis of tuberculous pericarditis is based on the demonstration of tubercle bacilli in pericardial fluid or on histologic section of the pericardium; and a “probable” diagnosis is made when there is proof of tuberculosis elsewhere in a patient with unexplained pericarditis; a lymphocytic pericardial exudate with elevated ADA enzyme activity >40 u/L, IFN-γ >50 pg/L or lysozyme level >6.5 µg/dL and/or an appropriate response to antituberculosis chemotherapy.2,5,6,9,10
The treatment of effusive-constrictive pericarditis is challenging because pericardiocentesis does not relieve the diastolic cardiac filling and surgical removal of edematous, friable, thickened epicardium is hazardous with attendant risks of hemorrhage. It is advisable to initiate antitubercular treatment and decide the optimal time for surgical stripping based on serial echocardiogram.2,6,9,37 A controlled clinical trial of complete open surgical drainage by substernal pericardiotomy and biopsy or percutaneous pericardiocentesis on 122 patients by Strang and colleagues showed that open drainage obviated the need for repeated pericardiocentesis, but not subsequent pericardiectomy.53
Tuberculous-Constrictive Pericarditis The timing of pericardiectomy is controversial. There have been no randomized studies of the practice of early pericardiectomy once antitubercular drugs have been
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started versus surgery in patients with CCP not responding to antitubercular drugs. Several investigators including ourselves recommend pericardiectomy for persistent pericardial constriction with hemodynamic deterioration after 4 to 8 weeks of antitubercular therapy.4-6,8-10,20,36,39,40 Surger y for calcific constr ictive per icarditis is challenging. A plane of cleavage is created above and below the calcified plaque. The circumferential calcified pericardial patches were then crushed with a thick hemostat and/or bone cutter and remove them piecemeal avoiding injury to the underlying cardiac chambers, vascular structures, coronaries and phrenic nerves, while removing calcified pericardial patches over the right atrium, right ventricle and the pulmonary artery. Cardiopulmonary bypass may be required for calcified cocooned pericardium. The risk of death after pericardiectomy in patients with tuberculous constrictive pericarditis ranges from 3% to 16%.39,40
Unresolved Issues and Controversies in Management of Tubercular Pericarditis Till date, limited evidence-based data are available to guide the management of tuberculous pericardial diseases. The unresolved issues include the difficulty in establishing a bacteriological or histological diagnosis, the role of diagnostic pericardiocentesis versus open drainage and biopsy, the use of adjunctive corticosteroids (particularly in HIV-infected patients), and the timing of pericardiectomy. Furthermore, published literature addresses the clinical features and outcome of tubercular pericarditis primarily in the pre-HIV era. It is likely that HIV infection modifies the clinical presentation and outcome of tuberculous pericarditis. There are no data on the management of persistent atrial fibrillation in patients with tuberculous pericardial effusion and normal cardiac function. These questions requires examination in large prospective studies of tuberculous pericarditis.
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41.
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42. Levine HD. Myocardial fibrosis in constrictive pericarditis electrocardiographic and pathologic observations. Circulation. 1973;48:1268-81. 43. Johnson TL, Bauman WB, Josephson RA. Worsening tricuspid regurgitation following pericardiectomy for constrictive pericarditis. Chest. 1993;104:79-81. 44. Ha JW, Oh JK, Schaff HV, et al. Impact of left ventricular function on immediate and long-term outcomes after pericardiectomy in constrictive pericarditis. J Thorac Cardiovasc Surg. 2008;136(5):1136-41. 45. Mayosi BM. Contemporary trends in the epidemiology and management of cardiomyopathy and pericarditis in subSaharan Africa. Heart. 2007;93(10):1176-83. 46. Chowdhury UK, Jena JK, Hasija S, et al. Successful use of intra-aortic balloon counterpulsation for systemic ventricular failure following total pericardiectomy for calcific chronic constrictive pericarditis. Accepted for publication in World J Pediatr Ciingenit Heart Surg. 2018 (In press). 47. Pinkey KA, Minich LL, Tani LY, et al. Current results with intra-aortic balloon pumping in infants and children. Ann Thorac Surg. 2002;13:887-91. 48. Gaines WE, Pierce WS, Prophet GA, et al. Pulmonary circulatory support: a quantitative comparison of four methods. J Thorac Cardiovasc Surg. 1984;88:958-64. 49. Kiley S, Sofia J, Machuca T. Venoarterial ECMO for recovery from right ventricular failure after pericardiectomy. SOCCA Post Session 2017 (Abstract), No. 1344. 50. Salami MA, Adeoye PO, Adegboye VO, et al. Presentation pattern and management of effusive-constrictive pericarditis in Ibadan. Cardiovasc J Afr Title. 2012;23(4): 206-11. 51. Cherian G. Diagnosis of tuberculous aetiology in pericardial effusion. Postgrad Med J. 2004;80(943):262-6. 52. Reuter H, Burgess LJ, Louw VJ, et al. Experience with adjunctive corticosteroids in managing tuberculous pericarditis. Cardiovasc J S Afr. 2006;17:233-8. 53. Strang JI: Tuberculous pericarditis in Transkei. Clin Cardiol. 1984;7(12):667-70. 54. George S, Salama AL, Uthaman B, et al. Echocardiography in differentiating tuberculous from chronic idiopathic pericardial effusion. Heart. 2004;90:1338-9. 55. Syed FF, Mayosi BM. A modern approach to tuberculous pericarditis. Prog Cardiovasc Dis. 2007;50(3):218-36. 56. World Heart Organization. Treatment of tuberculosis. Guidelines WHO/HTM/TB/2009. 420. 4th edition. Geneva: World Health Organization; 2010. 57. Ntsekhe M, Wiysonge C, Volmink JA, et al. Adjuvant corticosteroids for tuberculous pericarditis: Promising, but not proven. QJM. 2003; 96(8):593-9. 58. Critchley JA, Young F, Orton L, et al. Corticosteroids for prevention of mortality in people with tuberculosis: A systemic review and meta-analysis. Lancet Infect Dis. 2013;13(3):223-37. 59. Mayosi BM, Ntsekhe M, Bosch J, et al. Prednisolone and myocobacterium indicus pranii in tuberculous pericarditis. N Engl J Med. 2014;371(12):1121-30.
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64 Surgery for Chronic Constrictive Pericarditis, Tuberculous Pericarditis and Effusive-Constrictive Pericarditis
25.
ments of respiratory variations in pulmonary venous flow. J Am Coll Cardiol. 1993;22(7):1935-43. Von Bibra H, Schober K, Jenni R, et al. Diagnosis of constrictive pericarditis by pulsed Doppler echocardiography of the hepatic vein. Am J Cardiol. 1989;63:483-8. Ga rc i a M J, T h o ma s J D, K l e i n A L . Ne w D o p p l e r echocardiographic applications for the study of diastolic function. J Am Coll Cardiol. 1998;32:865-75. Notomi Y, Setser RM, Shiota T, et al. Assessment of left ventricular torsional deformation by Doppler tissue imaging: validation study with tagged magnetic resonance imaging. Circulation. 2005;111(9):1141-7. Sengupta PP, Eleid MF, Khandheria BK. Constrictive pericarditis. Circ J. 2008;72:1555-62. Rienmuller R, Groll R, Lipton MJ. CT and MR imaging of pericardial disease. Radiol Clin North Am. 2004;42:587-601. Francone M, Dymarkowski S, Kalantzi M, et al. Assessment of ventricular coupling with real-time cine MRI and its value to differentiate constrictive pericarditis from restrictive cardiomyopathy. Eur Radiol. 2006;16:944-51. Hurrell DG, Nishimura RA, Higano ST, et al. Value of dynamic respiratory changes in left and right ventricular pressures for the diagnosis of constrictive pericarditis. Circulation. 1996;93:2007-13. Vaitkus PT, Kussmaul WG. Constrictive pericarditis versus restrictive cardiomyopathy: A reappraisal and update of diagnostic criteria. Am Heart J. 1991;122(5):1431-40. White PD. Chronic constrictive pericarditis (Pick’s disease) treated by pericardial resection. Lancet. 1935;2:539-97. Harrington SW. Chronic constrictive pericarditis. Partial Pericardiectomy and Epicardiolysis in Twenty-Four Cases. Ann Surg. 1944;120(4):468-85. Bozbuga N, Erentug V, Eren E, et al. Pericardiectomy for chronic constrictive tuberculous pericarditis. Tex Heart Inst J. 2003;30:180-5. Copeland JG, Stinson EB, Griepp RB, et al. Surgical treatment of chronic constrictive pericarditis using cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1975;69:236-8. Clare GC, Troughton RW. Management of constrictive pericarditis in the 21st century. Curr Treat Options Cardiovasc Med. 2007;9:436-42. Merce J, Sagrista-Sauleda J, Permanyer-Miralda G, et al. Should pericardial drainage be performed routinely in patients who have a large pericardial effusion without tamponade? Am J Med. 1998;105(2):106-9. Kloster FR, Crislip RL, Bristow JD, et al. Hemodynamic studies following pericardiectomy for constrictive pericarditis. Circulation. 1965;32(3):415-24. Chowdhury UK, Seth S, Reddy SM. Pericardiectomy for chronic constrictive pericarditis. J Operative Tech Thorac Cardiovasc Surg. 2008;13:14-25. Chowdhury UK, Narag R, Malhotra P, et al. Indications, timing and techniques of radical pericardiectomy via modified left anterolateral thoracotomy (UKC’s modification) and total pericardiectomy via median sternotomy (Holman and Willett) without cardiopulmonary bypass. J Prac Cardiovasc Sci. 2016;2:17-27. Dines DW, Edwards JE, Burchell HB. Myocardial atrophy in constrictive pericarditis. Proc Staff Meet Mayo Clin. 1958;33(4):93-9.
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CHAPTER 65
An Update on Restrictive Cardiomyopathy Ramalingam Vadivelu, Rajesh Vijayvergiya
INTRODUCTION Restrictive cardiomyopathy (RCM) is a group of heterogeneous myocardial diseases, which is characterized by impaired ventricular filling secondary to increased myocardial stiffness. Its etiology may vary from infiltrative and noninfiltrative disorders, storage disorders, and idiopathic causes. Diagnosis of RCM is often overlooked leading to greater morbidity and mortality, at the time of presentation. The prognosis is often guarded, even after a correct diagnosis and appropriate treatment. A detailed knowledge and understanding of this entity is important for early diagnosis and management. We hereby briefly review the etiopathogenesis, clinical presentation, diagnosis and treatment options of RCM.
ETIOLOGY Table 1 describes the various etiologies of RCM.1
CLINICAL PRESENTATION Since RCM can involve either or both the left and right ventricles, the clinical presentation may have left and/or right heart failure. The common presentation of diastolic heart failure is breathlessness, easy fatiguability, lethargy, and peripheral edema. Palpitations and syncope are usually due to underlying arrhythmias and heart block. Children can have poor growth because of underlying RCM. Cardioembolic stroke and systemic embolization may be an unusual presentation. Underlying systemic disease causing RCM can have the predominant symptoms at the time of presentation. Table 2 describes the predominant symptoms and likely etiology of RCM.2 Characteristic clinical signs of RCM include elevated jugular venous pressure with Kussmaul! s sign, respiratory rales, ascites, hepatomegaly, peripheral edema, and additional heart sounds such as S3 and S4 gallops.
DIAGNOSIS After a detailed clinical evaluation, routine investigations, such as ECG (Table 3, Figures 1 to 4), X-ray chest, echocardiography, and blood investigations (Table 4) should be done. Certain investigations, such as cardiac
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MRI, cardiac catheterization, and endomyocardial biopsy, help in confirming the diagnosis. Certain investigations, such as skin, liver and muscle biopsy, iron profile, positron emission tomography-computed tomography (PET! CT), genetic analysis, etc. are relevant especially in autosomal dominant mutations, such as Noonan syndrome and desminopathy, and some variants of skeletal myopathies. Autosomal recessive mutations can be associated with RCM and musculoskeletal abnormalities.3
ECHOCARDIOGRAPHIC FINDINGS IN RCM Biatrial dilation, normal or undersized ventricles, normal or increased wall thickness, normal or near-normal left ventricular systolic function, mild-to-moderate mitral and/or tricuspid regurgitation are the common echocardiographic findings in RCM. Moderate-to-severe pulmonary artery hypertension (PAH) is a feature of RCM and is due to elevated left ventricle end-diastolic pressures (EDP). Concentric thickening of the LV free wall and septum, right ventricular (RV) free wall and atrial septum thickening with enlarged atria is commonly seen in RCM secondary to cardiac amyloidosis. Other features include thickened valves, the presence of pericardial effusion, and characteristic sparkling appearance of the myocardium in patients with cardiac amyloidosis. Sometimes when there is an overlap between echo features of RCM and CCP, cardiac biomarkers like BNP can be used to differentiate.5 The transmitral Doppler spectrum shows a high E-wave with a shortened deceleration time (< 150 ms) and an E/A ratio of > 2.6 In chronic constrictive pericarditis (CCP), there is 25% respiratory variation in transmitral flow velocity and 40% respiratory variation in transtricuspid flow velocity; whereas in RCM, there is no such respiratory variation seen. In RCM, the tissue annular Doppler velocities (Ea, Aa, and Sa) are reduced but not so in CCP (Figure 5). In CCP, pericardial thickness is increased; whereas in RCM, it is normal (Figure 6). The inferior vena cava (IVC) can be dilated both in RCM and CCP (Figure 7). In cardiac amyloidosis, global longitudinal strain (GLS) is typically more impaired in the basal and midwall segments than at the apex.7
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Table 1: Etiology of RCM
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An Update on Restrictive Cardiomyopathy
Infiltrative disorders zz Amyloidosis zz Sarcoidosis zz Primary hyperoxaluria Storage disorders zz Fabry disease zz Gaucher disease zz Hemochromatosis zz Glycogen storage disorders zz Mucopolysaccharidosis (Hurler and Hunter syndromes) zz Niemann-Pick disease Noninfiltrative causes zz Diabetic cardiomyopathy zz Pseudoxanthoma elasticum zz Myofibrillar myopathies zz Scleroderma zz Werner syndrome Endomyocardial causes zz Carcinoid heart disease zz Endomyocardial fibrosis zz Hypereosinophilia zz Churg Strauss syndrome zz Acute eosinophilic leukemia zz Drugs: Methysurgide, busulfan, mercurial agents, ergot alkaloids zz Endocardial fibroelastosis zz Cancer and cancer-related treatment: Metastatic cancer, lymphoma, multiple myeloma and radiation therapy and chemotherapeutic agents (Anthracycline) Genetic mutations zz MYH7 Cardiac β-myosin heavy chain (autosomal dominant) zz TNNT2 Cardiac troponin T (autosomal dominant) zz TPM1 α-tropomyosin (autosomal dominant) zz MYL3 Myosin light chain 2 (autosomal dominant) zz MYL2 Myosin regulatory light chain 2 (autosomal dominant) zz TNNI3 Cardiac troponin I (autosomal dominant) zz DES Desmin (autosomal dominant) zz MYPN Myopalladin (autosomal dominant) zz TTR transthyretin (autosomal dominant) amyloidosis Source: Adopted from Eli Muchtar, et al.1
Table 2: Clinical history and relevant association Previous malignancy
Metastatic tumors, lymphoma, multiple myeloma, postradiation therapy
Drug history
Anthracycline, doxorubicin, antimalarial agents, L-tryptophan, busulfan, mercurial agents
Weight loss
Amyloidosis, neuromuscular disorders
Renal dysfunction
Cystinosis, scleroderma, mitochondrial myopathy, amyloidosis, Fabry’s disease
Gastrointestinal involvement
Scleroderma, mitochondrial myopathy, carcinoid, amyloidosis
Lung involvement
Scleroderma, carcinoid, Churg-Strauss syndrome
Flushing
Carcinoid
Allergic rhinitis and Nasal polyps
Churg-Strauss syndrome
Diabetes mellitus
Hemochromatosis, mitochondrial myopathy
Hepatic dysfunction
Hemochromatosis, amyloidosis
Acroparesthesias
Fabry’s disease
Bone pain
Multiple myeloma
Fever
Reactive arthritis
Source: Adopted from Stollberger et al. Extra-cardiac medical and neuromuscular implications in restrictive cardiomyopathy.2
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Table 3: ECG findings in RCM4
Cardiomyopathy
8
zz
Left atrial and/or right atrial enlargement - tall, biphasic P waves
zz
Low voltage QRS complexes (in infiltrative causes)
zz
Biventricular hypertrophy
zz
ST segment depression with T wave inversions
zz
Obliquely elevated ST-T segments*
zz
Late peak T waves and notched biphasic T waves* (due to abnormal repolarisation)
zz
Prolonged QT interval
zz
Atrial fibrillation, atrial flutter (Figures 1 and 2)
zz
Atrial and ventricular ectopics
zz
Heart block-AV block (Figure 3), bundle branch blocks, intraventricular conduction delay
zz
Junctional bradycardia due to sinus node dysfunction (Figure 4)
zz
Tachy-bradycardia syndrome
*Indicates abnormal diastolic relaxation and ventricular repolarisation abnormalities
Figure 1: ECG in a patient with restrictive cardiomyopathy showing atrial flutter with variable atrioventricular conduction block. Courtesy: Dr Yash Lokhandwala, Mumbai
538
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Figure 2: ECG in a patient with restrictive cardiomyopathy showing atrial flutter with variable atrioventricular conduction. R/S in V1 >1 is suggestive of right ventricular hypertrophy (RVH) Courtesy: Dr Ajay Bahl, PGIMER, Chandigarh.
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65 An Update on Restrictive Cardiomyopathy
Figure 3: ECG in a patient with cardiac amyloidosis showing first degree atrioventricular block and pseudoinfarction pattern
Figure 4: ECG of a restrictive cardiomyopathy patient showing junctional bradycardia due to sinus node dysfunction
Table 4: Blood investigations and RCM etiology Peripheral blood eosinophilia
Hypereosinophilic syndrome, Churg-Strauss syndrome
Anemia and thrombocytopenia
Gaucher’s disease
Raise hepatic enzymes, renal dysfunction
Storage disorders, hemochromatosis, amyloidosis
Elevated serum muscle enzyme levels
Neuromuscular disorder
Serum and urine protein electrophoresis
Gammapathies-Amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) syndrome, Fabry’s disease
Hypothyroidism
Mitochondrial myopathy, POEMS syndrome, cystinosis
Raised plasma brain-natriuretic peptide5
To differentiate RCM from constrictive pericarditis
HEMODYNAMIC IN RCM The right and left atrial and ventricular EDP as well as the pulmonary capillary wedge pressure are increased in a majority of the patients with RCM. The left ventricle is commonly more affected than the right ventricle, the left ventricle EDP is greater than right ventricle EDP.
The left atrial hypertension results in large ! v! waves because of poor atrial compliance. The square root sign is characterized by a rapid dip and early plateau in the diastolic ventricular pressure and is due to rapid early filling in the end-diastolic pressure tracing. Though square root sign is very classical of CCP, it can be seen in about 43% of patients with RCM.6 539
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Figure 5: Tissue Doppler velocities (E’, A’, S’) in a patient with chronic constrictive pericarditis. In restrictive cardiomyopathy patients, there is reduction in these velocities
Figure 6: Echocardiographic image in subcostal view showing pericardial thickening in a case of chronic constrictive pericarditis
vasodilator is an adverse prognostic factor for cardiac transplantation.
Tissue Biopsy for Diagnostic Evaluation of RCM Endomyocardial biopsy though very rarely performed has diagnostic implication and at times may be a resort to arrive at a confirmative diagnosis of amyloidosis and sarcoidosis. Renal biopsy can confirm the diagnosis in amyloidosis (Figure 11). Muscle biopsy is useful in RCM cases associated with musculoskeletal diseases. Liver biopsy can often reveal the diagnosis of glycogen and lysosomal storage disorders (Figure 12). Figure 7: Ultrasound upper abdomen showing dilated, noncollapsing inferior vena cava in a case of restrictive cardiomyopathy
There are elevation and equalization of right and left atrial and ventricular pressures in diastole in CCP (Figure 8). In RCM, though all four chamber! s diastolic pressures are elevated, there is a difference of >5 mm Hg between right vs left ventricle. Dramatic x and y descents and Kussmaul! s sign can also be seen in RCM patients (Figure 9). Severe PAH can be present in RCM patients which is one of the differentiating features between RCM and CCP. One of the reliable features in differentiating RCM and CCP is the demonstration of interventricular dependence in CCP. In CCP, during inspiration, the right ventricular filling increases with concomitant excessive reduction in left ventricular preload due to exaggerated ventricular interaction. This results in respirophasic systolic ventricular dissociation in CCP; whereas in RCM, the right and left ventricular systolic pressures are concordant during respiration (Figures 10A and B).8 Pulmonary vascular resistance (PVR) estimation is important for heart transplant workup. A PVR value of >6 Wood units/m2 after administration of a pulmonary
Differentiating RCM from CCP Clinical and hemodynamic features of RCM and CCP may overlap and share some common features. At times, it may be difficult to differentiate these two causes of diastolic heart failure (Table 5). However, by taking into consideration of various findings of clinical examinations, echocardiography, cardiac catheterization, radionuclide angiography, computed tomography, cardiac magnetic resonance imaging, and cardiac biomarkers, such as plasma brain-natriuretic peptide (BNP) and histopathology, one can differentiate between the two entities. If the Doppler tracings of the transmitral flow do not show respiratory-dependent variations in their amplitudes, CCP is excluded. Plasma BNP levels are higher in RCM than in CCP.
COMMON CAUSES OF RCM Amyloidosis Cardiac amyloidosis is characterized by abnormal misfolded protein deposition in extracellular space leading to increased cardiac stiffness and RCM. The
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65 An Update on Restrictive Cardiomyopathy
Figure 8: Pressure tracing during cardiac catheterization showing classical elevation and equalization of left ventricular and right ventricular end-diastolic pressure as well as the dip and plateau or square root sign. This type of pattern is classically seen in chronic constrictive pericarditis, but can be seen in restrictive cardiomyopathy cases also Courtesy: Dr Yash Lokhandwala, Mumbai.
Figure 9: Pressure tracing during cardiac catheterization showing rapid x and y descents resembling a ‘W’ pattern. This is classical of chronic constrictive pericarditis, but can be seen in restrictive cardiomyopathy cases also Courtesy: Dr Yash Lokhandwala, Mumbai.
three common types of amyloidosis associated with RCM are light chain immunoglobulin (AL) (74%), wild-type transthyretin (ATTRwt) (22%), and mutant transthyretin (ATTRm) (4%) amyloidosis. 9,10 Patients with ATTRwt usually do not have additional visceral involvement outside the heart, but 5% of patients present with noncardiac organ damage. In ATTRm and in AL amyloidosis, up to 40% of patients may have the extra-cardiac disease in ≥2 organs. Other than the clinical manifestation of heart failure and diminished cardiac output, arrhythmias are frequent in cardiac amyloidosis. Atrial fibrillation is higher in ATTRwt (45%) than in AL (12%) or in ATTRm (15%) variant of amyloidosis.10 Sudden cardiac death (SCD) is
more common in the AL type and is more often due to electromechanical dissociation rather than ventricular tachycardia/fibrillation (VT/VF). Amyloidosis of AL variant carries the poorest prognosis with median survival of 6 months compared with 24! 66 months in ATTR variant.11,12 The SCD accounts for approximately one-third of early deaths in AL amyloidosis. Regarding the heart failure management, most of the medications, such as angiotensin-converting enzyme inhibitors, angiotensin receptor II blockers, β-blockers, and calcium-channel blockers, are not well tolerated as they can cause profound hypotension even with modest doses because of fixed cardiac output and associated autonomic neuropathy. 541
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A
B
Figures 10A and B: Simultaneous pressure tracing of both left and right ventricles. (A) showed respirophasic variation in left ventricular (LV) and right ventricular (RV) systolic pressures in chronic constrictive pericarditis (CCP). During inspiration, LV systolic pressure decreases while RV systolic pressure increases; and reverse happens during expiration. This respirophasic ventricular disconcordance is absent in restrictive cardiomyopathy; (B) Greater fall in pulmonary capillary wedge pressure than LV diastolic pressure during inspiration, which leads to greater expiratory gradient between the two in expiration, in CCP cases
542
Figure 11: Renal biopsy in a case of amyloidosis with multisystem involvement. Immunofluorescence stain showing kappa light-chain restricted amyloidosis in kidney Courtesy: Dr Balan Louis, Histopathologist, GKNM, Coimbatore.
Figure 12: Liver biopsy in a case of restrictive cardiomyopathy with suspected glycogen storage disorder. Periodic acid–Schiff (PAS) stain shows intracytoplasmic glycogen confirming glycogen storage disorder Courtesy: Dr Balan Louis, Histopathologist, GKNM, Coimbatore
Loop diuretics and aldosterone antagonists remain the mainstay of treatment. Digoxin can bind to amyloid fibrils, hence increases the risk of its toxicity. Implantable cardioverter defibrillator (ICD) is beneficial in selected patients as it does not result in overall survival benefit.13 Chemotherapy drugs melphalan and dexamethasone are effective in two-thirds of patients. Bortezomib, a proteasome inhibitor, has shown remarkable benefits when combined with melphalan, cyclophosphamide, and dexamethasone. Immunomodulatory drugs, such as thalidomide, lenalidomide, and pomalidomide, have antiplasma cell activity but have to be used at lower doses. Daratumumab is an IgGκ monoclonal antibody, targeting CD38 and hence has antiplasma cell activity and now being tested in cardiac amyloidosis management.
Monoclonal antibodies targeting the amyloid deposits are being investigated for therapeutic purposes. Orthotopic heart transplantation is the final therapeutic option but infrequently used because of involvement of organs other than the heart, and the risk of amyloid recurrence in the transplanted organ. Stabilization of transthyretin (TTR) in its tetrameric form can halt amyloidogenesis. Two tetramer stabilizers namely diflunisal and tafamidis are being tested. Doxycycline and tauroursodeoxycholic acid were shown to disrupt amyloid fibrils and facilitate tissue clearance in ATTR. Orthotopic liver transplantation is designed for ATTRm as a method to replace serum amyloidogenic TTR with a more stable wild-type tetramer. Combined heart and liver transplant is also an option in ATTRm.
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Table 5: Differentiation between chronic constrictive pericarditis (CCP) and restrictive cardiomyopathy (RCM) CCP Present
Variable
Pulses paradoxus
Present in ~1/3rd cases
Absent
Pericardial knock
Present
Absent
Equal right- and left-sided filling pressures
Present
Left-sided pressure is 3–5 mm Hg more than right side
Filling pressure >25 mm Hg
Rare
Common
RV end-diastolic pressure ≥1/3rd RV systolic pressure
Present
Present in 60 mm Hg
Absent
Common
Square root sign in ventricular diastolic filling pressure tracing
Present
Variable
Respiratory variation in left and right sided flow
Exaggerated
Normal
Vent wall thickness
Normal
May increase following infiltration
Enlargement of atrial size
Possible left atrial enlargement
Biatrial enlargement present
Septal bounce of interventricular septum on echo
Present
Absent
Tissue Doppler velocities
Normal
Reduced
Among patients with systemic sarcoidosis, cardiac involvement occurs in 2.5! 5% in clinical series14,15 and up to 25% in autopsy series.16 Noncaseating granulomas, the histopathological hallmark of cardiac sarcoidosis (CS), frequently infiltrate LV myocardium, but any other area of the heart including the right ventricle, atria, papillary muscles, valves, pericardium, and coronary arteries may be involved. The most common presentation is heart failure, but patients may present with syncope, palpitations, dyspnea, fatigue, chest pain, or SCD. Any patient of systemic sarcoidosis with cardiac symptoms should be thoroughly evaluated as per the guidelines of Japanese Ministry of Health and Welfare (JMHW) criteria and the Heart Rhythm Society (HRS) expert consensus statement (Table 6). 17,18 These criteria include the presence of noncaseating granulomas on endomyocardial biopsy and either positive extracardiac biopsy or clinical diagnosis based on major and minor criteria. Complete heart block and right bundle branch block are the most common presenting conduction abnormalities, but all types of conduction abnormalities may occur. Ventricular tachycardia, supraventricular arrhythmias, frequent premature ventricular contractions, and ventricular fibrillation can also occur before the diagnosis of CS. A 24-hour Holter recording should be done in any suspected case of CS. Cardiac positron emission tomography (PET) imaging involves two different scans: one to assess resting myocardial perfusion and areas of fibrosis or scar using 82Rubidium or 13N-ammonia; and another scan to image inflammation using F-18 fluorodeoxy glucose (FDG) (Figure 13); both of them are acquired in a single session. In the early stages of the disease, focal areas of increased FDG uptake are present and resting perfusion
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Prominent “Y” wave in jugular venous pulse
Sarcoidosis
65
RCM
defects may be seen. In the advanced stage, resting perfusion defects may be seen in the absence of FDG uptake, indicating the presence of noninflammatory scar. Whole-body FDG imaging, typically from the orbits to the mid-thigh level is increasingly being used to evaluate for extra-CS (Figure 13). In organs with high metabolic activity, a biopsy can be obtained. Hence, PET-CT is useful for diagnosis, staging, prognosis, and to guide immunosuppressive therapy. The presence of both a perfusion defect and focal FDG abnormality on baseline imaging is a strong predictor of death or VT. Although cardiac magnetic resonance (CMR) images may show thinned walls, aneurysms and segmental wall motion abnormalities in a noncoronary distribution, the principal method for detecting cardiac involvement is to identify areas of late gadolinium enhancement (LGE), usually in a subepicardial or transmural distribution. Identifying noncaseating granulomas in myocardial tissue is the gold standard for diagnosing sarcoidosis. However, because of the patchy nature, the sensitivity of endomyocardial biopsy for detecting granulomatous disease is 650 ng/L. Alternatively ≥2 class decline in NYHA functional class, with base line NYHA 3 or 4 (Table 2). From the year 2000 onwards–combination of novel anti myeloma drugs such as proteosome inhibitors (bortezomib)/immunomodulatory agents (thalidomide, lenalidomide), are being used as the standard therapy for AL amyloidosis. These drugs have replaced the earlier drugs, e.g. melphalan in combination with steroids (prednisolone or dexamethasone). When AL amyloidosis involves the heart, the outcomes are significantly worse. Four large European centers analyzed the outcomes of 346 patients with cardiac amyloidosis, and the median overall survival was reported as 7.1 months, whereas prognosis in those without cardiac involvement is significantly better, with average overall survival ranging between 40 and 94
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Table 2: Hematologic response criteria17 Amyloid complete response (ACR)
Negative serum and urine and normal FLC ratio
Very good partial response (VGPR)
Difference between involved and uninvolved FLCs [dFLC] 30% and 300 pg/ml (if baseline NT-proBNP >650 pg/mL), or a ≥2-point decrease in NYHA class (if baseline NYHA class III or IV)
Table 3: Revised mayo staging system for AL amyloidosis Assigned stage
Relative proportion of patients in the assigned cohort
Median survival in months
1 (0 points)
25
94.1
2 (1 point)
27
40.3
3 (2 points)
25
14
4 (3 points)
23
5.8
A score of 1 is assigned for each of three variables: cardiac troponin T ≥0.025 ng/mL, NT-ProBNP ≥1,800 pg/mL and dFLC ≥18 mg/dL
months.22 The Mayo Clinic group was able to demonstrate that NT-proBNP, troponin (I or C) and serum free light chains could stratify cardiac amyloidosis patients in to one of four stages with median overall survival ranging from 94 months in stage I disease to 6 months in stage IV disease (Table 3).17 Severe NT-proBNP elevation in combination with arterial hypotension carries particularly bad prognosis.17 A recent study involving stanniocalcin 1 suggests that AL amyloidosis induced cardiotoxicity may not be solely limited to deposition of amyloid protein leading to dysregulation of tissue functions, but also due to direct cardiotoxic effects of the protein.5, 10 Isolated cardiac involvement is rare, with fewer than 5% of patients presenting as such.10 Although there are no well conducted RCTs to guide the initial choice of therapy, based on available evidence bortezomib based regimen is the first choice (except in patients with severe neuropathy). Botezomib in combination with dexamethasone has a hematologic response rate from 68–77%. Combination of this with cyclophosphamide can increase the response rate up to 94%. Standard dose melphalan based regimens have response rates of 50–71%. In those not tolerating these regimens alternative regimens with lenalidomide/ pomalidomide can be used. Newer drugs recently approved in myeloma such as carfilzomib and daratumomab are being explored in amyloidosis now. In those patients who progress on any regimen alternative regimen should be tried for whom patients have not yet been exposed. For significant amyloid cardiac disease, management re q u i re s c o o rd i nat i o n b e t w e e n ca rd i o l o g y a n d hematology/oncology. It is advised to first give initial
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TRANSTHYRETIN-RELATED AMYLOIDOSIS The site of production of mutant transthyretin is liver. Before onset of significant cardiomyopathy liver transplantation can be done. OS at 5 years is 75%. Patients with mutation at V122I do not benefit from liver transplantation. In selected patients combination of liver and heart transplantation can be considered. After liver transplantation there is often progression of cardiomyopathy due to deposition of wild type of transthyretin over previous scaffolding of mutant transthyretin.23
NOVEL STRATEGIES Few phase I and II studies are available of agents which aim at stabilizing the amyloid. Diflunisal (NSAID), Tafamids are useful for stabilization of amyloid and showed promising results in transthyretin amyloidosis.24 Few drugs that act at the level of gene expression are under study for decreasing the production of mutant transthyretin. Small interfering RNA (siRNA) has been used in inhibiting the messenger RNA (mRNA) of transthyretin. 25 Similarly anti sense oligonucleotides combine and damage the mRNA. Phase III studies of these agents are underway.26 Few strategies aimed at disrupting the already deposited amyloid are experimental. Monoclonal antibodies against SAP, a non-fibrillary constituent of amyloid showed promising results in phase I study. There is also preliminary evidence of role of doxycycline in disrupting the amyloid.
CARDIAC TRANSPLANTATION Data on cardiac transplant is still limited, mostly in form of small case series. Donor shortage, high mortality, and relatively inferior survival compared to other conditions, cardiac amyloidosis is still not considered a priority in the list of indications for cardiac transplantation. Hematologic disease control is essential factor for successful transplant. Cardiac transplantation should be preceded by use of induction therapy to reduce the light chain load and
followed by ASCT is an acceptable strategy. This approach yields a five-year survival of 60%. Most patients do not tolerate ASCT prior to cardiac transplantation. Combined heart and liver transplantation is useful in transthyretin amyloidosis.5, 20, 27-28
SUMMARY Improved understanding of biology and availability of novel antimyeloma agents have improved outlook for patients of cardiac AL amyloidosis. Such patients should be carefully screened for presence of extracardiac involvement. Initial induction therapy followed by cardiac transplant followed by high dose chemotherapy and autologous blood stem cell transplantation is a reasonable option in selected patients. Based on levels of cardiac biomarkers and serum-free light chains it is now possible to prognosticate and tailor the therapy for patients of cardiac amyloidosis. Recently addition of more drugs is likely to translate into improved outcome of this disease.
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67 Cardiac Amyloidosis: Diagnosis and Management
induction therapy (bortezomib based) to minimize the burden or to eliminate plasma cells in the bone marrow producing light chains. Following induction therapy patients are considered for heart transplant, the interval between induction and cardiac transplant is typically about 6 months. This may then be followed by high-dose chemotherapy using melphalan followed by autologous hematopoietic peripheral blood stem cell transplant (ASCT). The interval between heart transplant and ASCT is also about 6 months. The objective is to replete bone marrow with healthy hematopoetic tissue elements and minimizes the production of amyloid protein, and hence delays further organ deposition and dysfunction.5
REFERENCES 1. Sipe JD, Cohen AS. Review: history of the amyloid fibril. J Struct Biol. 2000;130(2–3):88-98. 2. Cohen AS. Amyloidosis. N Engl J Med. 1967;277(10):522-30. 3. Westermark P, Benson MD, Buxbaum JN, et al. A primer of amyloid nomenclature. Amyloid Int J Exp Clin Investig. 2007;14(3):179-83. 4. Benson MD, Dasgupta NR. Amyloid Cardiomyopathy. J Am Coll Cardiol. 2016;68(1):25-8. 5. Sousa M, Monohan G, Rajagopalan N, et al. Heart transplantation in cardiac amyloidosis. Heart Fail Rev. 2017;22(3):317-27. 6. Kisilevsky R. The relation of proteoglycans, serum amyloid P and apo E to amyloidosis current status, 2000. Amyloid Int J Exp Clin Investig. 2000;7(1):23-5. 7. Bodin K, Ellmerich S, Kahan MC, et al. Antibodies to human serum amyloid P component eliminate visceral amyloid deposits. Nature. 2010;468(7320):93-7. 8. Kyle RA, Bayrd ED. Amyloidosis: review of 236 cases. Medicine (Baltimore). 1975;54(4):271-99. 9. Reisinger J, Dubrey SW, Lavalley M, et al. Electrophysiologic abnormalities in AL (Primary) amyloidosis with cardiac involvement. J Am Coll Cardiol. 1997;30(4):1046–51. 10. Merlini G. AL amyloidosis: from molecular mechanisms to targeted therapies. Hematol Am Soc Hematol Educ Program. 2017;2017(1):1–12. 11. Ruberg FL , Berk JL . Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012;126(10):1286–300. 12. Cheng Z, Zhu K, Tian Z,et al. The findings of electrocardiography in patients with cardiac amyloidosis. Ann Noninvasive Electrocardiol Off J Int Soc Holter Noninvasive Electrocardiol Inc. 2013;18(2):157–62. 13. Pagourelias ED, Mirea O, Duchenne J, et al. Echo parameters for differential diagnosis in cardiac amyloidosis clinical perspective: A head-to-head comparison of deformation and nondeformation parameters. Circ Cardiovasc Imaging. 2017;10(3):e005588.
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14. Kristen AV, Siepen F aus dem, Scherer K, et al. Comparison of different types of cardiac amyloidosis by cardiac magnetic resonance imaging. Amyloid. 2015;22(2):132–41. 15. Fontana M, Chung R, Hawkins PN, et al. Cardiovascular magnetic resonance for amyloidosis. Heart Fail Rev. 2015;20(2):133–44. 16. Hawkins PN. Serum amyloid P component scintigraphy for diagnosis and monitoring amyloidosis. Curr Opin Nephrol Hypertens. 2002;11(6):649–55. 17. Kumar S, Dispenzieri A , Lac y MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012;30(9):989–95. 18. Sachchithanantham S, Wechalekar AD. Imaging in systemic amyloidosis. Br Med Bull. 2013;107:41-56. 19. Vrana JA, Theis JD, Dasari S, et al. Clinical diagnosis and typing of systemic amyloidosis in subcutaneous fat aspirates by mass spectrometry-based proteomics. Haematologica. 2014;99(7):1239–47. 20. Estep Jerry D, Bhimaraj A, Cordero-Reyes AM, et al. Heart transplantation and end-stage cardiac amyloidosis: a review and approach to evaluation and management. Methodist Debakey Cardiovasc J. 2012;8(3):8–16. 21. Falk RH, Alexander KM, Liao R, et al. AL (Light-Chain) Cardiac amyloidosis: A review of diagnosis and therapy. J Am Coll Cardiol. 2016;68(12):1323–41.
22. Wechalekar AD, Schonland SO, Kastritis E, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood. 2013;121(17):3420–7. 23. Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol. 2015;66(21):2451–66. 24. Maurer MS, Grogan DR, Judge DP, et al. Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes. Circ Heart Fail. 2015;8(3):519–26. 25. Coelho T, Adams D, Silva A, et al. Safety and Efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819–29. 26. Ohno S, Yoshimoto M, Honda S, et al. The antisense approach in amyloid light chain amyloidosis: identification of monoclonal Ig and inhibition of its production by antisense oligonucleotides in in vitro and in vivo models. J Immunol. 2002;169(7):4039–45. 27. Wechalekar AD, Whelan C. Encouraging impact of doxycycline on early mortality in cardiac light chain (AL) amyloidosis. Blood Cancer J. 2017;7(3):e546. 28. Dubrey SW, Burke MM, Hawkins PN, et al. Cardiac transplantation for amyloid heart disease: the United Kingdom experience. J Heart Lung Transplant Off Publ Int Soc Heart Transplant. 2004;23(10):1142–53.
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CHAPTER 68 Cardiac Sarcoidosis Ajit Thachil
INTRODUCTION Sarcoidosis is a multi-system disease of unknown etiology, characterized by chronic non-necrotizing granulomatous inflammation of the involved organs. In the myocardium, chronic inflammation usually, but not invariably, leads to patchy scarring. The inflammatory and scar phases of the disease often co-exist in the same/different areas of an involved heart; both phases contribute to all manifestations of the disease. 1,2 The incidence of sarcoidosis, the likelihood of cardiac involvement in sarcoidosis, and the presentations of cardiac sarcoidosis all seem to vary in different areas of the world. Familial aggregation has been reported; however, the interactions between familial factors, potential inciting pathogens and/or triggering environmental stimuli are unclear.3
INCIDENCE AND PREVALENCE The estimated incidence of sarcoidosis is highest among African Americans in the USA (35.5 per 100,000) followed by the Scandinavian countries (14, 11.5, 11.4 and 7.2 per 100,000 population respectively in Norway, Sweden, Denmark and Finland respectively). 4,5 Among Asian countries, Japan has the highest reported incidence (1.01 per 100,000 population), with a higher proportion of patients exhibiting cardiac involvement (reliable incidence and prevalence reports are not available for Asian countries other than Japan, South Korea and Singapore, and for Africa and South America). 6 Sarcoidosis has a slight female preponderance, and usually (~70%) presents between the ages of 25 and 60 years.6-8 Pulmonary involvement is present in ~ 90% of patients with clinically detectable sarcoidosis. Clinically obvious cardiac sarcoidosis has been reported in ~5% of patients with pulmonary/systemic sarcoidosis, whereas subclinical cardiac sarcoidosis is present at autopsy in 20–25% of patients with pulmonary/systemic sarcoidosis from North America, and in up to 58% of patients from Japan.9,10
PRESENTATIONS The most common manifestations of cardiac sarcoidosis are atrioventricular conduction blocks (26–62%), bundle branch blocks (12–61%), ventricular tachyarrhythmias
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(2–42%), sudden death (12–65%), and ventricular dysfunction/heart failure (10–30%). 11 Two features regarding the morphology of the VT are strongly suggestive of cardiac sarcoidosis as the etiology of VT, and thus deserve special mention. Recurrence of monomorphic VT of a morphology that is clearly distinct from the index morphology (even if the occurrences are recorded several months apart) in a patient with apparently idiopathic VT is a strong pointer towards cardiac sarcoidosis, especially in patients with normal or near normal LV function. This finding was observed in 78% of patients with VT due to cardiac sarcoidosis, and is extremely rare in true idiopathic VT.12 Occurrence of pleomorphic VT (defined as two distinct monomorphic VT morphologies) within the same ongoing VT, especially if associated with cycle length variations of >50 ms in the VT, suggests a complex VT circuit with multiple exits, a finding typical of cardiac sarcoidosis (Figure 1). This finding was observed in 49% of patients with VT due to cardiac sarcoidosis, as opposed to 0% of patients with idiopathic VT.13 Subtle fractionations of the QRS/fragmented QRS complexes (Figures 2A and B) are present during sinus rhythm in up to 60% of patients with cardiac sarcoidosis, and provide a diagnostic clue. QRS fractionation by itself lacks sufficient sensitivity and specificity to be diagnostic of cardiac sarcoidosis.14,15 Rarely, cardiac sarcoidosis has also been shown to cause atrial flutter and atrial fibrillation by direct involvement of the atrial myocardium.16,17 Cardiac sarcoidosis usually causes left ventricular dysfunction, with/without right ventricular dysfunction. Occasionally, it can present as isolated right ventricular involvement, and masquerade as arrhythmogenic right ventricular cardiomyopathy. It can rarely cause patchy myocardial thickening during the granulomatous inflammatory phase, and thus mimick hypertrophic cardiomyopathy. Case series of cardiac sarcoidosis from India show ventricular arrhythmia as the predominant presentation, with AV block being distinctly uncommon.12 In the author’s personal experience, out of 43 consecutive patients diagnosed with cardiac sarcoidosis, 84% presented with ventricular arrhythmia, whereas only 2% had AV block (unpublished data from CARE Hospitals, Hyderabad, India). This may be due to referral/investigatory bias,
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Figure 1: Pleomorphic VT in a patient with cardiac sarcoidosis. Note the variations in QRS morphology and cycle length. This was the fourth different morphology of VT recorded in this patient
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or may reflect a true geographical variation in the presentation of cardiac sarcoidosis. A case series from Japan reported AV block as a manifestation of the early, steroid-responsive phase of the disease, and ventricular tachycardia as a manifestation of the late (scarred), steroid non-responsive phase of the disease. 18 Reports from North America too described that ventricular tachycardia occurred relatively late in the course of disease (mean LVEF 36 ± 14%; right ventricle dysfunction in 16/21 patients; NYHA ≥2 : 11/21 patients), implying greater role for catheter ablation in the management of VT, and poorer patient outcomes.19 This contrasts with case series from India which report a larger fraction of patients presenting with ventricular tachycardia in the early, inflammatory phase of the disease (LVEF 53 ± 12%; NYHA I status in 15 out of 18 patients), implying greater response of VT to immunosuppressive therapy, and better patient outcomes.1,12 Cardiac manifestations may be the first and only clinical presentation of sarcoidosis in a significant number of patients. One major reason for this is that whereas cardiac involvement often causes significant symptoms, extracardiac involvement often causes only milder symptoms. Previous case series have reported that cardiac sarcoidosis was the underlying etiology in 28% of patients presenting with unexplained monomorphic VT; clinically silent extracardiac sarcoidosis was present in 75% of these pateints.20 32 patients presenting with isolated, unexplained AV block between the ages of 18–60 years were evaluated for sarcoidosis; cardiac sarcoidosis was the etiology of AV block in 34% of them; all the patients with cardiac sarcoidosis were detected with clinically silent extracardiac sarcoidosis.21 A diagnosis of cardiac sarcoidosis as the etiology of AV block also altered the long-term prognosis. Among the patients with cardiac sarcoidosis as the cause of AV block, 27% went on to develop heart failure, and 18% went on to develop
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recurrent VT; in contrast, none of the patients with true idiopathic AV block developed these events at follow up.21 Two presentations of cardiac sarcoidosis deserve special attention: cardiomediastinal sarcoidosis, and isolated cardiac sarcoidosis (ICS). The strong association of mediastinal adenopathy with cardiac sarcoidosis among patients presenting with idiopathic VT was demonstrated in a case series from India wherein mediastinal adenopathy was observed in all 12 patients with cardiac sarcoidosis presenting with VT.12 In the author’s personal experience, mediastinal adenopathy was present in 42 out of 43 consecutive patients diagnosed with cardiac sarcoidosis (unpublished data from CARE Hospitals, Hyderabad, India). Case series from Japan and Finland have also shown mediastinal adenopathy in 65–100% of patients who were diagnosed with cardiac sarcoidosis as the cause of idiopathic dilated cardiomyopathy; sampled mediastinal nodes showed sarcoid granulomas in 92% patients in one of these reports.22,23 The finding of significant, unexplained mediastinal adenopathy in a patient with unexplained VT/ left ventricular dysfunction/AV block should thus trigger a search for cardiac sarcoidosis as the potential etiology. True ICS is difficult to diagnose within the current diagnostic framework (see discussion later) and is, more often than not, an autopsy diagnosis. Autopsy studies have shown a 23–30% prevalence of ICS among patients suspected to have cardiac sarcoidosis but did not meet diagnostic criteria for cardiac sarcoidosis.23-26
PROGNOSIS In the current era, the most important determinant of prognosis in cardiac sarcoidosis is the ventricular function at the time of diagnosis. Earlier reports indicated a median survival of two years after the diagnosis of cardiac sarcoidosis.27 Subsequently, as we learned to effectively diagnose and treat the inflammation early on in the course
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A
B Figures 2A and B: (A) QRS fractionation in inferior leads; (B) QRS fractionation in V1 during sinus rhythm in patients with cardiac sarcoidosis
of disease, and manage the associated arrhythmias, prognosis has improved remarkably. Currently, patients diagnosed at the stage of normal ventricular function and managed appropriately have a near normal long-term survival. 12,28 In contrast, despite administration of the best available therapy, patients diagnosed at a stage of ventricular dysfunction (LVEF 36 ± 14%; right ventricle dysfunction in 16/21 patients, NYHA Class ≥2 : 11/21 patients) had a 43% incidence of death/heart transplant at two year follow up.19
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DIAGNOSIS The diagnosis of cardiac sarcoidosis was previously made based on the Japanese society guidelines, which were revised in 2006 (Tables 1 and 2).29 Currently, the 2014 consensus statement from the heart rhythm society is preferred for the diagnosis of cardiac sarcoidosis (Table 3).30 Angiotensin-converting enzyme levels are elevated in 60% of patients with sarcoidosis; however, serum angiotensin-converting enzyme levels lack sensitivity and specificity in diagnosing or managing
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Table 1: Diagnostic guidelines for cardiac sarcoidosis from the Japanese society, 2007 revision24
8
Criteria for cardiac involvement of sarcoidosis
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1. Major criteria a. High-grade atrioventricular block (including complete atrioventricular block) or fatal ventricular arrhythmia (e.g. sustained ventricular tachycardia and ventricular fibrillation) b. Basal thinning of the ventricular septum or abnormal ventricular wall anatomy (ventricular aneurysm, thinning of the middle or upper ventricular septum, regional ventricular wall thickening) c. Left ventricular contractile dysfunction (left ventricular ejection fraction less than 50%) d. 67Ga citrate scintigraphy or18 F-FDG PET reveals abnormally high tracer accumulation in the heart e. Gadolinium-enhanced MRI reveals delayed contrast enhancement of the myocardium 2. Minor criteria f. Abnormal ECG findings: Ventricular arrhythmias (nonsustained ventricular tachycardia, multifocal or frequent premature ventricular contractions), bundle branch block, axis deviation, or abnormal Q waves g. Perfusion defects on myocardial perfusion scintigraphy (SPECT) h. Endomyocardial biopsy: Monocyte infiltration and moderate or severe myocardial interstitial fibrosis Cardiac findings should be assessed based on the major criteria and the minor criteria. Clinical findings that satisfy the following 1) or 2) strongly suggest the presence of cardiac involvement. 1. Two or more of the five major criteria (a) to (e) are satisfied . 2. One of the five major criteria (a) to (e) and two or more of the three minor criteria (f ) to (h) are satisfied. Diagnostic groups in cardiac sarcoidosis 1. Histological diagnosis group (those with positive myocardial biopsy findings) Cardiac sarcoidosis is diagnosed histologically when endomyocardial biopsy or surgical specimens demonstrate non-caseating epithelioid granulomas. 2. Clinical diagnosis group (those with negative myocardial biopsy findings or those not undergoing myocardial biopsy) The patient is clinically diagnosed as having sarcoidosis (1) when epithelioid granulomas are found in organs other than the heart, and clinical findings strongly suggestive of the above-mentioned cardiac involvement are present; or (2) when the patient shows clinical findings strongly suggestive of pulmonary or ophthalmic sarcoidosis; at least two of the five characteristic findings of sarcoidosis (see below); and clinical findings strongly suggest the above-mentioned cardiac involvement Characteristic findings of sarcoidosis 1. Bilateral hilar lymphadenopathy 2. High serum angiotensin-converting enzyme (ACE) activity or elevated serum lysozyme levels 3. High serum soluble interleukin-2 receptor (sIL-2R) levels 4. Significant tracer accumulation in 67Ga citrate scintigraphy or18 F-FDG PET 5. A high percentage of lymphocytes with a CD4/CD8 ratio of >3.5 in BAL fluid
Table 2: Diagnostic guidelines for isolated cardiac sarcoidosis from the Japanese society, 2006 revision29 Diagnostic guidelines for isolated cardiac sarcoidosis Prerequisite 1. No clinical findings characteristic of sarcoidosis are observed in any organs other than the heart (The patient should be examined in detail for respiratory, ophthalmic, and skin involvements of sarcoidosis. When the patient is symptomatic, other etiologies that can affect the corresponding organs must be ruled out) 2. 67Ga scintigraphy or 18F-FDG PET reveals no abnormal tracer accumulation in any organs other than the heart 3. A chest CT scan reveals no shadow along the lymphatic tracts in the lungs or no hilar and mediastinal lymphadenopathy (minor axis >10 mm) 4. Histological diagnosis group: Isolated cardiac sarcoidosis is diagnosed histologically when endomyocardial biopsy or surgical specimens demonstrate non-caseating epithelioid granulomas 5. Clinical diagnosis group: Isolated cardiac sarcoidosis is diagnosed clinically when the criterion (d) and at least three other criteria of the major criteria (a)-(e) are satisfied (Table 1).
sarcoidosis.31 ACE is produced by activated pulmonary macrophages. ACE levels are typically increased in pulmonary sarcoidosis and have been specifically shown to be not useful for the diagnosis or monitoring of cardiac sarcoidosis without pulmonary involvement. 32 Hence, studies have focused on finding new biomarkers to assess disease activity. Serum levels of neopterin and soluble interleukin-2 receptor levels have been shown to be significantly elevated in active disease.33 Although promising, none of these biomarkers are ready for clinical use. Endomyocardial biopsy, though the gold standard for diagnosing cardiac sarcoidosis, has low sensitivity due to
the focal and usually midmyocardial/epicardial location of the disease, and reveals noncaseating granulomas in 10 mm) in a patient with a non-caseating granuloma suggests simultaneous occurrence of tuberculosis and sarcoidosis, rather than refute the diagnosis of sarcoidosis.40 A negative tuberculin test is the norm in sarcoidosis; a negative tuberculin test, though, can also occur in patients with simultaneous tuberculosis and sarcoidosis, where cutaneous anergy due to sarcoidosis has suppressed the response to tubercular antigen.40 A meta-analysis found M. tuberculosis DNA (and occasionally atypical Mycobacterial DNA) positivity in 26.4% of sarcoid granulomas using polymerase chain reaction (PCR) tests. 41 While the etiological role of this finding is still debated, it makes a case for NOT diagnosing tuberculosis based on DNA PCR positivity as the sole criterion. In the light of these confusing findings, cardiac sarcoidosis, myocardial tuberculosis, and the overlap syndrome can be diagnosed and treated using a previously described algorithm which has been found to be clinically effective (Figure 3). 12 This algorithm diagnoses tuberculosis in presence of AFB stain or culture positivity, sarcoidosis in presence of AFB stain, culture,
Mantoux test and TB PCR negativity, and an overlap syndrome if TB PCR/Mantoux test is positive along with a negative AFB stain and culture. Other differential diagnoses include giant cell myocarditis (differentiated on endomyocardial biopsy), arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy and idiopathic ventricular tachycardia. Another close mimick which is difficult to differentiate is the idiopathic variant of “arrhythmogenic inflammatory cardiomyopathy” (patients presenting with PVCs/VT/VF in whom clinical features and FDG PET findings are consistent with cardiac sarcoidosis, but biopsies do not show non-necrotising granulomas), another entity wherein ventricular arrhythmia responds to immunosuppressive therapy.42 It is quite likely that many cases of so-called idiopathic VT and idiopathic arrhythmogenic inflammatory cardiomyopathy are actually cases of cardiac sarcoidosis wherein the site chosen/accessible for biopsy does not harbor a granuloma. It is also possible that some of these are cases of myocardial tuberculosis.
IMAGING IN CARDIAC SARCOIDOSIS Imaging modalities have a major role to play in the diagnosis, prognostication and monitoring of cardiac sarcoidosis. Echocardiographic abnormalities are described in 30–35% of patients with cardiac sarcoidosis. Other than systolic and diastolic ventricular dysfunction, the most common finding described is a discrete thinning of the basal anteroseptum, found in 20–30% of patients (Figures 4A and B). Other findings include areas of focal thinning and thickening (during the granulomatous infiltration phase; Figure 4C), and discrete aneursyms. None of these findings are sensitive or specific enough to be diagnostic on their own. Gallium scans and Technetium scans were previously used to diagnose active cardiac sarcoidosis, but are currently not recommended due to 563
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Figure 3: Diagnostic and therapeutic algorithm for VT due to suspected cardiac sarcoidosis or myocardial tuberculosis12
their low sensitivity and specificity.43 The best currently available tool for diagnosis of active cardiac sarcoidosis seems to F 18-FDG PET-CT showing discrete areas of high FDG uptake (Figure 5). Adding a perfusion scan to the PET-CT to demonstrate perfusion defects (in the
absence of CAD) in the area of high FDG uptake further increases the utility of the FDG scan. FDG PET needs to be performed after a specific dietary preparation for up to 72 hours for it to be accurate to diagnose cardiac sarcoidosis. The blood glucose level should be normal at the time
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A
C
B
Figures 4A to C: (A) Discrete basal anteroseptal thinning on 2D echo in advanced cardiac sarcoidosis; (B) Subtle discrete basal anteroseptal thinning on 2D echo in early cardiac sarcoidosis; (C) Focal thickening of the mid-septum in cardiac sarcoidosis. This picture can mimick HCM. This patient had inflammation in the thick area on FDG PET-CT, and biopsy from this area showed the typical granuloma, without evidence of HCM
Figure 5: Use of 18 F-FDG PET-CT to diagnose, and demonstrate treatment response in cardiac sarcoidosis. The upper panel shows discrete FDG uptake in the apical, lateral and diaphragmatic aspects of myocardium (yellow arrows), and in deep cervical, hilar and subcarinal lymph nodes (blue arrows) at the time of diagnosis. The bottom panel shows that all these FDG avid areas have become FDG non avid after treatment
of performing the FDG PET. Besides, significant interoperator variability calls for an experienced interpreter for the findings.44,45 Reduction in FDG uptake on PETCT is probably the best available tool for monitoring
treatment response in cardiac sarcoidosis. In a study of 14 patients with cardiac sarcoidosis who underwent serial FDG PET guided therapy, it was noted that at 5.8 months of therapy, 67% of patients showed reduction and 33% 565
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A
B
Figures 6A and B: Time course of response of active cardiac sarcoidosis to immunosuppressive therapy, and illustrating the use of serial FDG PET-CTs to guide therapy32 (see text for further discussion)
showed resolution of myocardial inflammation; at 11.6 months, 92% had shown reduction and 67% had shown resolution of inflammation; at 20.3 months, no patient had myocardial inflammation. Reduction in myocardial inflammation on PET-CT correlated with quiescence of arrhythmia and improvement of ventricular function (Figures 6A and B). 32 Reappearance of FDG uptake in previously non-FDG avid areas has been the most promising tool to diagnose relapse of active cardiac sarcoidosis.1 Late gadolinium enhancement on cardiac MRI is the gold standard for diagnosing myocardial scars in cardiac sarcoidosis. Extent of myocardial scarring (>18 g) correlates with prognosis of cardiac sarcoidosis. The LGE is found most commonly in the septum. Mid myocardial and epicardial scars not corresponding to a coronary artery distribution are the usual findings on DE-CMR.46,47 Cardiac MRI detecting scar, and FDG PET detecting inflammation thus yield complementary information in cardiac sarcoidosis.2,48 (Figures 7A and B). More recently, myocardial edema, detected as increased signal on T2 weighted cardiac MRI has also been used to evaluate inflammation in cardiac sarcoidosis.
TREATMENT Treatment of cardiac sarcoidosis should include disease specific treatment for the cardiac sarcoidosis per se, as well as treatment for the arrhythmias/ventricular dysfunction. Immunosuppressant therapy, usually using corticosteroids, is effective to manage ventricular arrhythmia, reverse AV block and to preserve ventricular function, if initiated during the inflammatory phase of disease.49 As long-term therapy is usually required, steroid sparing immunosuppressive agents are often added to avoid the adverse effects of long-term steroid use. The most commonly used and effective second line immunosuppressant, used for steroid-sparing effect in the long-term, is Methotrexate. Yalagudri et al. has laid
down a framework for tailoring immunosuppressive therapy to suit the stage of disease (Figure 8).1 In this regime, patients with VT in the inflammatory phase were given oral corticosteroids (prednisolone 1 mg/kg/day, to a maximum dose of 60 mg/day or equivalent dose of methylprednisolone) for 8 weeks and tapered over a period of the next 3–4 months before stopping. Oral methotrexate (7.5 mg/week) was started concurrently with steroids and continued for 2 years (increased up to 20 mg/week as tolerated). In the report by Thachil et al. wherein serial FDG PET-CTs were used to guide therapy, the mean duration of treatment required was 14.1 ± 4.5 months.32 Some of the previous studies and analyses have questioned the role of corticosteroid therapy in cardiac sarcoidosis. All such studies suffer from one major limitation: steroids have been used for all patients diagnosed with cardiac sarcoidosis, rather than only for patients diagnosed with cardiac sarcoidosis in the active inflammatory phase. Blanket corticosteroid therapy for all patients with cardiac sarcoidosis has not been shown to be useful.50 Corticosteroids have been found to be useful in cardiac sarcoidosis provided they are administered to patients in the active, inflammatory phase of disease (usually diagnosed by an 18FDG PET-CT showing myocardial inflammation), preferably before the onset of severe left ventricular dysfunction.1,12,51,52 There is no standardization of the dose or duration of steroid therapy. The majority of the sparse literature available suggests 20–40 mg/day (or 0.5 mg/kg/day) of prednisolone for ~ 3months, followed by reduction to 5–15 mg/day and maintaining this low dose for 9–12 months.51 These recommendations are based on incomplete evidence. The major evidences behind these recommendations are: (i) 30 mg/day was found to have the same effect as 60 mg/day in the only dose finding study, which is an older study where steroids were administered without
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A
B Figures 7A and B: Complementary role of DE-CMR and 18FDG PET-CT in cardiac sarcoidosis2
evaluating the patients for objective evidence of active myocardial disease.28 (ii) The regimen simply extends the regimen used for treatment of extracardiac sarcoidosis to cardiac sarcoidosis, without systematic verification of whether it may be effective in cardiac sarcoidosis. 31 In the regime developed at CARE Hospitals, Hyderabad, and described by Yalagudri et al. all 14 patients with active cardiac sarcoidosis initially responded to oral prednisolone at a dose of 1 mg/kg/day (maximum 60 mg/day), administered for two months and then tapered and stopped over the next 12 weeks in patients showing
clinical response. Myocardial inflammation on FDG PET-CT took longer to completely resolve, though most patients showed reduction in inflammation at 3 months itself. Methotrexate was added as a steroid sparing agent in all of these patients, usually after an initial two months of high dose prednisolone. The initial dose of methotrexate was 7.5 mg once/week; the dose was increased (usually in increments of 2.5 mg) once every two to four weeks to reach a maximum dose of 20 mg once/week if tolerated. Most patients received 18 to 24 months of therapy. In an analysis by Thachil et al. carried out on patients treated 567
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Figure 8: Suggested guideline for tailoring therapy for VT in cardiac sarcoidosis according to the stage of disease1
using this regimen, among patients who underwent serial FDG PET guided therapy, it was noted that at 5.8 months of therapy, 67% of patients showed reduction and 33% showed resolution of myocardial inflammation; at 11.6 months, 92% had shown reduction and 67% had shown resolution of inflammation; at 20.3 months, no patient had myocardial inflammation.32 On this regime, 4 out of 14 patients had reactivation of disease, and were managed by additional immunosuppression, usually by administering IV methylprednisolone and/or increasing the dose of prednisolone for a brief period.1 IV methylprednisolone (up to 1 g/day, for 1–3 days) can be used for more rapid control of recurrent VT during the inflammatory phase of cardiac sarcoidosis, especially during reactivation of cardiac sarcoidosis.1,53 This regime was tolerated without serious side effects. Methotrexate is the most common second line drug used in cardiac sarcoidosis. It has been usually used along with steroids as a “steroid sparing
agent” to avoid the adverse effects of long-term steroid use. 54 It has also been used predominantly for steroid resistant cases. There is no standardization of the use of methotrexate in cardiac sarcoidosis. Birnie et al. used methotrexate for only steroid refractory cases or in case of significant adverse effects of steroids. 51 Nagai et al. reported a regime involving lower doses of prednisolone and methotrexate for longer durations as compared to the regime reported from CARE Hospitals, Hyderabad. They administered 5–15 mg/day of prednisolone along with 6 mg/week of methotrexate for all patients for up to 5 years; this was done without serial imaging studies to monitor for active cardiac sarcoidosis.54 Other immunosuppressive drugs that have been effectively used in place of steroids for initial control of disease include monthly cyclophosphamide, and infliximab.55,56 Azathioprine has been used in place of methotrexate as a steroid-sparing agent.57
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Table 4: The 2014 HRS consensus statement for management of arrhythmias in cardiac sarcoidosis30
68
Management of conduction abnormalities Device implantaton can be useful in CS patients with an indicatin for pacing, even if the atrioventricular block reverses transiently
IIa
zz
Immunosuppression can be useful in CS patients with second-degree (Mobitz II) or third-degree atrioventricular block
IIa
zz
ICD implantation can be useful in patients with CS and an indication for permanent pacemkar implantations
IIa
Management of ventricular arrhythmias zz
Assessment of mycardial inflammation with FDG-PET can be useful in CS patients with ventricular arrhythmias
zz
Immunosuppression can be useful in CS patiens with ventricular arrhythmias and evidence of myocardial inflammation
IIa
zz
Antiarrythmic drug therapy can be useful in patients with ventricular arrhythmias refractory to immunosuppressive therapy
IIa
Catheter ablation can be useful in patients with CS and ventricular arrhythmias refractory to immunosuppresive and antiarrhythmic therapy
IIa
zz
IIa
Cardiac Sarcoidosis
zz
Risk stratification for sudden cardiac death zz
zz
An electrophysiological study for the purpose of sudden death risk stratification may be considered in patients with LVEF >35% despite optimal medical therapy and a period of immunosuppression (if there is active inflammation)
IIb
CMR for the purpsoe of sudden death risk stratification may be considered
IIb
ICD implantation zz
Spontaneous sustained ventricuar arrhythmias, including prior cardiac arrest
zz
LVEF 10 mm Hg systolic blood pressure in limb), fever, neck pain, transient amaurosis, blurred vision, syncope, dyspnea or palpitations
Ten Minor Criteria 1. High ESR
Unexplained high ESR >20 mm/hour (Westergren) at diagnosis or evidence in patient’s history
2. Carotid artery tenderness
Unilateral or bilateral tenderness of common carotid arteries on palpation. Neck muscle tenderness is unacceptable
3. Hypertension
Persistent blood pressure >140/90 mm Hg brachial or >160/90 popliteal
4. Aortic regurgitation or annuloaortic ctasia
By auscultation, Doppler echocardiography or angiography
5. Pulmonary artery lesion
Lobar or segmental arterial occlusion or equivalent determined by angiography or perfusion scintigraphy, or presence of stenosis, aneurysm, luminal irregularity or any combination in pulmonary trunk or in unilateral or bilateral pulmonary arteries determined by angiography.
6. Left mid common carotid lesion
Presence of the most severe stenosis or occlusion in the mid portion of 5 cm in length from the point 2 cm distal to its orifice determined by angiography.
7. Distal brachiocephalic trunk lesion
Presence of the most severe stenosis or occlusion in the distal third determined by angiography.
8. Descending thoracic aorta lesion
Narrowing, dilation or aneurysm, luminal irregularity or any combination determined by angiography; tortuosity alone is unacceptable.
9. Abdominal aorta lesion
Narrowing, dilation or aneurysm, luminal irregularity or any combination
10. Coronary artery lesion
Documented on angiography below the age of 30 years in the absence of risk factors such as hyperlipidemia or diabetes mellitus
The presence of two major or one major and two minor criteria or four minor criteria suggests a high probability of TA.
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Table 5: The EULAR/PRINTO/PRES criteria for childhood Takayasu’s arteritis Criterion
Definition
Angiographic abnormality (Mandatory criterion)
Angiography (conventional, computed tomography, or magnetic resonance imaging) of the aorta or its main branches and pulmonary arteries showing aneurysm/dilatation, narrowing, occlusion or thickened arterial wall not due to fibromuscular dysplasia, or similar causes; changes usually focal or segmental
Pulse deficit or claudication
Lost/decreased/unequal peripheral artery pulse(s). Claudication: focal muscle pain induced by physical activity
Blood pressure discrepancy
Discrepancy of four limb systolic blood pressure >10 mm Hg difference in any limb
Bruits
Audible murmurs or palpable thrills over large arteries
Hypertension
Systolic/diastolic blood pressure greater than 95th percentile for height
Acute phase reactants
Erythrocyte sedimentation rate >20 mm per first hour or C-reactive protein any value above normal (according to the local laboratory)
Takayasu’s arteritis (TA) is classified when the mandatory criterion is present plus any other criteria.
(PRES) and by the Pediatric Rheumatology International Trials Organization (PRINTO) in 2005 proposed classification criteria. It was further validated in 2008. This is known as EULAR/PRINTO/PRES criteria and is meant to be used in individuals younger than 18 years. The criteria for childhood TA (c-TA) include angiographic abnormalities in the aorta or its main branches and pulmonary arteries as a mandatory criterion and five additional features of c-TA (Table 5). When the patient has the mandatory criterion and at least one of the 5 other features, c-TA is diagnosed. EULAR/PRINTO/PRES criteria for c-TA are more modern and include CT and MR imaging techniques. These criteria for diagnosis of c-TA are 100% of sensitive and 99.9% of specific.
SUGGESTED READING 1. Arnaud L, Haroche J, Malek Z, et al. Is 18F‐fluorodeoxyglucose positron emission tomography scanning a reliable way to assess disease activity in takayasu arteritis? Arthritis Rheum. 2009; 60(4):1193-200. doi: 10.1002/art.24416. 2. de Souza AW, de Carvalho JF. Diagnostic and classification criteria of Takayasu arteritis. J Autoimmun. 2014; 48-49:7983. 3. Freitas DS, Camargo CZ, Mariz HA, et al. Takayasu arteritis: assessment of response to medical therapy based on clinical activity criteria and imaging techniques. Rheumatol Int. 2012; 32:703-9. 4. Hayashi K, Fukushima T, Matsunaga N, al. Takayasu arteritis: decrease in aortic wall thickening following steroid therapy, documented by CT. Br J Radiol. 1986; 59(699):281-3. 5. Ishikawa K. Diagnostic approach and proposed criteria for the clinical diagnosis of Takayasu’s arteriopathy. J Am Coll Cardiol. 1988; 12:964-72. 6. Johnston SL, Lock RJ, Gompels MM. Takayasu arteritis: a review. J Clin Pathol. 2002; 55(7):481-6.
7. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis. Ann Intern Med. 1994; 120(11):919-29. 8. Luqmani RA, Suppiah R, Grayson PC, et al. Nomenclature and classification of vasculitis e update on the ACR/EULAR diagnosis and classification of vasculitis study (DCVAS). Clin Exp Immunol. 2011; 164:11-3. 9. Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients. Arthritis Rheum. 2007;56(3):1000-9. 10. Mason JC. Takayasu arteritis- advances in diagnosis and management. Nat Rev Rheumatol. 2010; 6(7):406-15. 11. Matsunaga N, Hayashi K, Sakamoto I, et al. Takayasu Arteritis: Protean Radiologic Manifestations and diagnosis. RadioGraphics. 1997; 17:579-94. 12. Nastri MV, Baptista LP, Baroni RH, et al. Gadoliniumenhanced Three-dimensional MR Angiography of Takayasu Arteritis. Radiographics. 2004 ; 24(3):773-86. 13. Ozen S, Pistorio A, Iusan SM, et al. Paediatric Rheumatology International Trials Organisation (PRINTO). EULAR/ PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis. 2010;69:798-806. 14. Rav-Acha M, Plot L, Peled N, et al. Coronary involvement in Takayasu’s arteritis. Autoimmun Rev 2007; 6(8):566-71. 15. Ruper to N, Ozen S, Pistor io A , et al. Pae diatr ic Rheumatology International Trials Organisation (PRINTO). EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part I: overall methodology and clinical characterisation. Ann Rheum Dis. 2010; 69:790-7. 16. Schmidt WA, Nerenheim A, Seipelt E, et al. Diagnosis of early Takayasu arteritis with sonography. Rheumatol. 2002; 41(5):496-502.
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Immunotherapy for CHAPTER 70 Nonspecific Aortoarteritis Narendra Bagri, Uma Kumar
INTRODUCTION Nonspecific aortoarteritis (NSAA), also known as Takayasu arteritis (TA), is a rare chronic granulomatous primary large vessel vasculitis which predominantly involves aorta, its main branches and pulmonary artery. The disease can affect any age group right from infancy to adulthood; however, it predominantly affects young females between 20 and 40 years of age. The prevalence of disease varies according to geographic region. The incidence of TA varies from 1.2 to 2.6/million/year depending on the geographical region.1 The clinical manifestations var y widely from asymptomatic to life-threatening manifestations depending on the stage of disease and organ involvement. The disease has three stages: (1) systemic inflammation and pre-stenotic/pre-pulseless phase extending over many years and is characterized by nonspecific complains like fever, malaise, anorexia, weight loss and arthralgia (2) stenotic/aneurysmal stage/late occlusive phase characterized by feeble or absent pulses, claudication, hypertension and lifethreatening complications like stroke, seizures, myocardial infarction, aortic regurgitation, mesenteric ischemia and retinopathy (3) fibrotic or burnt out phase. Unfortunately owing to the prolonged pre-pulseless phase, blurred transition between three stages and absence of any reliable biomarker for early diagnosis, there is a considerable diagnostic delay spanning from months to years which leads to damage accrual and cardiovascular morbidities. Characteristic arteriographic findings and existing classification criteria for both adults and children assist in diagnosis of TA.2,3 Majority of patients demonstrate progressive course requiring immunotherapy while 20% patients can have monophasic self-limiting illness.4 The pathogenesis of TA is yet not well understood but it is assumed to be predominantly a T cell mediated disease. The inflammation is mediated by raised levels of many inflammatory cytokines like tumor necrosis factor α (TNFα), interferon γ (IFN-γ), interleukin (IL)-2 , IL-3, IL-4, IL-6 and IL-8. There is also some evidence of involvement of B lymphocytes in the pathogenesis of TA as suggested by the documentation of antibodies against aortic endothelial cells (AAECA) and anti annexin V in patients.5 Several
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reports have hinted that genetic factors might play a role. HLAB*52 is the most significant HLA region associated with TA. The underlying pathophysiology forms the basis of targeted immunosuppressive therapy that is described in the subsequent section of this chapter. While administering and optimizing immunotherapy, knowledge about assessment of disease activity and severity is essential. This chapter shall illustrate the various drugs available in the therapeutic armamentarium for immunotherapy in TA. However, it is important to mention here that immunotherapy forms only one arm of the multipronged treatment strategy for TA which includes other modalities like surgical and endovascular interventions, anti-platelet agents, supportive care and physiotherapy.
DISEASE ACTIVITY AND SEVERITY The aim of immunotherapy is to dampen the ongoing arterial inflammation and it needs to be tailored depending on the intensity of ongoing inflammation. However, it is often difficult to predict the underlying inflammation owing to lack of reliable biomarker, which can define disease activity with precision. Acute phase reactants (ESR and CRP) are variably associated with disease activity and are not reliable predictors of disease activity. Elevated levels of Pentraxin 3 (PTX3) may be a potential biomarker of disease activity. Paucity of sensitive laboratory biomarkers to detect active TA has led to the development of various composite criteria and scoring systems. In 1994 Kerr et al. proposed NIH criteria which included four categories (1) ESR more than 20 mm/hr, (2) systemic features like fever, malaise (3) features suggestive of vascular ischemia like claudication, bruits and diminished or absent pulses (4) angiographic features consistent with TA; new onset or worsening of two or more out of these four criteria suggest active disease.6 In 2005, the Indian Rheumatology Association Core Group on Vasculitis (IRAVAS) proposed new set of criteria based on the Birmingham Vasculitis Activity Score (BVAS) called Disease Extent Index in TA (DEI.Tak) to assess the disease activity, which was subsequently modified to Indian Takayasu’s arteritis clinical activity score (ITAS2010), which scores 33 items in six different organ systems.
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Further, ITAS-A, an activity version of ITAS2010, takes into account the acute phase reactants, ESR and CRP may help in tailoring immunotherapy.7 Various imaging modalities viz. computed tomographic angiography (CTA), magnetic resonance angiography (MRA) and ultrasonography (USG) have been utilized to evaluate the disease activity. On CTA, vessel wall thickening with enhancement and low attenuation ring on delayed phase images is suggestive of disease activity. Likewise vessel wall thickening and enhancement on MRA is consistent with disease activity. On 18Ffluorodeoxyglucose positron emission tomography (18F-FDG-PET), vessel wall edema and mural contrast enhancement is suggestive of disease activity; the pooled sensitivity and specificity of FDG-PET for determining disease activity remains 70.1% and 77.2%, respectively. Carotid intima medial thickness (CIMT) of more than 2 mm by USG has shown to have equal concordance with CTA to predict disease activity. The sensitivity and specificity of these imaging modalities in predicting the disease activity has varied across studies. 8 Progressive arterial injury manifesting as stenosis or dilatation/aneurysm is typically considered inflammatory and treated with enhanced immunosuppression.4 However, there remains a caveat for this approach; in TA, stenosis can also result from noninflammatory remodeling response due to myofibroblast proliferation or resolution of inflammation with fibrosis and luminal contraction; wherein the temptation to increase immunosuppression may not actually translate into an evident clinical response.9 In conclusion, Monitoring disease activity in TA is a complex process which involves combined inference derived from clinical assessment, acute phase reactants, imaging modalities and the use of validated composite scores. The manifestation of TA varies from slow simmering course with incidentally detected hypertension to severe life threatening presentations like hypertensive emergencies. The severity of presentation can guide the initial therapy and deciding choice of immunosuppressive agent. 10 For the purpose of selecting the initial immunosuppressive agent we generally categorise the cases as severe TA in presence of either of the following: life or vital organ threatening conditions (hypertensive emergency), retinal vasculitis, pulmonar y arter y involvement with or without aneurysm, severe aortic regurgitation or myocarditis.
IMMUNOTHERAPY
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There is paucity of good quality data to advocate consensus treatment plans with high quality of evidence for most large vessel vasculitis. However, there is consensus agreement that early diagnosis and therapeutic interventions can improve disease outcomes. Oigahsi et al. in their cohort of 106 subjects with Takayasu arteritis showed that those
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with early diagnosis and aggressive treatment (combined immunosuppressive agents) had better overall outcome.11 Approximately 20% of patients with TA have a monophasic illness, while remaining 80% have a chronic course with relapsing and remitting disease requiring long term immunosuppression.12 Although there is no agreement on optimal preference of the agent and duration of therapy, we would summarize the recent evidence and propose an algorithmic approach (Figure 1) for the management of TA based on the existing literature. The armamentarium of various immunotherapeutic drugs in TA includes corticosteroids, non-biological and biological disease modifying drugs.
CORTICOSTEROIDS Steroids form the foundation for the long-term management of TA. They are effective in suppressing systemic symptoms and can attenuate vascular changes in early TA. The European League Against Rheumatism (EULAR) recommend high-dose oral glucocorticoids (prednisolone, 1 mg/kg/day) as the initial treatment in TA. 13 Usually this dose is continued for 4–6 weeks (depending on the severity of disease) followed by slow tapering to lowest possible dose depending on the clinical response, which is continued over many years. Up to two-third of the patients may relapse while tapering corticosteroids, necessitating the use of steroid sparing agents. Also, daily doses are associated with less chance of relapses than alternate day regime.
NONBIOLOGICAL DISEASE MODIFYING ANTIRHEUMATIC DRUGS The long-term use of glucocorticoids is often associated with steroid toxicity and therefore, an additional immunosuppressive agent is required for sustained remission. The EUL AR recommends use of 2nd immunosuppressant to achieve control of disease activity and to facilitate reduction of the cumulative dose of steroids. 13 However, due to lack of large randomized controlled tr ials compar ing the efficac y of one immunosuppressant with another, often the choice of disease modifying anti-rheumatic drug (DMARD) is variable across physicians and institutions. We usually consider methotrexate for mild to moderate disease while more potent immunosuppressive agent like cyclophosphamide as upfront drug is reserved for severe disease manifestations as described above. The duration of therapy would usually last for many years depending on the disease course. Methotrexate is widely used as a 1st line immunosuppressive agent for TA and also as steroid sparing agent. Although there is paucity of large well designed prospective controlled trials, however, when used in conjunction with corticosteroids it has been found to be efficacious in achieving remission in addition to allowing
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70 Immunotherapy for Nonspecific Aortoarteritis
Figure 1: Approach to a patient with non-specific aortoarteritis (NSAA) *Severe disease: Life or vital organ threatening conditions (hypertensive emergency), retinal vasculitis, pulmonary artery involvement with or without aneurysm, severe aortic regurgitation or myocardium
glucocorticoid dose reduction. 14 Given the long-term safety profile and affordable cost methotrexate seems a reasonable initial immunosuppressive agent for TA in our setting. The usual dose of methotrextae is 15–25 mg/m2/ week either orally or parenterally. Azathioprine has also been used as an steroid sparing drug in management of TA. In an Indian study of 15 patients followed for 1 year, Valaskumar et al. have shown that azathioprine (2 mg/kg/day) in addition to prednisolone is safe, well tolerated, and effective in controlling systemic symptoms and laboratory measures of disease activity in TA without any progression of angiographic lesions.12 However, further studies with larger sample size are required to conclusively validate the role of azathioprine. Cyclophosphamide is a potent immunosuppressive agent with established efficacy in vasculitic conditions. However, owing to its adverse effect profile including increased risk of infections it should be used cautiously and judiciously; more so in adolescent population due to the associated risk of gonadal toxicity. It has also been used either orally (2 mg/kg/day) or intravenously
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(500–750 mg/m2 as monthly pulses) in TA. Stern et al. in their study of 23 children showed that only 40% could achieve remission with cyclophosphamide while 60% were shifted to Infliximab.15 Its use is generally reserved for patients with severe manifestations such as retinal vasculitis, pulmonary artery involvement with or without aneurysm, severe aortic regurgitation or myocarditis.16 Mycophenolate mofetil: The results of recent meta-analysis to evaluate the efficacy of mycophenolate mofetil MMF in TA has shown that MMF could stabilize the disease progression in addition to achieving reductions in steroid dosage and level of inflammatory markers. 17 MMF (750–800 mg/m2/day) seems to be an effective alternative immunosuppressant with relatively lower hepatic, renal and bone-marrow toxicity, however larger studies are required to establish its long-term efficacy.
OTHER DMARDs Leflunomide is effective in controlling disease activity in the initial stages but is ineffective to sustain remission.18
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There are anecdotal studies reporting use of other DMARDs in TA like cyclosporine (CSA) and tacrolimus with successful results.16 Currently, it seems that these agents should be reserved for refractory disease.
BIOLOGIC DISEASE MODIFYING ANTIRHEUMATIC DRUGS There is upcoming evidence of use of biological agents in TA. Raised levels of inflammatory cytokines such asTNFα, IL-6 forms the basis of more specific and targeted therapy in TA. The use of biological agents is associated with increased risk of infections and therefore should be prescribed cautiously in our setting. Additionally, these agents are out of reach for most of our patients because of exuberant cost, we use these agents for either refractory or relapsed disease. Refractory disease is defined as increased disease activity following reduction of the steroid dose or persistent disease activity despite use of at least one conventional immunosuppressive agent for at least 6 months.
Anti-TNF Agents A recent systematic review describing details of 96 patients (77 received infliximab, 17 Etanercept and 5 Adalimumab) with TA treated with anti-TNF agents has shown that 61% subjects improved in terms of reduction in steroid doses and levels of inflammatory markers, however only 3 subjects showed an improvement on imaging and a total of 28 relapses were observed over a follow up of 2 years.19 In an another systematic review of the 75 patients on infliximab: remission was achieved in 74.7%, and steroids were discontinued in 32%, however 28.6% had relapse during follow up.20 Ten out of 12 patients treated with Etanercept initially achieved remission but 9 patients had a relapse on follow-up. The use of Anti-TNF agents in settings like ours where the incidence of tuberculosis is high should be guarded and close watch for evolution of any symptoms suggestive of tuberculosis is warranted.
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Raised levels of IL-6 in patients of TA form the basis for the use of tocilizumab in TA. In a systematic review including 24 patients tocilizumab could achieve clinical improvement in 58.3% and steroids could be stopped in 20.8% subjects while 16.6% relapsed during 1 year follow up period. 18 Interestingly, 71% subjects also showed improvement in imaging findings as assessed by FDGPET or MRA or CTA. In refractory cases it has helped in achieving remission by 4th monthly infusion.21 More robust data is required to make a conclusive statement on the efficacy and safety of long-term use of tocilizumab in Takayasu arteritis.
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OTHER BIOLOGICAL AGENTS Abatacept is a fully humanized soluble fusion protein compromising the extracellular domain of CTLA-4 (cytotoxic T-lymphocyte associated protein-4) and Fc component of IgG1, which selectively inhibits the costimulatory signal necessary for T-cell activation has failed to maintain sustained remission in newly diagnosed and refractory cases. B-cell dysregulation is thought to play a role in the pathogenesis of TA, and B-cell depletion using anti CD20; rituximab a monoclonal antibody that binds B-cell CD 20 receptor has been tried in few patients of refractory TA; however, reports are limited to anecdotal reports or case series. There is evidence of increased Th 17 helper cell in TA which are maintained in active state by IL-23, accordingly ustekinumab; a monoclonal antibody against IL12/23p40 was studied in a pilot study of 3 patients with active TA showing short-term benefit. More studies with larger sample size are required before recommending the routine use of these novel biological agents in TA. At this point we usually reserve use of biological agents (anti-TNF or tocilizumab) for patients with refractory TA. The definition of “Refractory disease” is variable but most studies define refractory disease as a disease with increased disease activity following reduction of the steroid dose or persistent disease activity despite use of at least one conventional immunosuppressive agent for at least 6 months.
IMMUNOTHERAPY DURING SURGERY AND PERIOPERATIVE PERIOD In the chronic stages of TA and critical vessel narrowing, e.g. cerebrovascular or coronary ischemia or renal artery stenosis, surgical interventions are indicated to restore the vascular supply and prevent end organ damage. This can be achieved either by surgery or endovascular interventions, including balloon angioplasty, stent and stent graft replacement. As a general rule, both endovascular interventions and surgery should be tried only after the suppression of inflammation using immunotherapy in the vessel wall. Perioperative immunosuppression has resulted in better outcomes and hence immunosuppression should be continued in perioperative period.
FOLLOW-UP
Patients with TA should be followed up every 3–6 months for assessment of treatment response (using clinical, imaging and laboratory parameters), disease activity (using instruments like ITAS) and drug toxicity. If there is suspicion of active disease (e.g. worsening ITAS with constitutional symptoms) repeat imaging (MRA) may be considered.
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CONCLUSION Ti m e l y d i a g n o s i s a n d o p p o r t u n e i n i t i a t i o n o f immunotherapy is the key for reduced long-term complications and the resultant morbidities and mortality related to TA. The patients with TA should be regularly followed for comprehensive evaluation of disease activity using clinical, laboratory and imaging modalities. Like any other vasculitis, corticosteroids forms the basis of immunotherapy in TA, however, owing to accompanying side effects, a steroid sparing second immunosuppressive agent is always required. Methotrextae is the agent of choice for non-severe disease whereas more potent agent like cyclophosphamide is preferred for severe TA. Due to exuberant cost and increased risk of infections use of Biological agents should be reserved for refractory disease. Long-term prognosis depends on arterial complications and progressive course. 15-year survival for patients with or without arterial complications was 66.3% & 96.4% and 58.3% & 92.7% for those with and without progressive course respectively.22 However, in a French study 10 years event free survival (vascular complications, relapse and death) was 36.4%.23 Perioperative immunotherapy results in better surgical outcomes. There is a need to conduct large, multicentre randomized controlled trails to generate high-quality evidence and formulate consensus treatment recommendations for the management of TA.
REFERENCES 1. Fries JF, Hunder GG, Bloch DA, et al. The American College of Rheumatology 1990 criteria for classification of vasculitis.Summary. Arthritis Rheum. 1990;33(8):1135-6. 2. Arend WP, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum. 1990;33(8):1129–34. 3. Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/ PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010;69(5):798–806. 4. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis. Ann Intern Med 1994;120(11):919-29. 5. Tombetti E, Mason JC. Takayasu arteritis: advanced understanding is leading to new horizons. Rheumatology (Oxford). 2018 ; doi: 10.1093/rheumatology/key040. [Epub ahead of print] 6. Valsakumar AK, Valappil UC, Jorapur V, et al. Role of immunosuppressive therapy on clinical, immunological, and angiographic outcome in active Takayasu’s arteritis. J Rheumatol. 2003;30(8):1793–8.
7. Barra L, Kanji T, Malette J, et al. Imaging modalities for the diagnosis and disease activity assessment of Takayasu’s arteritis: A systematic review and meta-analysis. Autoimmun Rev. 2018;17(2):175–87. 8. Nicolosi PA, Tombetti E, Maugeri N, et al. Vascular Remodelling and Mesenchymal Transition in Systemic Sclerosis. Stem Cells Int. 2016;2016:4636859. 9. Misra R, Danda D, Rajappa SM, et al. Development and initial validation of the Indian Takayasu Clinical Activity Score (ITAS2010). Rheumatology. 2013;52(10):1795–801. 10. Keser G, Direskeneli H, Aksu K . Management of Takayasu arteritis: a systematic review. Rheumatology. 2014;53(5):793–801. 11. Ohigashi H, Haraguchi G, Konishi M, et al. Improved prognosis of Takayasu arteritis over the past decade-comprehensive analysis of 106 patients. Circ J Off J Jpn Circ Soc. 2012;76(4):1004–11. 12. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis. Ann Intern Med.1994:120(11):919–29. 13. Mukhtyar C , Guillevin L , Cid MC , et al. EUL AR recommendations for the management of large vessel vasculitis. Ann Rheum Dis.2009;68(3):318–23. 14. Misra DP, Sharma A, Kadhiravan T, et al. A scoping review of the use of non-biologic disease modifying anti-rheumatic drugs in the management of large vessel vasculitis. Autoimmun Rev. 2017;16(2):179–91. 15. Stern S, Clemente G, Reiff A,et al. Treatment of Pediatric Takayasu arteritis with infliximab and cyclophosphamide: experience from an American-Brazilian cohort study. J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis. 2014;20(4):183–8. 16. Keser G, Direskeneli H, Aksu K. Management of Takayasu arteritis: a systematic review. Rheumatology. 2014 ;53(5):793–801. 17. Dai D, Wang Y, Jin H, et al. The efficacy of mycophenolate mofetil in treating Takayasu arteritis: a systematic review and meta-analysis. Rheumatol Int. 2017;37(7):1083–8. 18. de Souza AWS, da Silva MD, Machado LSG,et al. Short-term effect of leflunomide in patients with Takayasu arteritis: an observational study. Scand J Rheumatol. 2012;41(3):227– 30. 19. Ferfar Y, Mirault T, Desbois AC, et al. Biotherapies in large vessel vasculitis. Autoimmun Rev. 2016;15(6):544–51. 20. Osman M, Pagnoux C, Dryden DM,et al. The role of biological agents in the management of large vessel vasculitis (LVV): a systematic review and meta-analysis. PloS One. 2014;9(12):e115026. 21. Goel R, Danda D, Kumar S, et al.Rapid control of disease activity by tocilizumab in 10 “difficult-to-treat” cases of Takayasu arteritis. Int J Rheum Dis. 2013;16(6):754–61. 22. Ishikawa K, Maetani S. Long term outcome of 120 Japanese patients with Takayasu disease. Clinical and statistical analysis of related prognostic factors. Circulation. 1994;90:1855-60. 23. Comamond C, Biard L, Lambert M, Mekinian A, Ferfar Y, Kahn JE et al. Long tern outcomes and prognostic factors of complications in Takayasu arteritis: a multicenter study of 318 patients. Circulation. 2017;136(12):1114-22.
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In case of stable disease for 18-24 months gradual tapering of immunosuppressants may be considered. In case of refractory disease; add another immunosuppressant whichever is not used earlier or Biological agent (anti IL-6 or anti-TNF ).
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Interventions in Takayasu Arteritis CHAPTER 71 (Nonspecific Aortoarteritis) Sanjay Tyagi, Ankit Bansal
INTRODUCTION Takayasu arteritis (TA) is a chronic, granulomatous, large-vessel panarteritis with preferential involvement of the aorta, its major branch arteries and the pulmonary artery. The disease though more common in Asians and Africans, has worldwide distribution. The TA is usually progressive with relapses and remissions. It more commonly affects young with predilection for females. Early in the disease course, nonspecific constitutional symptoms, such as fever, malaise, and weight loss, may occur. Later on, inflammation of the involved arteries progresses, resulting in segmental stenosis, occlusion, dilatation, and/or aneurysm. This may present as extremity pain, claudication, bruits, absent or diminished pulses, and inability to record blood pressure. Severe stenosis leads to organ ischemia which may present with severe hypertension, heart failure, acute visual loss, or stroke. Endovascular interventions have emerged as the treatment of choice for stenotic lesions. The major advantages of endovascular interventions include safety, efficacy, ease of performance, the feasibility of talking multiple lesions at the same sitting, and the ability to repeat the procedure without any significant morbidity in cases of recurrence.
bark’ appearance, a feature common to many arteritides. Chronic inflammation involves all layers of the vessel wall, extensive periarterial fibrosis, thickening and adhesions result in tough, noncompliant, rigid vessel walls. This may be tough to dilate by balloon angioplasty and may require high-pressure balloon dilatation.
IMAGING FOR INTERVENTIONS IN TAKAYASU ARTERITIS Due to variations in the pattern of arterial involvement, accurate imaging is essential for planning interventional procedure in TA Noninvasive vascular imaging has provided new insights into TA. Color Doppler ultrasound is useful in initial evaluation of arch and renal arteries. Doppler ultrasound can detect carotid stenosis with high sensitivity and specificity (Figure 1). Contrastenhanced computed tomography angiography (CTA) and particularly magnetic resonance angiography (MRA) can demonstrate arterial anatomy, wall enhancement, edema, and thickening, which might enable early disease detection where luminal diameter is still preserved. Angiography is nowadays resorted to when intervention is planned. Its invasive nature, contrast-requirement, and high radiation dose, limit its use.
PATHOPHYSIOLOGY Takayasu’s disease is a granulomatous vasculitis, with an acute period of large vessel vasculitis, followed by chronic phase of fibrosis and scarring. In the acute stage, the adventitial vessels of the arterial walls become inflamed. Though TA is a panarteritis, the initial site of inflammation is around the vasa vasora and at the medioadventitial junction. There is edema and mononuclear cell infiltration (CD4 and CD8 lymphocytes, plasma cells, and macrophages) in the outer thirds of the media and adventitia.1 Rapid or more severe inflammation leads to loss of smooth muscle cells, medial weakening, vascular dilatation, and even aneurysm formation. In the chronic stage, the elastic tissue is replaced by fibrosis, with thickening of all three layers. There is luminal narrowing, often affecting multiple sites. Macroscopically, the intima may be rigid, with a ‘tree
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Figure 1: Doppler ultrasound evaluation in a young girl with severe arch vessel stenosis shows marked thickening of intima causing severe stenosis of carotid artery in Takayasu arteritis
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High-resolution Ultrasound
CT Angiography Computed tomography (CT) is useful to image the vascular lumen and the arterial wall, allowing diagnosis at an early stage, before significant luminal remodeling has occurred. Images are acquired in the early arterial phase following infusion of iodinated contrast medium. Delayed acquisition is needed to assess late contrast enhancement, which has the appearance of a double ring, especially in the venous phase. The hyperplastic intima is seen as inner poorly enhanced rim, while the outer, highly enhanced rim represents vasa vasorum neo-angiogenesis in the actively inflamed media and adventitia. 2 Electrocardiogramgating study is needed to see coronary and pulmonary involvement. The clinical utility of CT angiography (CTA) in diagnosis, assessment of disease extent, and follow-up of TA patients is similar to MR. CT scores over MR in shorter acquisition times and provision of images that are typically more intuitive than MR, with improved anatomical detail. Thus, CTA is particularly useful for preoperative planning in the event that revascularization is required. However, radiation exposure and the use of iodinated contrast medium limit the use of CTA.
Magnetic Resonance Imaging Magnetic resonance (MR) imaging is an important imaging technique for TA because of its ability to evaluate a wide range of vascular territories and lack of radiation exposure, allowing multiple evaluations in young patients. MR-angiography (MRA) requires a relatively short acquisition time and generates images of the arterial lumen. Specific MRA sequences can be used to obtain angiographic images without contrast medium.3 In general, T1-weighted imaging is used to provide anatomical depiction of arterial wall lesions, while T2weighted imaging (to assess wall edema) and contrastenhanced T1-weighted imaging (to assess late contrast enhancement) are used to look for changes suggestive
Angiography Cine angiography and digital subtraction angiography (DSA) is performed when intervention is planned. It provides superior spatial resolution and finer detail of images compared to those acquired by CT or MR; hence, DSA still represents the gold standard for studying the lumen of the affected arteries. Use of biplane or orthogonal views is very important to assess the severity and extent of lesions. Sufficiently long runs to be taken so see the collateral filling in case of total occlusions. In addition to anteroposterior (AP) projection, use of right anterior oblique (RAO) projection is strongly recommended while imaging the right subclavian artery as right subclavianvertebral bifurcation is best seen in this view. Similarly, aortogram in lateral view is must where visceral arterial involvement or dissection is suspected. Angiographic appearance can range from discrete or diffuse long segment stenosis with or without collaterals. Stenotic lesions of aortic branches are often osteal. Angiographic appearance helps in planning the intervention and also for definitive sizing of balloon angioplasty and for deployment of stents. However, important limitations of DSA are its invasive nature and failure to characterize the arterial wall. In addition, patients need hospitalization and there is a low but measurable risk of procedural complications.
CHAPTER
71 Interventions in Takayasu Arteritis (Nonspecific Aortoarteritis)
High-resolution color duplex ultrasound (US) is relatively inexpensive (nonexpensive), well tolerated, can readily distinguish the arterial wall from the lumen, measure intima-media thickness (IMT), and delineate degrees of stenosis or aneurysm. It is very useful for assessment of the carotid and vertebral circulation, proximal subclavian and axillary arteries (Figure 1). In TA, US reveals concentric arterial wall thickening, which may appear bright as a consequence of active arterial wall inflammation and edema. The US may also be used to study the abdominal aorta in TA. Doppler evaluation of renal arteries is very useful in initial evaluation and followup after renal angioplasty.
of active inflammation in the arterial wall. Some authors have suggested that arterial wall thickening and more intense postcontrast enhancement may reflect active disease.3,4 The predominant role for MR in the follow-up of patients with TA is to provide a safe, noninvasive mean of assessing changes in vascular anatomy over time.
INTERVENTIONS IN TAKAYASU ARTERITIS Indications of Endovascular Intervention Depending upon the site of arterial obstruction, Takayasu diseases produce a multiplicity of syndromes. Involvement of the arch with occlusion of stenosis of the brachiocephalic trunks causes the ‘pulseless’ syndrome with a plethora of visual and cerebral manifestation. Abdominal coarctation is usually associated with renal artery stenosis or occlusion. Severe hypertension is usual presentation. Infrarenal aorta stenosis may present with leg claudication. Major indications for endovascular/surgical treatment are: Hypertension from stenotic coarctation of the aorta or renovascular disease End-organ ischemia or peripheral limb ischemia Cerebral ischemia Coronary ischemia 587
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Mesenteric ischemia from occlusion of multiple branches of abdominal aorta Aortic or arterial aneurysms or severe aortic regurgitation. Revascularization should ideally be performed during periods of disease remission. There appears to be a clear benefit by achieving good control of disease activity with the use of immunosuppression both pre- and postoperatively. Intensity and duration of immunosuppressive treatment is determined according to each patient’s clinical condition and disease activity. In patients with increased erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP), we start steroids before endovascular intervention adding methotrexate if the disease activity is not controlled. Immunosuppressive treatment usually needs to be continued for prolonged period, i.e. 2–3 years. Lifelong follow-up is required after surgical or endovascular intervention in TA. This is to monitor any progression of the disease and/ or restenosis. Prompt escalation of immunosuppressant treatment is necessary in patients with increased disease activity. In a study of 25 patients, who underwent 58 endovascular procedures, with or without stenting, only after patients were treated with immunosuppressive therapy, and after the ESR had normalized, there was a 17% restenosis rate over a mean of 23.7 months.5 However, sometimes, the clinical scenario (e.g. intractable syncope, impending loss of vision, resistant severe hypertension) of the patient mandates urgent intervention even before complete control of disease activity. Endovascular interventions, particularly for discrete stenosis, provide good relief with low morbidity and mortality (Table 1). The procedure provides immediate symptomatic relief, high initial and intermediate success rate with lower morbidity and mortality compared to surgery. A large multicenter study from France analyzed the outcome of vascular surgery and endovascular interventions in the management of arterial complications of TA.6 Among the 104 surgical procedures, 39 (37.5%) presented a complication, versus 31 (50%) of the 62 with endovascular repair. Out of the 42 patients, who had endovascular procedure with stenting, 20 (47.6%) experienced a vascular complication. Main complications included restenosis (n = 53, 75.7%), and in a lesser extent thrombosis in 7 (10 %). The most striking conclusions drawn by this study were: (1) the overall 5-year arterial
complication rate was of 44%; and (2) biological inflammation at the time of revascularization increases the likelihood of complications by 7 times. A small single center experience suggested that the use of stent grafts may improve patency rates7 due to deprivation of blood flow to the inner layers of the vessel. The reasons for poor long-term outcomes are: longer lesion length, more fibrotic and noncompliant vessels, and persistence of vessel wall inflammation despite clinical or laboratory evidence of quiescent disease.
Endovascular Interventional Procedure Endovascular intervention in the form of balloon angioplasty with or without stenting may be undertaken if indicated by organ ischemia in patients with anatomy suitable for endovascular intervention. Informed and written consent explaining procedure, especially explaining the need of repeated imaging and reintervention, should be taken from the patient before the procedure. Proper planning and availability of all the hardware that may be required during interventions should be ensured prior to intervention procedure. Appropriate size stent and stent graft should be available to manage any complication. Usually, the procedure is done under local anesthesia and sedatives with continuous ECG, SPO 2, and blood pressure monitoring. Femoral access is the most common, brachial or radial access is used for renal and visceral interventions. Both femoral and brachial access may be required in cases of aortic dissection, thoracic aneurysms, and severe stenosis of aorta. Graded dilatation starting with smaller diameter balloon should be done for severe stenosis. Balloon diameter should not exceed the diameter of adjacent normal segmented artery. When using high pressure dilation for stenosis resistant to dilatation, balloon size for high-pressure dilatation should be less than the diameter of normal segment of artery. High-pressure dilation for resistant lesions increases the success rate of angioplasty; however, it also increases the chance of artery dissection and rupture, which may be catastrophic. Dilatation should stop if the patient complains of severe pain. If stenting is required, then a self-expandable/balloon expandable stent delivery catheter is advanced over the immobilized guide wire. Aggressive postdilation should be avoided and to be done only when residual stenosis is >30%.
Table 1: Angioplasty/stenting in aortoarteritis at GB Pant Hospital, New Delhi, India Vessel treated (POBA/Stenting) No. of patients No. of lesions Aorta 356 387 Renal 236 307 Arch 220 276 Iliac 10 10 Celiac/Mesenteric 11 13 Total 709 963
588
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Abbreviation: POBA, plain old balloon angioplasty
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Table 2: Subclavian artery interventions Study/Author
Complications
Follow-up
Joseph 1994
n = 24 lesions = 26
Technical and clinical success in 81%
No major complication
Mean F/u 26 months Restenosis rate Angioplasty 28.6%
Tyagi 1998
n = 32
Technical and clinical success 92.8% in stenosis and 60% in total occlusion
Complication in 5.4%
Mean F/u 43.3 months Restenosis rate Angioplasty 19%
ARCH ARTERY INTERVENTIONS Loading doses of aspirin 300 mg and Clopidogrel 600 mg is given well before percutaneous intervention for aortic branches. During percutaneous intervention, 5,000 IU IV bolus is given followed by 1000 IU an hour later, then additional heparin to achieve an activated clotting time of 250–350 seconds. Judkins Right guiding catheter 8 F or Shuttle sheath 7 F (Cook) is most commonly used both for selective angiography and angioplasty of aortic arch arteries. Guiding catheter is introduced into the proximal portion of the stenotic artery; the stenosis is initially crossed with a 0.014˝ soft tip coronary guidewire. Monorail balloon of appropriate size is positioned across the stenosis and inflated using diluted contrast. When using over-the-wire balloons or stents, then a 260–300 cm 0.014” coronary guidewire or 018” soft tip peripheral guidewire is used. After balloon angioplasty, if there is flow limiting dissection, then stent needs to be implanted. Balloon expandable stents to be used in aorto-ostial locations and self-expandable nitinol stents are preferred in extrathoracic portion of subclavian/ carotid arteries. After the procedure, dual antiplatelet to be continued for 6 months and then aspirin 75 mg lifelong. Long-term immunosuppressive is also required in most cases to control disease activity.
Subclavian Artery Interventions Subclavian arteries are amongst the most commonly involved vessels in TA. Surgical revascularization involving bypass of the steno-occlusive lesions is not the preferred option due to high mortality (5–8%) and complication rates (up to 23%), comprising of chylothorax, endarterectomy thrombosis, pneumothorax, pleural effusion, neck lymph fistula, phrenic nerve palsy, and Horner’s syndrome. In our experience of 126 cases with long-term follow-up, high inflation pressures were required for dilation of these lesions (9.9 ± 4.6 atm).8 The procedure was successful in 88.8% cases of subclavian artery stenosis and 50% cases with short segment chronic total occlusion (Table 2). Restenosis occurred mostly in patients with diffuse long segment disease, chronic total occlusion, or evidence of disease activity. Use of peripheral cutting balloon angioplasty (Figures 2A to C) is recommended both for restenosis and native lesions as these lesions are highly fibrotic.9
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Due to chronic nature of the disease, good collateral formation is common in TA. Angioplasty for diffuse long segment stenosis or chronic total occlusion in this disease should be attempted only if the patient has severe symptoms as the results in these vessels are often suboptimal and restenosis rate is high (Figure 3). However, short segment chronic total occlusions can be recanalized with the help of hard coronary wires or 035” hydrophilic straight tip Glide wire (Terumo). Retrograde approach through ipsilateral brachial or radial artery can also be used in select cases. Vertebral artery interventions are indicated in cases of severe cerebral ischemia, where carotid arteries are totally occluded or diffusely diseased and vertebral arteries are the sole supply. Since the diameter of vertebral artery matches with coronaries, coronary balloons and stents can be readily used.
Interventions in Takayasu Arteritis (Nonspecific Aortoarteritis)
Balloon angioplasty Results
10
Carotid Interventions Carotid angioplasty is indicated for severe cerebral ischemia leading to recurrent syncope, transient ischemic attacks (TIAs), and visual loss. Usually, multiple arch arteries are involved. The aim of intervention in such cases is to improve cerebral perfusion and provide symptomatic relief.11,12 It is not advisable to target the diffusely diseased or chronic total occlusion in arch vessels because of limited success, higher restenosis, and complication rate. Contrary to subclavian angioplasty, where prolonged balloon inflation is advised, in carotids, the balloon inflation and deflation has to be quick to prevent worsening of cerebral ischemia. Serious complications, such as hyperperfusion, cerebral hemorrhage, and infarct, may also occur after arch artery interventions. Lesions of TA are usually nonthrombotic; hence, use of embolic protection devices is usually not necessary. In patients with multiple arch vessel involvement and severe cerebral ischemia, the blood pressure is often high due to cerebral autoregulation. During angioplasty in such cases, sudden hypotension and bradycardia may be seen after relieving the stenosis, which is treated with intravenous Atropine and Mephentermine. The experience in carotid angioplasty is limited (Table 3, Figures 4 and 5).
Renal Angioplasty The TA is a common cause of renovascular hypertension in children and young adults in Asian countries. Renal lesions
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A
B
C
Figures 2A to C: In-stent restenosis in left subclavian artery (A), treated by cutting balloon (CB) angioplasty (peripheral cutting balloon 6 × 20 mm) (B and C)
Figure 3: Long segment chronic total occlusion of left subclavian and axillary artery with collateralization. Such lesion has very high restenosis rates and should be managed medically
in TA are usually ostial and often bilateral. Revascularization is indicated in uncontrolled hypertension, recurrent heart failure, or acute decompensated heart failure. Surgical revascularization involves use of aortorenal bypass grafts [saphenous vein or polytetrafluoroethylene (PTFE)], direct aortic re-implantation or linorenal shunt. Surgical procedure is made difficult because of extensive perivascular fibrosis and diffuse multifocal disease. Some patients with nonfunctioning kidney may require nephrectomy due to uncontrolled hypertension.17
Renal Angioplasty Procedure
590
The femoral approach is used as a standard, except in patients with caudal angulation or occlusion of infrarenal aorta (Figure 6). Guiding catheter technique is generally preferred and requires a 6 or 7 F sheath with a hemostasis valve or guiding catheter with connections like for percutaneous transluminal coronary angioplasty (PTCA). Selective catheterization of the renal artery is usually performed through the guiding catheter using a steerable 0.014 inch soft tip PTCA guide wire with a flexible tip
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(Figure 7). For dilatation, a monorail balloon catheter is passed over the wire and positioned across the stenosis. Balloon is inflated with a pressure gauge until the neck on the balloon disappears or the patient complains of pain. Antiplatelets and heparin are given as for arch artery interventions. We reported17 our initial results of renal angioplasty in 54 patients with a success rate of 89.3% (Table 4). Restenosis was observed in 13.5% cases. In pediatric age group, restenosis is higher.24 The higher restenosis rate in children was probably because of small diameter of renal vessels, and active phase of disease. We observed that although the disease activity increases the chances of restenosis, not all vessels develop restenosis after angioplasty. In some patients with severe stenosis, hypertension and congestive heart failure, waiting for disease activity to subside, may be risky; and in the intervening period, the artery may become completely occluded so as to preclude any further procedure. Therefore, in case of severe uncontrolled renovascular hypertension and severe renal artery stenosis, the angioplasty procedure may have to be carried out despite evidence of disease activity while the patient is on aggressive immunosuppressive treatment. In most angioplasty series of TA, long segment renal artery stenosis, unable to relive the stenosis completely, length are associated with higher restenosis rates, stent implantation is used only for flow limiting dissection and not reduce restenosis. If high pressure balloon dilatation is not able to completely relive this stenosis, stent implantation will not improve result further. Restenosis is treated by re-intervention preferably by cutting balloon angioplasty with good results. In our center, a total of 236 renal angioplasties were performed in the last two decades with a cumulative success rate of 90% and restenosis was seen in approximately 25% of the cases (Table 5). Stenting of renal artery in TA may have a higher incidence of restenosis than balloon angioplasty. This may be due to reactive fibrosis, intimal thickening, thrombus
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Table 3: Carotid interventions13-16 Balloon angioplasty
Results
Complications
Follow-up
Tyagi 2008
n = 10 lesions = 12
Technical success 100% Symptomatic improvement in 80%
No major complication
Mean F/u 25 months Restenosis rate 20%
Kim 2011
n = 12 lesions = 21
Technical success 91.6% >50% residual stenosis in 1 patient
No major complication
Mean F/u 39 months Restenosis rate Angioplasty 27.2%
Chen 2015
n = 11
Technical success 82%
Complete occlusion of carotid in 2 patients
Mean F/u 31.6 months Restenosis 11.1%
Lou 2017
n = 12 lesions = 14
Technical success 92%
Transient hemiparesis in 1
Mean F/u 40 months Restenosis 33.3%
formation or stent-related exaggeration in intimal tissue proliferation. The diameter of renal artery is smaller than other aortic branches so intimal proliferation may lead to higher restenosis rate.
Aortoplasty Procedure Balloon angioplasty offers a relatively simple, cost effective, and safe method for the relief of discrete stenotic lesions of aorta. Stenosis of aorta is crossed preferably with 0.035”, flexible tip, exchange length guidewire and aortic angiography performed using a pigtail catheter. A flexibletip, 260 cm long exchange guide wire (0.035” in diameter) is passed through the angiography catheter and positioned above the lesion. In each case, 100 U/kg of heparin (maximum = 2,500 U) is given intravenously. With the exchange guidewire kept in position, the angiography catheter is replaced by a deflated, air free, balloon dilatation catheter. The balloon size is selected as 60-100%
A
B
C
71
of the normal aortic segment, but not to exceed three times the constricted segment. Graded dilation (i.e. initial dilatation with a balloon of smaller diameter that was followed by dilatation with a balloon of larger diameter) is used in patients with severe ( 5 hours) deeply comatose patients,
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and patients with advanced features of mesenteric ischemia, gangrene, and sepsis.4,28,29 Even if the patient has got advanced renal failure, or hemiplegia, myocardial ischemia or limb ischemia, dissection repair should take the priority. The chances are that the malperfusion will resolve with proximal dissection repair in majority.29 Postdissection repair, the patient should be re-assessed again for persisting malperfusion. If malperfusion persists, corrective measures are required. The only exception to this rule is advanced mesenteric ischemia with gangrene and sepsis requiring extensive bowel resection.30 Stroke is also not a contraindication for surgery. The risk of hemorrhagic conversion is very small. Sometimes, if the patient undergoes early surgery, there is complete resolution of neurological deficit.29,31 In patients with coma who present early (5.5 cm)
presenting after 48 hours, the patient can be operated on urgent basis before next sunset. Management of acute type B dissection: Optimum medical therapy (OMT), control of blood pressure and pain, constitutes a gold standard in management of Type B dissection.4 Irrespective of clinical stage (acute, subacute, chronic), OMT is the first line of treatment. Intervention, surgery or endovascular, is reserved for complicated or high-risk Type B dissections (Table 2). Nowadays, surgery is rare in cases of complicated acute Type B dissection, and has been replaced largely by endovascular therapy.37,38 Lower extremities artery disease, severe tortuosity of the iliac arteries, a sharp angulation of the aortic arch, and the absence of a proximal landing zone for the stent graft are factors that indicate open surgery for the treatment of acute complicated Type B dissection.4 In the presence of connective tissue disorder, surgery is preferred over endovascular repair by majority.
Subacute and Chronic Dissection Subacute and chronic type A dissection: The presence of dissection in intrapericardial aorta, irrespective of clinical stage (subacute, chronic) is an indication for surgical intervention. However, in the absence of complications (aneurysmal dilatation, aortic regurgitation, malperfusion, and pericardial tamponade), surgery can be planned electively. In the elderly patients (>80 years) with comorbidities, the risk of surgery should be balanced against the risk of complications. Subacute and chronic type B dissection: The indications and choice for intervention in subacute Type B dissection is similar to that of acute Type B dissection. There is growing evidence for beneficial effect of endovascular repair in uncomplicated subacute Type B dissection. 39 However, open surgical repair is not considered for prophylactic intervention. Optimal medical therapy is the first line of management for uncomplicated chronic Type B dissection. A complicated chronic Type B dissection may present with aneurysmal dilatation (>55 mm in diameter), rapid expansion (>10 mm/year), malperfusion, or resistant
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Intramural Hematoma Intramural hematoma (IMH) is defined as a hematoma within the medial layer of the aortic wall without detectable intimal injury. Acute IMH accounts for 5–20% of all acute aortic syndromes, 40 and is considered a precursor of dissection. The current belief is that a majority of radiographicallyappearing IMH are, in fact, acute dissection with undetected intimal tears and thrombosis of the false lumen.14,41-43 The IMH may progress, dissect, regress, or resorb,44-49 with regression in 10%, progression to classic aortic dissection in 28–47%, and a risk of rupture in 20– 45%.40 Similar to dissection, depending upon involvement of intrapericardial aorta, IMH is also classified into Type A and Type B. Several series have shown that 30–40% Type A IMH evolved into frank dissection and mortality of Type A IMH was similar to Type A aortic dissection. 4 Predictors of IMH complications in acute phase include persistent and recurrent pain despite aggressive medical treatment, difficult blood pressure control, ascending aortic involvement, maximum aortic diameter ≥50 mm, progressive maximum aortic wall thickness (>11 mm), enlarging aortic diameter, recurrent pleural effusion, penetrating ulcer or ulcer-like projection secondary to localized dissections in the involved segment, and the presence of organ ischemia (brain, myocardium, bowels, kidneys).4,40,43,44 Similar to Type A and B aortic dissection, surgery is advocated for acute IMH of the ascending aorta and aggressive medical therapy for IMH in the descending aorta.4,44,45-48 In the elderly patients or those with significant comorbidities, ‘wait-and-watch strategy’ (optimal medical therapy and repetitive imaging) may be considered, particularly in the absence of aortic dilation (10 mm represent a higher risk for disease progression and may be candidates for early intervention.4,40 Treatment is based on anatomical features, clinical presentation, and comorbidities. In descending thoracic aorta, endovascular stent grafting is emerging as preferred therapeutic modality. 40,50,54,55 Graft replacement of the ascending aorta is the standard treatment of a PAU of the ascending aorta. Transverse arch PAUs can be managed by open graft replacement or endovascular techniques.
TRAUMATIC AORTIC INJURY
604
Blunt aortic injury occurs in less than 1% of motor vehicle crashes but is responsible for 16% of the deaths. This injury is second only to head injury as the leading cause of death after road traffic accident. About 80% of patients die before their arrival at a hospital. Of those who survive the initial injury, a majority will die without definitive treatment. Blunt aortic injury most often occurs after sudden deceleration, usually in automobile crashes. The descending aorta is fixed to the chest wall, whereas the heart and great vessels are relatively mobile. Traditional views have held that sudden deceleration causes a tear at the junction between the fixed and mobile portions of the aorta, usually near the isthmus. Based on imaging, TAIs were classified into grade 1–4 in severity. These included: grade 1, intimal tear; grade 2, intramural hematoma; grade 3, aortic pseudoaneurysm; and grade 4, free rupture. When intimal flap is less than 10 mm in length without any accompanying periaortic
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Table 4: Indications for delayed surgical intervention in traumatic aortic injuries S. no.
Indication
1.
Late presenters
2.
Prohibitive risk of heparinization
3.
Severe hemodynamic instability from concomitant injuries (liver, pelvis)
4.
Comatose patient
5.
Coagulopathy
6.
Sepsis
7.
Grossly contaminated wounds
hematoma, TAI is also designated as ‘minimal aortic injury’. Grade 1 or minimal traumatic aortic injury (TAI) is managed conservatively. Grade 2 and 3 need urgent intervention after taking care of other concomitant injuries. Grade 4 TAI demand urgent intervention. If the expertise and adequate sized stent graft are available, endovascular repair is the first option. When endovascular option is not available, urgent open surgical repair should be considered. A delayed surgical intervention, in the same admission, is also a suitable option in selected patients (Table 4).
ARTERITIS Lesions in arteritis are stenotic in the majority. Less commonly, the arteries become aneurysmal. Treatment is mainly based on the clinical symptomatology, complications, and the possible immunologic basis of the disease. The goals of therapy include: (i) control of clinical activity by pharmacologic treatment with steroids and/ or immunosuppressive therapy, (ii) restoration of blood flow to the stenosed vessel by surgical or endovascular techniques, (iii) management of aneurysmal disease, (iv) correction of aortic regurgitation, if any, (v) pharmacologic control of blood pressure, and (v) supportive management. In the chronic stages of arteritis, one of the principles of treatment is revascularization of the affected organs either by surgery or endovascular interventions, including percutaneous transluminal angioplasty (PTA), stent and stent graft replacement. The success rate and outcome of endovascular interventions depend upon the site, length, and stage of the arterial stenosis. Though satisfactory results are obtained in lesions involving thoracic aorta, infra-renal aorta, and renal artery, the outcomes of endovascular interventions in the supra-aortic branches are less rewarding. Due to the presence of diffuse lesions and increased wall thickening, the stenosis in the carotid and subclavian arteries responds less well to balloon angioplasty. In aortic involvement, patients with short segment (4 cm long) stenosis. Eccentricity of the stenosis, presence of diffuse adjacent disease, location of the stenosis in juxtadiaphragmatic
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10.
11.
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72 Aortic Diseases: When to Proceed with Surgery?
segment of the aorta, and presence of calcification adversely affect the outcome of PTA. All lesions are not amenable to PTA . Surgical procedures are required for total aortic occlusion, severe aortic incompetence, critical central nervous system ischemia, coronary ischemia, aneurysmal dilatation, ostial lesions, tight stenosis, extensive renal segmental artery involvement, and, occasionally, in case of failure of angioplasty.
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26. Eagle KA, DeSanctis RW. Aortic dissection. Curr Probl Cardiol. 1989;14(5):225-78. 27. Fann JI, Miller DC. Aortic dissection. Ann Vasc Surg. 1995;9(3):311-23. 28. Tsai TT, Nienaber CA, Eagle KA. Acute aortic syndromes. Circulation. 2005;112(24):3802-13. 29. Bonser RS, Ranasinghe AM, Loubani M, et al. Evidence, lack of evidence, controversy, and debate in the provision and performance of the surgery of acute type A aortic dissection. J Am Coll Cardiol. 2011;58(24):2455-74. 30. Girdauskas E, Kuntze T, Borger MA, et al. Surgical risk of preoperative malperfusion in acute type A aortic dissection. J Thorac Cardiovasc Surg. 2009;138(6):1363-9. 31. Estrera AL, Garami Z, Miller CC, et al. J Thorac Cardiovasc Surg. 2006;132(6):1404-8. 32. Pocar M, Passolunghi D, Moneta A, et al. Coma might not preclude emergency operation in acute aortic dissection. Ann Thorac Surg. 2006;81(4):1348-51. 33. Fujii H. Is coma an absolute contraindication for emergency central aortic operation? J Thorac Cardiovasc Surg. 2004;128(5):749-50. 34. Song JK, Kim HS, Kang DH, et al. Different clinical features of aortic intramural hematoma versus dissection involving the ascending aorta. J Am Coll Cardiol. 2001;37(6):1604-10. 35. Iss elbacher EM, Cigar roa JE, Eagle K A . Cardiac tamponade complicating proximal aortic dissection. Is pericardiocentesis harmful? Circulation. 1994;90(5):2375-8. 36. Kaji S, Nishigami K, Akasaka T, et al. Prediction of progression or regression of type A aortic intramural hematoma by computed tomography. Circulation. 1999; 100:281-6. 37. Grabenwoger M, Alfonso F, Bachet J, et al. Thoracic Endovascular Aortic Repair (TEVAR) for the treatment of aortic diseases: a position statement from the European Association for Cardio-Thoracic Surgery (EACTS) and the European Society of Cardiology (ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2012;33(13):1558-63. 38. Fattori R, Tsai TT, Myrmel T, et al. Complicated acute type B dissection: is surgery still the best option? A report from the International Registry of Acute Aortic Dissection. JACC Cardiovasc Interv. 2008;1(4):395-402. 39. Nienaber CA, Kische S, Rousseau H, et al. Endovascular repair of type B aortic dissection: long-term results of the randomized investigation of stent grafts in aortic dissection trial. Circ Cardiovasc Interv. 2013;6(4):407-16. 40. Ganaha F, Miller DC, Sugimoto K, et al. Prognosis of aortic intramural hematoma with and without penetrating atherosclerotic ulcer: a clinical and radiological analysis. Circulation. 2002;106(3):342-8.
41. Uchida K, Imoto K, Karube N, et al. Intramural haematoma should be referred to as thrombosed-type aortic dissection. Eur J Cardiothorac Surg. 2013;44(2):366-9. 42. Park KH, Lim C, Choi JH, et al. Prevalence of aortic intimal defect in surgically treated acute type A intramural hematoma. Ann Thorac Surg. 2008;86(5):1494-500. 43. Kitai T, Kaji S, Yamamuro A, et al. Detection of intimal defect by 64-row multidetector computed tomography in patients with acute aortic intramural hematoma. Circulation. 2011;124(11):S174-8. 44. von Kodolitsch Y, Csosz SK, Koschyk DH, et al. Intramural hematoma of the aorta: predictors of progression to dissection and rupture. Circulation. 2003;107(8):1158-63. 45. Moizumi Y, Komatsu T, Motoyoshi N, et al. Clinical features and long-term outcome of type A and type B intramural hematoma of the aorta. J Thorac Cardiovasc Surg. 2004;127(2):421-7. 46. Evangelista A, Mukherjee D, Mehta RH, et al. Acute intramural hematoma of the aorta: a mystery in evolution. Circulation. 2005;111(8):1063-70. 47. Chirillo F, Salvador L, Bacchion F, et al. Clinical and anatomical characteristics of subtle-discrete dissection of the ascending aorta. Am J Cardiol. 2007;100(8):1314-9. 48. Nienaber CA, Richartz BM, Rehders T, et al. Aortic intramural haematoma: natural history and predictive factors for complications. Heart. 2004;90(4):372-4. 49. Nienaber CA, Powell JT. Management of acute aortic syndromes. Eur Heart J. 2012;33(1):26-35. 50. Eggebrecht H, Plicht B, Kahlert P, et al. Intramural hematoma and penetrating ulcers: indications to endovascular treatment. Eur J Vasc Endovasc Surg. 2009;38(6):659-65. 51. Coady MA, Rizzo JA, Hammond GL, et al. Penetrating ulcer of the thoracic aorta: what is it? How do we recognize it? How do we manage it? J Vasc Surg. 1998;27(6):1006-15. 52. Cho KR, Stanson AW, Potter DD, et al. Penetrating atherosclerotic ulcer of the descending thoracic aorta and arch. J Thorac Cardiovasc Surg. 2004;127(5):1393-9. 53. Nathan DP, Boonn W, Lai E, et al. Presentation, complications, and natural history of penetrating atherosclerotic ulcer disease. J Vasc Surg. 2012;55:10-5. 54. Eggebrecht H, Herold U, Schmermund A, et al. Endovascular stent-graft treatment of penetrating aortic ulcer: results over a median follow-up of 27 months. Am Heart J. 2006;151(2):530-6. 55. Botta L, Buttazzi K, Russo V, et al. Endovascular repair for penetrating atherosclerotic ulcers of the descending thoracic aorta: early and mid-term results. Ann Thorac Surg. 2008;85(3):987-92.
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Aortic Diseases: When and How to Proceed for Interventional CHAPTER 73 Management? Mumun Sinha, Sanjiv Sharma
INTRODUCTION The aorta is composed of different segments, namely the aortic root, ascending aorta, arch, descending thoracic and abdominal aorta. Each of these segments is affected by a variety of disease pathologies which may be congenital, traumatic, inflammatory, neoplastic or atherosclerotic in etiology. In addition, certain disease pathologies have a predilection or affinity for specific aortic segments (Table 1). Symptomatically, there is a wide spectrum of clinical presentation across the various disease states ranging from clinically asymptomatic and detected as incidental finding, to acutely life-threatening clinical manifestations. With regards to the temporal sequence of events, the disease states may have a hyperacute (2.2 m/sec
Right atrial area (end-systole) >18 cm2
PA diameter >25 mm. Abbreviation: ESC, European Society of Cardiology
patients of group 1 PH unless contraindicated. Agents used for acute vasodilator testing include inhaled nitric oxide (NO), intravenous (IV) epoprostenol and IV adenosine. An acute response is defined as a decrease in mean PAP by at least 10 mm Hg to an absolute value lower than 40 mm Hg in the absence of decreased cardiac output. Calciumchannel blockers are found to be very effective in patients who show a robust response to acute vasodilator testing. The RHC is also helpful in differentiating patients who have PH due to left heart disease (group 2 - systolic dysfunction, diastolic dysfunction, or valvular heart disease). This group is defined as postcapillary PH on the basis of hemodynamics (Figure 3). It is characterized by mean PAP ≥25 mm Hg and pulmonary capillary wedge pressure (PCWP) of >15 mm Hg. Rest of the PH groups (1, 3, 4, and 5) are included in precapillary group in which PCWP is ≤15 mm Hg. Although chronic thromboembolic pulmonary hypertension (CTEPH) can be diagnosed by CT pulmonary angiography and ventilation/perfusion lung scan (V/Q scan), presurgical work-up of CTEPH requires RHC and traditional pulmonary angiography in most of the patients.
CT Scan Chest CT is invaluable noninvasive imaging modality which is gaining importance as one of the frontline test for evaluation of PH. It provides multifold benefits in evaluation of PH in the form of: Assessment of cause of PH Allows comprehensive evaluation of pulmonary vasculature and lung parenchyma Additional evaluation of cardiovascular changes for assessment of disease severity. The CT signs suggestive of PH include pulmonary artery dilatation (PA diameter ≥29 mm) and pulmonary ascending aorta diameter ratio (≥1.0). A segmental artery bronchus ratio >1:1 in three or four lobes is highly specific for PH. It is the best method for evaluation of PH due to lung parenchymal diseases (group 3). Diseases that involve pulmonary microvasculature, such as pulmonary venoocclusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) (group 1); and miscellaneous causes, such as sarcoidosis, hematological disorders,
75 Evaluation of Pulmonary Hypertension: A Simplified Algorithm
A: The ventricles
CHAPTER
Table 4: Grading of pulmonary hypertension based on pulmonary artery pressures Severity of PH
PASP (mm Hg)
Mean PAP (mm Hg)
Mild
30–49
25–34
Moderate
50–70
35–49
Severe
>70
>50
Abbreviations: PH, pulmonary hypertension; PASP, pulmonary artery systolic pressure; PAP, pulmonary artery pressure
Table 5: Echocardiographic probability of pulmonary hyperten-sion in symptomatic patients with a suspicion of pulmonary hypertension (ESC guidelines 2015) Peak tricuspid regurgitation velocity (m/s)
Echocardiographic probability of pulmonary hypertension
≤2.8 or not measurable
No
Low
≤2.8 or not measurable
Yes
Intermediate
2.9–3.4
No
2.9–3.4
Yes
>3.4
Not required
Abbreviation: PH, pulmonary hypertension
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Presence of other echo ‘PH signs
High
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Table 6: Indications of right heart catheterization in pulmonary hypertension
9 Vascular System
Indications z
To confirm the diagnosis of pulmonary arterial hypertension and for treatment decisions
z
Vasodilator testing should be performed in all patients of pulmonary hypertension (group 1)
z
To assess the treatment effect of drugs in pulmonary arterial hypertension (group 1) and follow up
z
RHC is recommended in patients with congenital cardiac shunts to look for operability
z
z
RHC is helpful when PH is suspected due to left heart disease (post capillary hypertension). It reliably differentiates postcapillary hypertension from precapillary hypertension RHC is indicated in patients with CTEPH (group 4) for diagnosis and treatment purpose
Abbreviations: RHC, right heart catheterization; CTEPH, chronic thromboembolic pulmonary hypertension
neoplastic obstruction, and Langerhans cell histiocytosis (LCH) (group 5), are easily diagnosed with chest CT. The contrast-enhanced computed tomography (CECT) performed with multiple detector computed tomography (MDCT) scanners is the reference standard for diagnosis of CTEPH as already discussed.
Ventilation/Perfusion Lung Scan The V/Q scan is useful in the patient with suspected CTEPH. It has a higher sensitivity as compared to CT pulmonary angiography. A normal or low probability V/Q scan effectively rules out CTEPH. However, CT scan is the preferred modality now since it is easily available in most of the centers. Single photon emission CT could be better modality than V/Q scan and CT pulmonary angiography; however, more studies are needed to prove its superiority.
Exercise Testing and 6-minute Walk Test
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Exercise tests have predictive abilities for both diagnosis and prognosis. Evaluation of exercise capacity is recommended in the recent guidelines for the assessment of PH. The recommendations have relied on 6-minute walk test (6MWT) distance (6MWD) and particular key variables obtained from cardiopulmonary exercise testing (CPET). Whilst less frequently used than the 6MWT to assess functional capacity, CPET remains the gold standard for assessing cardiorespiratory fitness and is part of various PH specialty centers. However, CPET is not easily available. The 6MWT is an important test to quantify functional capacity. It is a useful prognostic indicator in all major trials of PH. A lower 6MWT test is associated with poor prognosis The subject is instructed to walk as far as possible in six minutes in a 30-meter walkway or corridor. Oxygen saturation, breathlessness, and heart rate are measured before, during, and at the completion of the 6MWT. Rest is permissible and if walking aids are used, it is noted in the report. The 6MWT has been found to be reliable, with intraclass correlation coefficient values ranging between 0.72 and 0.99. The outcome of the test is expressed in total distance covered.
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In the randomized SERAPHIN trial, patients with a 6MWD >400 m versus ≤400 m at month 6 had a reduced risk of PAH-related death or hospitalization (hazard ratio 0.48; 95% confidence interval 0.33-0.69). Exercise testing is helpful in the following ways: Patients who have moderate-to-high probability of PH and normal pulmonary artery pressure at rest should be subjected to exercise to look for exercise induced PH. To define the World Health Organization (WHO) functional class on which treatment algorithm is based. Deterioration or improvement exercise in capacity on follow-up further guides changes in treatment therapy. To rule out other alternative diagnosis.
Overnight Oxymetry and Polysomnography Overnight oxymetry can recognize patients who develop significant nocturnal desaturation. Such patients require supplemental oxygen therapy during sleep. Formal polysomnography is indicated for sleep-related breathing disorder (obstructive sleep apnea).
Pulmonary Function Test Role of pulmonary function test (PFT) in evaluation of PH is limited. The PFT are done when significant pulmonary disease (restrictive or obstructive) is suspected. However, PH has a variable association with the degree of lung damage as assessed radiologically and by lung function. The PH is usually seen in more advanced chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Moreover, mild-to-moderate abnormalities in PFT may be seen in group 1 PH and other groups since many patients of PH have mild-to-moderate reduction in various PFT parameters. Thus, PFT offers little help in differentiating various groups of PH unless grossly abnormal.
Additional Investigations Additional blood tests are indicated when a specific etiology of PH is suspected. Routine hematology and
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75
thyroid function test should be performed in all the patients. Various investigations include: Liver function test (LFT) when portopulmonary hypertension is suspected. However, LFT may be abnormal due to advanced disease because of hepatic congestion, cardiac cirrhosis, or use of endothelin receptor antagonist. Serological testing for connective tissue disorders [such as antinuclear antibody (ANA)], viral hepatitis, and human immunodeficiency virus (HIV). Laboratory studies for hemolytic anemia. Thrombophilia screening for CTEPH such as antiphospholipid antibodies, anticardiolipin antibodies, and lupus anticoagulant. N-terminal pro-brain natriuretic peptide (NT-proBNP)/BNP may be elevated in both left and right heart failure. Thus, it does not have any diagnostic value. However, raised NT-pro-BNP/BNP is an indicator of poor prognosis.
CONCLUSION Diagnosing PH in timely manner offers a significant challenge to clinicians. A high index of suspicion is always required. Out of various diagnostic modalities appropriate investigations is based on clinical profile of the patient and echocardiographic findings. The CT chest is quite useful while evaluating using
parenchyma and vasculature (group 3 and group 4). The RHC remains gold standard for evaluation. It should be performed, whenever indicated since risk of RHC is minimal. Role of basic investigations, such as PFT, oxymetry, and polysomnography, is equally important. Hence, a step-wise systematic approach is advisable.
SUGGESTED READING 1. Bossone E, D’Andrea A, D’Alto M, et al. Echocardiography in pulmonary arterial hypertension: from diagnosis to prognosis. J Am Soc Echocardiogr. 2013;26(1):1–14. 2. Dunlop B, Weyer G. Pulmonary Hypertension: Diagnosis and Treatment. Am Fam Physician. 2016;94(6):463-9. 3. Farber HW, Gibbs S. Under pressure: pulmonar y hypertension associated with left heart disease. Eur Respir Rev. 2015;24(138):665-73. 4. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119. 5. Grignola JC. Hemodynamic assessment of pulmonary hypertension. World J Cardiol. 2011;3(1):10-7.
Evaluation of Pulmonary Hypertension: A Simplified Algorithm
Figure 3: Differentiation of pulmonary hypertension due to left heart disease from other groups
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Recent Advances in the Management of Idiopathic CHAPTER 76 Pulmonary Artery Hypertension Rajesh Kalyankar, BKS Sastry
INTRODUCTION Idiopathic pulmonary hypertension (PAH) is a rare disease with poor prognosis. Though there have been advances in pharmacotherapy in the last few years, the prognosis for this condition remains poor with estimated 5-year survival of about 7–8 years at present. Patients in India are further disadvantaged due to the fact that some of the proven medications are not available and are very expensive to import. When the patient continues to be in functional class IV despite maximum medical therapy, the only viable option available is heart-lung transplantation. It is prohibitively expensive with uncertain outcomes in Indian scenario. In this chapter, we will review some of the recent advances in the management of idiopathic PAH.
PHARMACOTHERAPY Most important mechanism for development of PAH is endothelial dysfunction and/or injury, which leads to imbalance in production of endogenous vasodilators (prostacyclin & nitric oxide) and vasoconstrictors (endothelin & serotonin). Current pharmacotherapy (selective pulmonary vasodilators) mainly involves working on these molecular pathways involved in the maintenance of pulmonary vascular tone. These drugs basically decrease the pulmonary artery muscle tone thereby decreasing the resistance and pressure. The basic pathogenic hall mark of endothelial and smooth muscle proliferation is not targeted. Hence, in spite of the socalled targeted therapy, the progression of underlying disease is relentless. The three molecular pathways that are involved include nitric oxide pathway, prostaglandin pathway, and endothelin pathway. The existing drugs for nitric oxide pathway include inhaled nitric oxide or phosphodiesterase-5 (PDE-5) inhibitors, sildenafil, and tadalafil. Riociguat is a new drug in this pathway. The existing drugs in prostaglandin pathway include intravenous epoprostenol, inhaled iloprost, and treprostinil that can administered through oral, subcutaneous or intravenous routes. Oral treprostinil and selexipag are the recent additions in this pathway. Bosetan and ambrisentan are endothelin receptor antagonists (ERA) that have been
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available for years and macitentan is the new addition. Sildenafil, tadalafil, bosentan, and ambrisentan have been available in India for many years. Macitentan and riociguat are recently introduced in India.
COMBINATION THERAPY It has been a common practice to introduce targeted therapy sequentially as per the clinical response. The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial has shown that upfront combination therapy with ambrisentan and tadalafil is superior to sequential administration. Upfront combination therapy is advised to patients especially those who present with severe symptoms or advanced disease.1
ORAL ANTICOAGULANTS Small retrospective studies but not randomized controlled trials have shown the benefit of oral anticoagulants in PAH patients. In two large contemporary registries, the question has been addressed. In a European PAH registry, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), oral anticoagulants have shown survival benefit in patients with idiopathic PAH but not in other forms of PAH. In contrast, the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) from the USA did not show any survival advantage with oral anticoagulants and was actually harmful in patients with systemic sclerosis-associated PAH.2,3
Riociguat Riociguat is a soluble guanylate cyclase (sGC) stimulator. The sGC converts guanosine triphosphate (GTP) to cyclic guanylate monophosphate (cGMP) which causes vasodilatation and decreases smooth cell proliferation. Administration of riociguat leads to increased production of cGMP and pulmonary vasodilatation. In the pivotal phase 3 study, Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1), the maximum tolerated dose of riociguat (0.5–2.5 mg)
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Macitentan Macitentan is an endothelial receptor antagonist. Unlike ambrisentan, macitentan is a dual endothelin receptor antagonist working on both ETA and ET B receptors. It has increased affinity for receptors with long-lasting occupancy. In preclinical studies, it has shown better efficacy compared to other ERA. Unlike bosentan, it does not interact with bile salt export pump and does not cause any hepatotoxicity. It was evaluated in a global event-driven outcome randomized controlled trial, Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN), the primary end point of which was time to clinical worsening. It was a novel end point for a clinical trial in PAH. All earlier drug trials in PAH utilized change in 6MWD over a short period ranging from 12 to 16 weeks. The study was conducted in patients with Group 1 pulmonary hypertension (PH). Patients could be drug naïve, or using background therapy with PDE-5 inhibitors or inhaled or oral prostanoids. They should not be using other ERAs. Macitentan 3 mg or 10 mg once a day dose was compared with placebo in 1:1:1 ratio. The study was done in 742 patients with median treatment duration of 115 weeks. Over the study period, patients receiving macitentan had a 45% relative risk reduction in morbidity and mortality events. There was significant improvement in functional class, 6MWD and quality of life. Drug was well tolerated. Unlike bosentan, there was no signal for hepatotoxicity; and unlike ambrisentan, there was no incidence of pedal edema. Nasopharyngitis is a common side effect and occasionally anemia may be seen. From the available evidence, it cannot be commented whether the drug is superior to bosentan or ambrsentan since headto-head comparative studies are not done. However, the major advantage of this drug seems to be the absence of
significant side effects and proven efficacy in preventing morbidity and mortality events.6
Selexipag Selexipag is a prostacyclin receptor agonist that can be administered orally. Structurally, it is different from other prostanoids used in the treatment of PAH. It decreases PVR and increases cardiac output. In an event-driven phase-3 clinical trial, the Prostacyclin (PGI2) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON), it was studied in 1,156 patients. Selexipag was given at a maximum tolerated dose (beyond which patients will have intolerable prostaglandin-related side effects) ranging from 200 to 1,600 mg twice a day. Patients were permitted to take background medication ERA or PDE-5 inhibitors but not prostanoids. The primary end point is morbidity and mortality composite end point. There was a significant 40% reduction in the primary end point. Selexipag is consistently effective at each maximally tolerated dose, which means a maximum tolerated dose of 200 mg twice a day is as effective as maximum tolerated dose of 1,600 mg twice a day.7 It is important to up titrate the dose to maximum tolerated dose. Prostaglandinrelated side effects are dose dependent and include headache, diarrhea, nausea, jaw pain, flushing, myalgia, arthralgia, and extremity pain. However, over a period of time, the severity of the side effects decreased and the drug became more tolerable. It is noteworthy that selexipag was beneficial over and above the background therapy with ERA and PDE-5 inhibitors.
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76 Recent Advances in the Management of Idiopathic Pulmonary Artery Hypertension
thrice a day was compared to placebo in group 1 PAH patients. 4 Patients could be drug naïve or could be taking background ERA or prostaglandins excluding intravenous prostanoids). Patients taking PDE-5 inhibitors are excluded. It is a 12-week study and change in sixminute walk distance (6MWD) was the primary end point. At the end of 12 weeks, there was a 30-meter increase in riociguat arm compared to 6-meter decrease in placebo arm which is statistically significant. There was significant improvement in other parameters such as pulmonary vascular resistance (PVR), N-terminal pro-b-type natriuretic peptide (NT-proBNP) levels, and functional class. The drug was well tolerated without any major side effects. The benefit was noted irrespective of the background therapy. Riociguat is the only drug that was shown to be beneficial in the management of chronic thromboembolic pulmonary hypertension.5 It has been approved by the US Food and Drug Administration (FDA).
Treprostinil Oral trepostinil is being developed by United Therapeutics which had successfully developed injectable treprostinil that can be administered subcutaneous or intravenous route. However, until today, oral treprostinil is not a very successful drug in PAH treatment. Oral treprostil is less effective and poorly tolerated due to its side effects. In short-term clinical trials, it has improved 6MWD in drug naïve patients but has no significant effect on 6MWD in patients who have been taking ERAs or PDE-5 inhibitors.8,9 A large multicenter trial is underway that has a combined morbidity and mortality end point. Results are expected soon and its exact role can be defined. However, like selexipag, exact dosing for each patient will be a challenge in clinical practice.
Ranolazine Right ventricular (RV) systolic function is an important prognostic determinant of survival in PAH. Ranolazine is a metabolic modulator that improves systolic function. In short-term studies, administration of ranolazine to patients with RV dysfunction, due to PAH, led to 631
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Vascular System
9
improvement in RV systolic function indices such as tricuspid annular plane systolic excursion (TAPSE), RV free wall longitudinal strain, and fractional area change. Its role in improving clinical outcomes, if any, is not known.10
Spironolactone Activation of endothelial cell ETA receptors on pulmonary artery endothelial cells is associated with pulmonary vasodilatation. Hyperaldosteronism as seen in PAH results in increased oxidative stress which in turn results in inhibition of ETA receptors. Spironolactone, an aldosterone antagonist, decreases the inhibitory effect of oxidative stress thus enhancing vasodilatation. In a short-term clinical trial, combination of spironolactone to ambrisentan led to more decrease in brain natriuretic peptide (BNP) concentrations and more increase in 6MWD compared to treatment with ambrisentan alone.11
Imatinib Imatinib inhibits platelet-derived growth factor receptors, a tyrosine kinase, that is strongly upregulated in small pulmonary arteries leading to pulmonary vascular remodeling and subsequently pulmonary hypertension. In a small randomized, double blind, placebo-controlled trial, Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), 202 patients with PVR ≥ 800 Dynes sec cm–5 symptomatic on more than 2 PAH therapies were randomized to imatinib vs. placebo and followed up for 24 weeks. Imatinib showed improvement in exercise capacity and hemodynamics, but serious adverse events and drug discontinuations were limitations of the study. 12 There could be an occasional patient who would respond to imatinib. It is not recommended for routine use but can be tried in a rare patient who is worsening and has no other treatment option. Close monitoring for efficacy and side effects is warranted. Patients should not receive concomitant anticoagulants as there is increased incidence of subdural hematomas with this combination.
STEM CELL THERAPY Many clinical trials are going on in animal models; but, to date, there is only one small published study in seven patients. There was some improvement in 6MWD but not in hemodynamic parameters. There is no proven clinical efficacy.13
PULMONARY ARTERY DENERVATION C h e n e t a l . h av e d e s c r i b e d p u l m o n a r y a r t e r y denervation therapy in patients with PAH. 14 They have done radiofrequency ablation similar to renal artery denervation at pulmonary artery bifurcation, at the ostia of right and left pulmonary arteries. The procedure
was done in 13 patients and 8 patients who refused the procedure served as controls. They reported sustained clinical and hemodynamic benefit and improvement in 6MWD. Interestingly, there are no other publications on this treatment modality.
POTTS SHUNT Potts shunt is creation of anastomosis between left pulmonary artery and descending thoracic aorta. It can be done by surgery, transcatheter route or by stenting a probe patent PDA.15,16 Conceptually, it works when the patient has suprasystemic PA pressures. By shunting into lower pressure aorta from PA with suprasystemic pressures, RV afterload is decreased. In balloon atrial septostomy, there is shunting of desaturated blood at atrial level and coronary and cerebral circulations get hypoxic blood; while in Potts shunt, desaturated blood is shunted to lower body. Multiple publications have reported good midterm clinical benefits and probable survival advantage.17-19 This can be considered in patients who are not candidates for heart-lung transplantation. Surgical correction is easier in childhood. In adults, the surgery can be challenging due to the fact that the distance between pulmonary artery and aorta increases. Transcatheter Potts shunt is technically challenging and only a few cases are reported till date. These procedures, both surgery and transcatheter route, carry high mortality and there is steep learning curve. In patients with subsystemic PA pressures, a valved conduit may be used to direct right-to-left shunting and prevent left-to-right shunt.20 Its role in patients with subsystemic PAH needs to be established. Theoretically, it is possible that even in patients with subsystemic PA pressures, there can be intermittent right-to-left shunt depending upon relative pulmonary and systemic vascular resistance. Further, measured PA pressures reflect both the pulmonary vascular resistance as well as the right ventricle systolic function. Failing right ventricle may not be able to generate suprasystemic pressures, even in the presence of very high pulmonary vascular resistance. In such situations, Potts shunt may still shunt right to left in the presence of what appears to be subsystemic PA pressure. This therapy should be developed further in countries like India, where heart-lung transplantation is prohibitive.
EXPERIMENTAL THERAPIES There are many molecules that are shown to be effective in rat model of PAH but not in human beings. There are many promising new treatment targets currently in experimental stages.21 Some of the drugs being evaluated are listed below: Nuclear factor eryrythroid 2–related factor 2 (Nrf2) activator and Nuclear Factor Kappa B (NFkB) suppressor: Bardoxolone methyl.
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Nuclear Factor Erythroid 2–related Factor 2 (Nrf2) Activator and Nuclear Factor Kappa B (Nfkb) Suppressor Bardoxolone methyl is an oral, once-daily antioxidant inflammation modulator. It activates Nrf2, a protein that induces molecular pathways that protect against oxidative damage due to inflammation and injury. A Dose-Ranging Study of the Efficacy and Safety of Bardoxolone Methyl in Patients with Pulmonary Hypertension (LARIAT) is an ongoing phase 2 study examining safety, tolerability, and efficacy of bardoxolone methyl for the treatment of patients with pulmonary hypertension.22
BMP Signaling Activator: FK 506 (Tacrolimus) Dysfunctional BMP signaling is a general feature of PAH and tacrolimus, an inhibitor of nuclear factor of activated T-cells (NFAT) family, was reported to reverse severe PH in the hypoxia model by restoring bone morphogenetic protein receptor type 2 (BMPR2) signaling. Tacrolimus has been studied in the single center randomized controlled phase 2 safety and efficacy trial, FK506 (Tacrolimus) in Pulmonary Arterial Hypertension (TransformPAH). Early experience with compassionate use in end-stage patient appears promising but further clinical trials are warranted.23
Inflammatory Pathway Tocilizumab, an anti-IL-6 monoclonal antibody is being studied in an open label phase 2 study, TRANSFORM-UK, to assess the safety and efficacy of the drug in WHO group 1 PAH with WHO functional class 2 to 4. Final results of the study are awaited.24
Glutamine-NMDA Receptor Axis Glutamine-NMDA (N-Methyl-D-aspartate) receptor axis is dysregulated in PAH. Vascular NMDA receptors could be potential targets for antiremodeling in PAH.25
CONCLUSION Treatment of PAH (Group 1 of PH diseases) continue to be frustrating. While the recent drug discoveries have made a significant change in patients’ outcome, a lot more needs to be done.
REFERENCES
CHAPTER
1. Hoeper MM, McLaughlin VV, Barberá JA, et al. Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study. Lancet Respir Med. 2016;4(11):894-01. 2. Hoeper MM, Huscher D, Ghofrani HA, et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. International journal of cardiology. 2013;168(2):871-80. 3. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376-87. 4. Ghofrani H, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study (PATENT-1). Chest. 2012;142(4):1027. 5. Ghofrani HA, D’Armini AM, Grimminger F et al. CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319-29. 6. Pulido T, Adzerikho I, Channick RN, et al.. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809-18. 7. Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(26):2522-33. 8. Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation. 2013;127(5):624-33. 9. Tapson VF, Jing ZC, Xu KF, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013;144(3):952-8. 10. Mardi Gomberg-Maitland, Robert Schilz, Anuj Mediratta, et al. Phase I safety study of ranolazine in pulmonary arterial hypertension Pulm Circ.2015;5(4):691–700. 11. Maron BA, Waxman AB, Opotowsky AR, et al. Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials). Am J Cardiol. 2013;112:720-5. 12. Frost AE, Barst RJ, Hoeper MM et al. Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. J Heart Lung Transplant. 2015;34(11):1366-75. 13. Granton J, Langleben D, Kutryk MB, et al. Endothelial NO-Synthase Gene-Enhanced Progenitor Cell Therapy for Pulmonary Arterial Hypertension: The PHACeT Trial. Circ Res. 2015;117(7):645-54. 14. Chen SL, Zhang FF, Xu J, et al. Pulmonary artery denervation to treat pulmonary arterial hypertension: the single-center, prospective, first-in-man PADN-1 study (first-in-man pulmonary artery denervation for treatment of pulmonary
76 Recent Advances in the Management of Idiopathic Pulmonary Artery Hypertension
Bone morphogenetic protein (BMP) signaling activator: FK 506 (tacrolimus) Interleukin-6 (IL-6) pathway (tocilizumab) Glutamine-N-methyl-D-aspartate (NMDA) receptor axis.
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15.
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17.
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19.
artery hypertension). Journal of the American College of Cardiology. 2013;62:1092-100. Kula S, Atasayan V. Surgical and transcatheter management alternatives in refractory pulmonary hypertension: Potts shunt. Anatol J Cardiol. 2015;15(10):843-7. Latus H, Apitz C, Moysich A, et al. Creation of a functional Potts shunt by stenting the persistent arterial duct in newborns and infants with suprasystemic pulmonary hypertension of various etiologies. J Heart Lung Transplant. 2014;33:542-6. Baruteau AE, Belli E, Boudjemline Y, et al. Palliative Potts shunt for the treatment of children with drug-refractory pulmonary arterial hypertension: updated data from the first 24 patients. Eur J Cardiothorac Surg. 2015;47:105-10. Boudjemline Y, Patel M, Malekzadeh-Milani S, et al. Patent ductus arteriosus stenting (transcatheter Potts shunt) for palliation of suprasystemic pulmonary arterial hypertension: a case series. Circ Cardiovasc Interv. 2013;6:18-20. Gorbachevsky SV, Shmalts AA, Barishnikova IY, et al. Potts shunt in children with pulmonary arterial hypertension: institutional experience. Interact Cardiovasc Thorac Surg. 2017;25:595-9.
20. Keogh AM, Nicholls M, Shaw M, et al. Modified Potts shunt in an adult with pulmonary arterial hypertension and recurrent syncope - three-year follow-up. Int J Cardiol. 2015;182:36-7. 21. Hu J, Xu Q, McTiernan C, et al. Novel targets of drug treatment for pulmonary hypertension. American Journal of Cardiovascular Drugs. 2015;15(4):225-34. 22. Bardoxolone methyl evaluation in patients w ith pulmonary arterial hypertension (PAH)—LARIAT. Reata Pharmaceuticals. Available from: http://clinicaltrials.gov/ ct2/show/NCT02036970. Accessed May 2018. 23. Spiekerkoetter E, Sung YK , Sudheendra D, et al. Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. Eur Respir J. 2017;50(3). 24. Hernández-Sánchez J, Harlow L, Church C, et al. Clinical trial protocol for TRANSFORM-UK: A therapeutic openlabel study of tocilizumab in the treatment of pulmonary arterial hypertension. Pulm Circ. 2018;8(1). 25. Dumas SJ, Bru-Mercier G, Courboulin A, et al. NMDAtype glutamate receptor activation promotes vascular remodelling and pulmonary arterial hypertension. Circulation. 2018;137:2371–89.
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Kawasaki Disease: CHAPTER 77 What We Should Know? M Zulfikar Ahamed, Z Sajan Ahmad ‘It licks the skin and mucosal membrane, and bites the coronaries.’
INTRODUCTION Kawasaki disease (KD) is a disease of the young, frequently affecting children below 5 years. Adult population may have coronary artery disease (CAD) as a consequence of childhood KD. KD is now considered to be the second most common cause of acquired heart illness in India, next only to rheumatic fever/rheumatic heart disease (RF/ RHD). In Kerala, it has, probably, overtaken RF/RHD. KD is now established as a ‘novel’ risk factor for CAD in adults; and, hence, the pediatricians, pediatric cardiologists, and cardiologists should know about this enigmatic illness.
HISTORICAL PERSPECTIVE The first case of KD was reported in a 4-year-old child in Japan by Tomisaku Kawasaki in 1964. In 1974, the first English language report was published. In the 1990s, diagnostic criteria were refined, role of echocardiography was defined, and use of intravenous immunoglobulin (IVIG) was initiated. Single-dose IVIg was introduced in the 1990s. This century saw the development of new drugs and re-emergence of steroids in the therapeutics of KD. When the first case of KD in India was reported by Taneja from Delhi in 1987, it was greeted with skepticism but later the disease seems to have become widespread in varying regions of India. Acceptance arrived later. The first major series on KD was published from Kerala in 1997.
EPIDEMIOLOGICAL PERSPECTIVE Kawasaki disease is a disease of infants and young children, 80% of KD occurs below five years; more than half (60%) occurs before 2 years, and the peak age is around one year. It is more common in boys than girls (1.5:1) and is more
UK Prevalence/100,000
5–10
Rank in acquired HD
1
Below 5 years M/F ratio Peak age Seasonality
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commonly expressed in Japanese and Asian children. It occurs throughout the year with occasional seasonal clustering and is not likely to be communicable. The youngest age of KD worldwide is 2 weeks and the oldest is in the thirties. Neonates have KD very rarely and also adults. KD is particularly uncommon beyond 8 years. An older child may have atypical KD and late diagnosis; and, hence, increased prevalence of coronary lesions. The slow emergence of KD in India is due to many reasons. Underdiagnosis, under-reporting, late diagnosis, lack of awareness, geographic localization, and lack of specific tests are some of them. In addition, sequential evolution of various clinical criteria, multiple physicians involved (e.g. pediatricians, ophthalmologists and dermatologists), atypical presentation, less sensitization among pediatric community and lesser number of pediatric cardiologists may be other reasons.
Prevalence The prevalence in various countries is as follows: Japan: 240/100,000—Children < 5 years USA: 25/100,000—Children < 5 years UK: 5-10/100,000—Children < 5 years Kerala with 3.5 million population of children below 5 years is presumed to have a prevalence of 5–10/100,000 (Table 1). Host susceptibility may be genetically mediated. Twins have a 13% incidence in KD. However, the sibling risk is only 2% and offspring risk 1%. Genetic influence is suggested by the presence of high prevalence in Japan, Asia, and in the USA. Not only KD susceptibility but also the outcome may depend on genetic influence. Various human leukocyte antigens (HLA) are being implicated.
Table 1: Epidemiological profile of KD USA India
Kerala
10–20
?
5–10?
1
2
1
75% 1.5:1
80% 1.5:1
80% 2:1
70% 1.5:1
6–12 mon ?
18–24 mon +
18–24 mon ?
18–30 mon 0
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Kawasaki Disease Recurrence: Japan: 5/1000 patient years USA; 2/1000 patient years Death: 0.015 to 0.1%
PATHOLOGY Possible causative agents postulated include bacteria, viruses, dust mite, and certain noninfectious agents such as carpet shampoo, insecticides, and mercury. Recently, bacterial superantigens (staphylococcal or streptococcal) have been strongly implicated in the genesis of KD. Virus may be having a helper role in immune-mediated vascular injury. None have been directly implicated. Of late, possible prenatal insults like advanced age of mother and maternal group B Streptococcus (GBS) colonization and infant with history of bacterial infection are implicated in the genesis of KD (Table 2 and Figure 1). Cardiac pathology in KD passes through four stages I to IV. They are stages of: Microvascular angitis (0–10 days) Panvasculitis with aneurysm development (12–25 days) Granulation of coronaries (28–31 days) Scarring (40 days to 4 years).
Table 2: Possible causative agents Bacteria:
Staphylococci Streptococci
Virus:
Measles EBV Adeno Parainfluenza Parvovirus
Corynebacterium Yersinia Propionibacteria Myobacteria Chlamydia
Polymorphous exanthema Bilateral nonpurulent conjunctival congestion. Changes in the lips of oral cavity Acute nonsuppurative cervical lymphadenopathy. If five principal features are present or if four are present with echocardiographic coronary artery lesions (CAL) demonstrated, the diagnosis of KD is made (Figure 2).
Other Significant Findings
We can also follow the Japanese Kawasaki Disease Research Committee (JKDRC) fourth revision diagnostic guidelines to diagnose KD.
The other significant findings include: Cardiovascular: S3 gallop, murmur, soft S1, ECG abnormalities, cardiomegaly, myocardial infarction, and pericarditis Gastrointestinal: Vomiting, diarrhea, colic, hydrops of gallbladder, paralytic ileus, and mild hepatitis Hematological: Polymorphonuclear leukocytosis, thrombocytosis, elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hypoalbuminemia, and anemia Urinary: Proteinuria, pyuria, and nephrotic syndrome Re s pi rat o r y : Pu l m o na r y n o d u l e, c ou g h, a n d pneumonia Joints: Arthralgia and polyarthritis Neurological: Aseptic meningitis and seizures. Fever is usually high grade, abrupt in onset and can spike. It may last for 10–14 days. Conjunctival congestion is nonpurulent and occurs within 1–3 days, oral mucosal changes occur within 2 days, causing changes in lips, oral mucosa, and a ‘strawberry’ tongue. These changes may last for 10 days. Extremity changes include palmar and plantar erythema with induration which starts on the 3rd to 5th day with desquamation occurring by 2nd and 3rd week. Polymorphous exanthematous rashes occur predominantly on trunk within 3–4 days and lasts for 1 week. Lymph node enlargement occurs in 75% and appears within 3 days of illness (Figure 3).
Principal Symptoms
Laboratory Findings
CLINICAL DIAGNOSIS The diagnosis of KD is still essentially clinical, supported by laboratory findings and echocardiography. In the absence of a specific diagnostic gold standard, clinical diagnosis is the major tool.
American Heart Association (AHA) Guidelines (2017) I. > 5 days of fever plus II. 4/5 of principal clinical features a. Changes of the extremities b. Rashes c. Conjunctival congestion d. Oral changes e. Lymphadenopathy
Japanese Kawasaki Disease Research Committee Criteria
636
KG-77.indd 636
Fever Changes in extremities — Acute – red palm/sole with indurative edema. — Subacute – desquamation of fingers, toes, sole and palm.
Hb 11000 Platelet count >4–5 L ESR >30 CRP +ve
65% 70% 45% 98% 72%
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77 Kawasaki Disease: What We Should Know?
Figure 1: Pathogenesis model
Figure 3: Clinical features of KD (n = 69) Source: SAT Hospital, Thiruvananthapuram
Figure 2: Kawasaki disease—time sequence of principal findings
Differential Diagnosis A number of childhood illnesses mimic KD. They include measles, staphylococcal scalded skin syndrome (SSSS), drug rashes, IMN, and other viral exanthems in infants. In toddlers and children, Steven-Johnson syndrome (SJS), measles, toxic shock syndrome, SSSS, systemic juvenile rheumatoid arthritis, drug reactions, scarlet fever and RF can be part of differential diagnosis. A careful history taking, clinical examination, and findings of clinical accompaniments, will more or less sort out the issue with the help of laboratory evaluation (Table 3).
LABORATORY EVALUATION Blood Counts A carefully done blood count is extremely useful. There could be mild anemia. Polymorphonuclear leukocytosis is present in more than half. A very high count (>30,000) is perhaps a risk factor/marker for coronary artery lesion (CAL). A raised ESR is almost always present, as is an elevated CRP. An ESR beyond 100 mm/hr or persistently high ESR or CRP could be indicators of development of CAL. Elevated ESR and CRP will become normal in 6–8 weeks. ESR may remain high for variable period if IVIg is administered. Thrombocytosis (platelet count >500,000) occurs in 60%. This occurs in the second week and may persist for 4–6 weeks. 637
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Table 3: Differential diagnosis of KD
Vascular System
9
KD
SSSS
SJA
Measles
Drug rash
RF
Age
8 mm: Giant aneurysm
Z-score Classification
Less than 2 Z 2.0–2.5 Z > 2.5–5.0 Z > 5–10.0 Z More than 10 Z
Normal Dilatation only Aneurysm (small) Medium aneurysm Giant aneurysm
Echocardiography (Other than CAL)
Low LV ejection fraction may be observed, especially in early phase of KD. Most of LV dysfunction recovers Pericardial effusion MR: 10–15% AR: 30,000/mm3 ESR > 100 mm/hr Persistently high ESR ECG showing acute Ml pattern Low Hb Hypoalbuminemia Late IVIg administration.
OTHER ABNORMALITIES Muscle Enzymes Creatine phosphokinase-MB (CPK-MB), could be elevated in KD, especially if an infarct or micro infarct has occurred or if significant myocarditis develops. Trop T and Trop I results in KD are variable and may not be very useful. Recently, BNP estimation has been touted as marker for risk of developing CAL, as also plasminogen activator inhibitor-1 (PAI-1), urinary neopterin, and cytokinesinterleukin-6 (IL-6), IL-8, and IL-2.
Lipid Profile There has been documentation of mildly elevated total cholesterol, low-density lipoprotein (LDL)-cholesterol and triglyceride (TG) and low high-density lipoprotein (HDL) following KD, especially in convalescence. This could be due to IVIg-induced protein fraction changes in plasma or a primary phenomenon.
OTHER INVESTIGATIONS
SPECIAL CONCERNS IN KD Incomplete KD/Atypical KD (10%) Both these diagnostic terms have been occasionally used with overlap. However, incomplete KD is defined as presentation of KD in those who do not fulfill the clinical criteria, with or without CAL. The term atypical KD is used for those who present with atypical presentation, but have CAL usually. Those situations would require the proactive role of a cardiologist for resolution of dilemma. Incomplete KD (ICKD) will have less of lymphadenopathy, rashes, and extremity changes, while mucosal changes will be very common (90%). ICKD may lead to late diagnosis and late initiation of IVIg treatment. This may lead to higher incidence of CAL. Some of the presentations in atypical KD include meningitis, sensory neural deafness, pleural effusion, and acute lymphadenitis. Laboratory evaluation will be helpful in decision making. Concomitant elevation of ESR, CRP, and platelet count will be quite useful. Newer markers like troponins, procalcitonin and pro-N-BNP could be useful.
Diagnosis Figure 4 shows incomplete kawasaki disease (AHA Algorithm 2004).
Coronary Angiogram
Supplementary Laboratory Criteria
They are usually indicated in prognostication and therapeutic strategy planning in KD with CAL. The children who need angiography are those with large coronary aneurysms, multiple aneurysms and who have clinical, ECG, or scintigraphic evidence of ischemia.
The supplementary laboratory criteria is used in decision making in incomplete KD S. albumin 15,000/mm3 Sterile pyuria.
Stress Studies Exercise treadmill test (TMT), dobutamine stress echocardiography, and stress thallium have been used in the assessment of ischemia in children.
Others These include PET, MRI, spiral CT, intravascular ultrasound (IVUS), and endomyocardial biopsy. They are limited to mostly research centers. MRI can characterize all cardiac abnormalities but has logistic issues such as cost, time taken, and need for anesthesia. IVUS can assess coronary lesions which are subtle and can also prognosticate.
NATURAL HISTORY 640
weeks; even without treatment. Response to IVIg is often dramatic—within 24 hours.
Kawasaki disease is a self-limiting disease. The mean duration of fever is 12 days. The maximum duration is four
KG-77.indd 640
Acute Myocardial Infarction In acute stage During convalescence Remote (Adult). Acute myocardial infarction (AMI) in KD has higher mortality and most often has a large thrombus load. Rupture as a cause of STEMI is unusual.
Future Atherosclerosis There have been studies showing increasing BP, adiposity and TG levels following KD which may cause accelerated atherosclerosis. Hence, there is an intriguing possibility of premature coronary artery disease (CAD) in KD
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77 Kawasaki Disease: What We Should Know?
Figure 4: Incomplete Kawasaki disease (AHA Algorithm 2004)
survivors due to interplay of multiplicity of factors such as gross coronary artery lesions, endothelial dysfunction, abnormal flow reserve, dyslipidemia, and possible adiposity and hypertension (Figure 5).
TREATMENT OF KD Even though etiology is unknown, current therapeutic strategy for KD is more or less standard. The goals are: To treat acute inflammation and prevent CAL. To prevent thrombosis. Figure 5: Coronary artery disease in Kawasaki disease
Intravenous Immunoglobulin Landmark trials in the 1980s in Japan and the USA have established the role of IVIg in reducing CAL and current recommendation of administration of 2.0 gm/kg/IVIg is based on major trials in the 1990s. IVIg should be administered within 10 days of illness and preferably within 6 days of illness. Very early IVIg may further reduce CAL. IVIg was first given in KD in 1983. IVIg with aspirin can bring down the percentage of CAL at 6 weeks from 25% to 5% that is a five-fold reduction. Late administration of IVIg is a risk factor for giant aneurysm formation. Multiple
doses are less efficacious. IVIg should be at least given as two doses (1 g/kg/day × 2) if there is a feasibility problem in administration. Harada scores have been used to assess the requirement of IVIg in KD in Japan.
Mechanism of IVIg in KD
Downregulation of cytokine production Fc receptor blocking Neutralizing antibodies Suppress T cell induction 641
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Concerns Regarding IVIg
It has a high osmolality and can cause fluid overload. Hence, it has to be given over 12 hours; starting with 0.03 mg/kg/min and building up to 0.1 mg/kg/min. Adverse reactions are rare (6 m): — In acute phase Low molecular weight heparin x 5 days Add clopidogrel 1.5 mg/kg. — In convalescent phase: Clopidogrel with aspirin. — In giant aneurysm (>8 mm): Anticoagulant added to low dose aspirin to keep INR 1.5–2.0 with warfarin Atypical KD: 10% Treat as KD with full complement of IVIg and aspirin if echocardiogram is abnormal or borderline normal/ higher number of risk factors present.
Late KD (>10 days) — Full dose aspirin is given — IVIG administration is individualized, depending on risk factors, cost, etc.
Steroids They are generally either not indicated or possibly contraindicated in acute KD as a primary therapy. This is based on a major initial trial of steroids in KD in the 1980s. However, there have been recent reports of administration of steroids in KD in selected cases. Drug used is methylprednisolone 30 mg/kg/IV × 3 doses - pulse methylprednisolone. The indications may be: Recrudescent or persistent clinical features. IVIg failure and re-treatment (20%). In 2003, a randomized controlled trial comparing IVIg alone vs IVIg + methylprednisolone showed reduced fever, shortened duration of illness, and rapid reduction of ESR and CRP, but no significant difference in coronary dimension. So, steroids are still not widely used in the initial treatment of KD. Steroids are used: As primary therapy—Not indicated As adjuvant with IVIg—Could be useful in reducing. CAL In refractory KD—Useful in reducing refractoriness in high-risk KD.
Antioxidants The α tocopherol and vitamin C may mitigate the clinical features of KD. So far there have been no genuine trials on these.
Cyclopsprine A There have been isolated reports of using cyclosporine A in IVIg failure in KD.
Oral Prednisolone They have been used in a few centers with variable success.
Abciximab/tPA/Streptokinase They have been used in acute coronary events in children with KD and also in large aneurysm in acute or subacute stage.
Ticlopidine/Clopidogrel This could be an alternative to dipyridamole in large CAL, especially in giant aneurysms.
Pentoxyphylline It is a TNF alpha inhibitor and may have a role in reduction of CAL.
03-11-2018 12:37:34
Plasma Exchange This could be used in resistant KD.
This is a trypsin inhibitor used as an adjunct to treating IVIG resistant KD.
Rest It is advised for 2 to 3 weeks. More prolonged rest may be offered in the presence of giant aneurysm.
Doses of Pharmacological Agents
IVIg: 2 g/kg over 12 hours Aspirin: 30–60 mg/kg/day in divided doses Low-dose aspirin: 5 mg/kg/day Methylprednisolone: 30 mg/kg/ dose × 3 day 2–3 hours infusion Infliximab: 5 mg/kg/IV infusion over 2 hours Prednisolone: 2 mg/kg/PO/day to begin with and then taper Recombinant tissue plasminogen activator (rtPA): 0.5 mg/kg/hr for 6 hours IV Streptokinase: 1000 IU/kg/bolus; 1000 IU/kg/hour infusion Unfractionated heparin: 50 U/ kg loading IV. 20 U/kg/ hour infusion Low-molecular-weight heparin (LMWH): 2 mg/kg/day BD SC Warfarin: 0.1 mg/kg/day to start Maintain International Normalized Ratio (INR) 2 Clopidogrel: 1.5 mg/kg/day
Refractory KD After IVIg, if fever does not respond beyond 36 hours, one can suspect refractory KD. It is usually seen in 5–10%. Other reasons for fever could be intercurrent infection, other diseases like systemic juvenile idiopathic arthritis (SJIA), viral fever, etc.
New Strategy A new strategy in KD could be as given in Figures 6 and 7.
LONG-TERM MANAGEMENT Long-term management of a child or infant who has recovered from KD is based on risk stratification. Risk stratification in turn depends primarily on CAL. Echocardiography is the primary tool in assessing CAL stratification. I. KD. Normal coronaries Z-score < 2.0 II. KD. Dilatation only Z-score 2–2-5 III. KD. CAL. Small aneurysm Z-score 2.5–5.0 1. Current/persistent 2. Decreased/Normal IV. KD CAL. Medium aneurysm Z-score 5.0–10 1. Current/Persistent 2. Decreased to small 3. Decreased to normal (Z score < 2.5). V. KD. Large/Giant aneurysm Z-score > 10 1. Current/Persistent 2. Decreased to medium 3. Decreased to small 4. Decreased to normal/dilatation.
Figure 6: New strategy in Kawasaki disease
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CHAPTER
77 Kawasaki Disease: What We Should Know?
Ulinastatin
Refractoriness could be predictable. There have been various scoring systems for this prediction – Egami, Sano, and Kobayashi. Most of them have sensitivity of 80-85% and specificity of 75%. T h e s t a n d a rd re g i m e n f o r re f r a c t o r y K D i s administration of one more dose of IVIg, 2 g/kg. Usually, 80% will respond favorably. The nonresponders may have to be given either methylprednisolone or infliximab. Other drugs/modes which could be used are ulinastatin, methotrexate, and plasmapheresis.
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Figure 7: Initial phase of Kawasaki disease and follow-up
PROTOCOL FOR MANAGEMENT (TABLE 7) Level I Normal
Stop aspirin at 8 weeks Ongoing follow-up: 6 months–12 months No follow-up later. Lifestyle modification.
Level II
Continue aspirin–Low dose for 6-8 weeks Ongoing follow–up up to 12 months. Lifestyle modification.
Level III
Continue aspirin indefinitely Reassess CAL at 6 months and 12 months Yearly follow-up Lifestyle modification No restriction of physical activity: Empirical statin – IIb – controversial Clopidogrel if child is intolerant to aspirin.
Level IV
Continue aspirin indefinitely Reassess CAL at 3, 6, 9, 12 months Ongoing follow-up 6 monthly Lifestyle modification Some restriction of physical activity Assess for inducible ischemia Imaging if indicated Empirical statin therapy (IIb) Dual antiplatelet (especially, if CAL > 6 mm (IIb).
Level V
644
KG-77.indd 644
Assess at 1, 2, 3, 6, 9, 12 months and later at 3–6 months Continue aspirin indefinitely Add warfarin to keep INR to 2–3
Lifestyle modification Restriction of physical activity Empirical statin (11b) Empirical β-blockers (11b) Assess for inducible ischemia and if needed imaging.
INTERVENTIONS IN KD Intervention can be either percutaneous or surgical. It is offered in both acute situations (acute coronary syndrome) or in chronic CAD.
Acute Coronary Syndrome
STEMI: It is a medical emergency and needs restoration of coronary circulation. The standard approach is intravenous thrombolysis with intravenous/oral antiplatelet agents. Coronary artery bypass grafting (CABG) is not indicated. Percutaneous coronary intervention (PCI) may not be ideal as the reason for occlusion is thrombus rather than plaque rupture. NSTEMI: Pharmacological therapy with intravenous antiplatelets and LMWH is advocated. STEMI in an adult with distant KD, immediate coronary angiography and PCI may be the preferred option, unlike a child with STEMI. Pharmacotherapy can be contemplated in appropriate situations.
Chronic CAD
It can be either by catheter intervention or by CABG. Catheter intervention can be by percutaneous transluminal coronary angioplasty (PTCA), with stent or rotablation. CABG is preferred in the left main CAD and multivessel CAD. PCI is preferred in single vessel disease or two-vessel disease amenable to PCI. Plain balloon angioplasty should not be used.
03-11-2018 12:37:35
CHAPTER
Table 7: Protocol for management LDA
DAPT
Warf
Statin
BB
TMT
I
No
0
0
0
0
0
0
II
Yearly +
0
0
0
0
0
0
III
Yearly
+
0
0
+
0
+
IV
6 months
+
+
0
+
0
+
V
3 months
+
+
=
+
+
+
77
Abbreviations: DAPT, dual antiplatelet therapy; LDA, low dose aspirin; Warf, warfarin; BB, beta-blockers; TMT, treadmill test
NATURAL HISTORY KD is a self-limiting disease. The mean duration of fever is 12 days. The maximum duration is four weeks; even without treatment. Response to IVIg is often dramatic–within 24 hours. Death in KD is now rare. It was 1–3% in the 1970s and now it has become < 0.1%. It occurs due to acute infarction and rarely due to aneurysm rupture. Late mortality is again due to infarction or intervention related events. Coronary involvement is usually between 20 and 30%. In our institution the CAL occurred in 24%. Usually, CAL regresses within 1 year in 50% children. Endothelial dysfunction is near universal in CAL and it could possibly occur in coronaries identified as normal by echocardiography. Hence, accelerated atherosclerosis is a potential risk in KD. In spite of apparently normal looking coronaries, carotid intima media thickness (CIMT) is altered in KD. ESR initially may go up after IVIg and will fall gradually. It will take 6–10 weeks to reach normal value. CRP will fall to normal by 4–6 weeks. Platelet count will become normal by 4–8 weeks, after peaking at 3 weeks. Regression of CAL occurs in approximately half. About 40% will develop aneurysm. Stenosis can occur in 5–10%. Giant aneurysm occurs in 5%. Aneurysm rupture less common. Regression is more likely when child is >1–0 year, female and the lesions are fusiform and less than 6 mm in diameter. KD with no initial CAL will have no CAL at the end of 10 years. KD with giant aneurysm is unlikely to become normal. About 50% KD with CAL of > 6 mm will develop stenosis.
LONG-TERM CARDIAC DAMAGE
Coronary: CAD Noncoronary: — LVd ysfunction — MR, AR — Aortic root dilation
INDICATIONS FOR CORONARY ANGIOGRAPHY
KG-77.indd 645
Stress test positive Giant aneurysm Ischemic symptoms
Table 8: What matters to whom—diagnosis Features Pediatrician Cardiologist Clinical recognition +++ + Predictors of CAL ++ + Optimization of laboratory work ++ + Incomplete KD
++
++
Atypical KD Newer imaging CAG Stress testing
++ 0 0 +
++ + + ++
Kawasaki Disease: What We Should Know?
Freq visit
Table 9: What matters to whom—treatment Methods Pediatrician Cardiologist 1. IVIg dosing +++ + 2. Treat refractory KD +++ ++ 3. Dosing of aspirin, clopidogrel, ++ ++ DAPT, warf 4. New pharmacological agents ++ ++ 5. STEMI management + +++ Table 10: What matters to whom—prognosis/follow-up Pediatrician Cardiologist 1. Follow-up ++ +++ 2. Regression of CAL ++ +++ 3. Prevention CAD ++ ++ 4. Management of CAD + +++ 5. Interventions O +++
Even though KD is primarily a vasculitis, all layers of heart can be involved. Myocardial involvement can be as high as 75% by biopsy. Pericardial effusion can occur in 10–20%; valvulitis could be cause of MR and AR. AR can occur due to root dilatation also. Papillary muscle dysfunction and ischemia can cause MR.
Interventions (Tables 8 to 10) Catheter (PCI) CABG. The indications are not data driven. Mostly they are empirical and derived from adult experience. The choice of catheter interventions is as given below: Plain balloon angioplasty: Not optimal Stent placement: Older children Rotablator: Better?
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CABG is reserved for LMCA lesion, 3-vessel disease with/without LV dysfunction. In significant occlusive coronary lesions, CABG is traditionally offered. Initially, saphenous vein grafts (SVG) were used but now current bilateral internal mammary artery (IMA) graft is preferred. Restenosis seems to be earlier in KD children or adults who undergo CABG. PTCA have been used with or without stent in children or adults with distant KD. Restenosis rate may be higher. The 10-year patency in KD is 80%.
CONCLUSION Kawasaki disease is emerging as an important acquired heart disease in children, probably next only to RF/RHD in our country. The regional variation occurs at national level also wherein a large number have been reported from Kerala. Even though etiology remains an enigma, effective acute therapy is currently available which can reduce coronary involvement five-folds. Some sort of long-term surveillance is warranted. Occasionally, revascularization may be required. Many features of KD–both mechanical and biochemical, might predispose to accelerated atherosclerosis and hence increased CAD occurrence in the future. Even though KD is a disease of young children and the chief stakeholder is the pediatrician, pediatric cardiologist and cardiologist have an integral role in diagnosis and management. There must be a synergy between three of them to prevent death, prevent development of CAL, long-term follow-up and management – both in acute setting and chronic setting. Interventional and surgical practices may have to be used in selective cases.
SUGGESTED READING
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1. Akagi T, Kato H, Inoue O, et al. Salicylate treatment in Kawasaki disease: high dose or low dose? Eur J Pediatr. 1991;150(9):642-6. 2. Akagi T, Kato H, Inoue O, et al. Valvular heart disease in Kawasaki syndrome: incidence and natural history. Am Heart J. 1990;120(2):366-72. 3. Akagi T, Ogawa S, Ino T, et al. Catheter interventional treatment in Kawasaki disease: A report from Japanese Pediatric Interventional Cardiology Investigation group. J Pediatr. 2000;137(2):181-6. 4. Akagi T, Rose V, Benson LN, et al. Outcome of coronary artery aneurysms after Kawasaki disease. J Pediatr. 1992;121(5):689-94. 5. Arjunan K, Daniels SR, Meyer RA, et al. Coronary artery caliber in normal children and patients with Kawasaki disease but without aneurysms: an echocardiographic and angiographic study. J Am Coll Cardiol. 1986;8:1119-24. 6. Baer AZ, Rubin LG, Shapiro CA, et al. Prevalence of coronary artery lesions on the initial echocardiogram in Kawasaki syndrome. Arch Pediatr Adolesc Med. 2006;160(7):686-90. 7. Barron KS. Immune abnormalities in Kawasaki disease: prognostic implications and insight into pathogenesis. Cardiol Young. 1991;1:206-11.
8. Burns JC, Kushner HI, Bastian JF, S et al. Kawasaki disease: A brief history. Pediatrics. 2000;106(2):E27. 9. Dajani AS, Taubert KA, Takahashi M,et al. Guidelines for long-term management of patients with Kawasaki disease. Report from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 1994;89(2):916-22. 10. Dale RC, Saleem MA, Daw S, et al. Treatment of severe complicated Kawasaki disease with oral predinosolone and aspirin. J Pediatr. 2000;137(5):723-6. 11. de Zorzi A, Colan SD, Gauvreauk, et al. Coronary artery dimensions may be misclassified as normal in Kawasaki disease. J Pediatr. 1998;133(2):254-8. 12. Durongpisitkul K, Gururaj VJ, Park JM, et al. The prevention of coronary artery aneurysm in Kawasaki disease: a metaanalysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics. 1995;96(6):1057-61. 13. Fujiwara H, Hamashima Y. Pathology of the heart in Kawasaki disease. Pediatrics. 1978;61(1):100-7. 14. Gopika SR, Ahamed MZ. Coronary artery diameter in normal infants and children of Kerala by two-dimensional echocardiography. Participants’ Handbook. Pedheart 2012. Department of Pediatric Cardiology, GMC, Trivandrum. 15. Hiracshi S, Misawa H, Takeda N, et al. Transthoracic ultrasonic visualisation of coronary aneurysm, stenosis, and occlusion in Kawasaki disease. Heart. 2000;83(4):4005. 16. JCS Joint Working Group. Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2013). Digest version. Circ J. 2014;78(10):252162. 17. Kato H, Ichinose E, Kawasaki T. Myocardial infarction in Kawasaki disease: clinical analysis in 195 cases. J Pediatr. 1986;108(6):923-7. 18. Kato H, Inoue U, Kawasaki T, e t a l . Adult coronar y ar ter y dis eas e probably due to childhood Kawasaki disease. Lancet. 1992;7:340(8828):1127-9. 19. Kato H, Sugimura T, Akagi T, et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation. 1996;94(6):1379-85. 20. Kawasaki T, Kosaki F, Okawa S, et al. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics. 1974;54(3):271-6. 21. Kim M, Kim K. Elevation of cardiac troponin I in the acute stages of Kawasaki disease. Pediatr Cardiol. 1999;20(3):184-8. 22. Kitamura S. The role of coronary bypass operation on children with Kawasaki disease. Coron Artery Dis. 2003;14(1):95. 23. Kobayashi T, Saji T, Otani T, et al. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. Lancet. 2012;379(9826):1613-20. 24. Kurotobi S, Nagai T, Kawakami N, et al. Coronary diameter in normal infants, children and patients with Kawasaki disease. Pediatric Int. 2002;44(1):1-4. 25. Liang CD, Huang SC, Su WJ, et al. Successful intravenous streptokinase treatment of a child with Kawasaki disease complicated by acute myocardial infarction. Cathet Cardiovasc Diagn. 1995;35(2):139-45.
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Kawasaki disease unresponsive to high-dose intravenous gammaglobulin. Pediatr Cardiol. 2001;22(5):419-22. Shulman ST. IVG G therapy in Kawasaki disease: mechanism(s) of action. Clin Immunol Immunopathol. 1989;53(2):S141-6. Silva AA, Macno Y, Hashmi A, et al. Cardiovascular risk factors after Kawasaki disease: a case-control study. J Pediatr. 2001;138(3):400-5. Stanley TV, Grimwood K. Classical Kawasaki disease in a neonate. Arch Dis Child Fetal Neonatal Ed. 2002;86(2): F135-6. Sundel R. Refractory Kawasaki disease. UpToDate 2015. Sundel RP, Baker AL, Fulton DR, et al. Corticosteroids in the initial treatment of Kawasaki disease: report of a randomized trial. J Pediatr. 2003;142(6):611-6. Suzuki A, Kamiya T, Ono Y, Kinoshita Y, Kawamura S, Kumura K. Clinical significance of morphological classification of coronary arterial segmental stenosis due to Kawasaki disease. Am J Cardiol. 1993;71(13):1169-73. Suzuki A, Tizard EJ, Gooch V, et al. Kawasaki disease: echocardiographic features in 91 cases presenting in the United Kingdom. Arch Dis Child. 1990;65(10):1142-6. Takahashi M, Mason W, Lewis AB. Regression of coronary artery aneurysms in patients with Kawasaki syndrome. Circulation. 1987;75(2):387-94. Takahashi M. Kawasaki syndrome (mucocutaneous lymph node syndrome). In: Allen HD, Gutgesell HD, Clark EB, Driscoll DJ, editors. Moss and Adams’ Heart Disease in Infants, Children, and Adolescents including the Fetus and Young Adults. 6th edn. Philadelphia: Lippincott Williams & Wilkins Co. 2001. p. 1216-25. Tatara K, Kusakawa S. Long-term prognosis of giant coronary aneurysm in Kawasaki disease: an angiographic study. J Pediatr. 1987;111(5):705-10. Taubert KA. Epidemiology of Kawasaki disease in the United States and worldwide. Prog Pediatr Cardiol. 1997;6:181-5. Tse SM, Silverman ED, McCrindle BW, et al. Early treatment with intravenous immunoglobulin in patients with Kawasaki disease. J Pediatr. 2002;140(4):450-5. Williams RV, VM, Tani LY, Minich LL. Does Abciximab enhance regression of coronary aneurysms resulting from Kawasaki disease? Pediatrics. 2002;109(1):E4. Yamakawa R, Ishii M, Sugimura T, et al. Coronary endothelial dysfunction after Kawasaki disease: evaluation by intracoronary injection of acetylcholine. J Am Coll Cardiol. 1998;31(5):1074-80.
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26. Manlhiot C, Miller K , Golding F, et al. Improved classification of coronary artery abnormalities based on coronary artery. Z-scores after Kawasaki disease. Pediatr Cardiol. 2010;31(2):242-9. 27. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135(17):e927-99. 28. Ministry of Health and Welfare, Research Committee on Kawasaki Disease. Report of the Subcommittee on Standardization of Diagnostic Criteria and Reporting of Coronary Artery Lesions in Kawasaki Disease. Tokyo: Japan: Ministry of Health and Welfare, 1984. 29. Neches WH. Kawasaki disease. In: Anderson RH, Baker EJ, MaCartney FJ, Rigby ML, Shinebourne EA, Tynan M, editors. Paediatric Cardiology. 2nd edn. London: Churchill Livingstone. 2002;1683. 30. Newburger JW, Burns JC, Beiser AS, et al. Altered lipid profile after Kawasaki syndrome. Circulation. 1991;84(2):625-31. 31. Newburger JW, Takahashi M, Beiser AS, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med. 1991;324(23):1633-9. 32. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110(17):2747-71. 33. Onouchi Z, Kawasaki T. Overview of pharmacological treatment of Kawasaki disease. Drugs. 1999;58(5):813-22. 34. Research Committee of the Japanese Society of Pediatric Cardiology; Cardiac Surgery Committee for Development of Guidelines for Medical Treatment of Acute Kawasaki Disease. Guidelines for medical treatment of acute Kawasaki disease: report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version). Pediatr Int. 2014;56(2): 135-58. 35. Satomi G, Nakamura K , Narai S, et al. Systematic visualization of coronary arteries by two-dimensional echocardiography in children and infants: evaluation in Kawasaki’s disease and coronary arteriovenous fistulas. Am Heart J. 1984;107(3):497-505. 36. Shen CT, Wang NK. Antioxidants may mitigate the deterioration of coronary arteritis in patients with
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Electrocardiology Common Pitfalls and Artifacts in ECG Interpretation
SB Gupta Computerized ECGs: Strengths and Limitations
Kartikeya Bhargava ECG Assessment of Supraventricular Tachycardia
Amit Vora, Samhita Kulkarni ECG Assessment of Wide QRS Tachycardia
Binay Kumar, Yash Lokhandwala Atrioventricular Block: Diagnosing the Level of Block
Avinash Anantharaj, Anandaraja Subramanian STEMI Equivalents
Arun K Chopra
S E C T I O N
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Common Pitfalls and Artifacts in ECG Interpretation SB Gupta
INTRODUCTION The invention of electrocardiography (ECG) is more than 100 years old and the use of ECG has become a standard medical practice. Sometimes, ECG is considered a reliable tool to diagnose or rule out medical problems as compared to bedside diagnosis. However, ECG has many limitations which have not been adequately emphasized. To minimize the limitations, ECG has to be read in clinical context. If ECG is interpreted in view of clinical history and examination, the interpretations will be far adequate than otherwise.
LIMITATIONS
NORMAL ECG IN PATHOLOGICAL CONDITIONS Paroxysmal arrhythmias: — Paroxysmal supraventricular tachycardia (SVT)/ atrial fibrillation (AF) — Idiopathic ventricular tachycardia (VT)/cate cholinergic polymorphic ventricular tachycardia (CPVT)/paroxysmal ventricular fibrillation — Paroxysmal atrioventricular (AV) blocks. Coronary artery disease (CAD): — Acute ACS — Stable CAD — Right ventricular or postwall myocardial infarction (MI). Intermittent syndromes: — Brugada syndrome — LQTS (long QT syndrome) — Intermittent preexcitation. Cardiomyopathies: — Dilated — Hypertrophic — Infiltrative. The ECG may be absolutely normal in various episodic arrhythmias when the patient has no symptoms. History taking is very important in such situations; and if there are episodic symptoms of palpitations, which are sudden in onset and offset; and if associated with giddiness or shortness of breath, such patients must be evaluated very carefully. The ECG at the time of episode may clinch the diagnosis; else, stress test, Holter monitoring, event recording, external loop recording for longer periods,
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The various limitations are as follows: 1. Lack of normal standards: There are tremendous variations in the ECG from person to person. However, the normal standards have been prescribed for reading ECG, but still lots of variation beyond these limits are considered normal. 2. Clinical and electrocardiographic correlations: The ECG cannot correlate the severity of cardiac disease and the degree of the abnormality in the record. Most simple example will be a normal ECG in a case of acute coronary syndrome (ACS) or acute evolving myocardial infarction (AMI). 3. Functional reserve: Though ECG can give information a b o u t h e a r t ’s r hy t h m i c i t y , e x c i t a b i l i t y , a n d conductivity, but it cannot give much information about its functional reserve. 4. Diagnostic information: The ECG cannot reliably give diagnostic information as there are so many overlap of ECG findings that one cannot come to a conclusion regarding one diagnosis just on the basis of ECG. For example, ST depression on ECG will have umpteenth differential diagnosis. 5. Certain specific patterns: Many patterns have been specified on ECG to diagnose various disorders; but in clinical context, these criteria are disappointing. For example, Q1S3T3 criteria of pulmonary embolism may only be seen in 20–30% of the cases. P mitrale of mitral stenosis is not specific for mitral stenosis, but it denotes left atrial abnormalities because of any cause.
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The ECG is a very important diagnostic tool in the armamentarium of clinicians for patients suffering from cardiovascular disorders, especially from acute coronary syndrome (ACS) or from various arrhythmias. However, ECG may be normal in episodic arrhythmias such as paroxysmal supraventricular tachycardia and in the early stages of acute coronary syndrome. The ECG may be abnormal with structurally normal hearts, especially with athletes or in the early repolarization syndromes.
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internal loop recording, or electrophysiological (EP) study may be required to come to conclusive diagnosis. While evaluating syncope, one should always remember that AV blocks or sinus pauses may be paroxysmal and may not be picked on single ECG. Carotid hypersensitivity or vasovagal syncope will show sinus bradycardia during the episode only. Hence, to evaluate syncope, when we come across normal ECG, we need to take the help of other tests as mentioned above is essential. The ECG is the most common test for evaluation of chest pain by the clinicians. However, ECG may be perfectly normal in anginal episodes and even in early phases of evolving acute MI. Up to 10% of patients presenting with ACS, may have normal ECG. 2,3 Right ventricular MI and postwall MI may also present with normal ECG. A large number of patients with stable CAD will also have normal ECG. It needs to be reemphasized that normal ECG does not rule out CAD. And, serial ECGs will be able to clinch the diagnosis. So, many cardiac disorders may present intermittently, such as Brugada syndrome, LQTS, or preexcitation with normal ECG in between the episode.4 Similarly, so many cardiomyopathies may present with normal ECGs and high index of suspicion will only clinch the diagnosis. Conditions, such as pulmonary embolism, may also present with almost normal ECG except may be with subtle sinus tachycardia and history taking and again high index of suspicion will be helpful in reaching to a conclusive diagnosis. The CAD is one of the most dreadful diseases in cardiology and a lot of emphasis has been laid on its diagnosis based on ECG. There are so many conditions which may mimic like CAD and mislead us in diagnosing the event correctly and erroneous diagnosis will be made leading to unnecessary treatment.5
COMMON PITFALLS IN DIAGNOSIS OF CORONARY ARTERY DISEASE ON ECG The common pitfalls in the diagnosis of CAD on ECG are discussed below:
Cardiac Conditions Myocardial Diseases i. P r i m a r y m y o c a r d i a l d i s e a s e : Hy p e r t r o p h i c cardiomyopathy, especially apical cardiomyopathy mimic myocardial infarction showing Q waves in inferior and anterior leads. Poor R wave progression and STT wave changes are common features in dilated cardiomyopathy mimicking anterior wall MI. ii. Secondary myocardial disease: Myocarditis, various infiltrative disorders, such as sarcoidosis and muscular dystrophies, and autoimmune conditions, such as scleroderma and cardiac tumors, may show STT wave changes which mimic CAD.
Conduction Defects i. Left bundle branch block (LBBB) may mimic or mask acute MI. Criteria have been laid down to diagnose acute MI in the presence of LBBB. One of the limitations of ECG is to diagnose acute MI in the presence of LBBB. The LBBB presents with QS complexes in right and midprecordial leads with ST elevation leading to confusion to diagnose additional MI. Sgarbossa criteria6 should be applied to diagnose MI in the presence of LBBB. The ST elevation more than 5 mm in limb leads and precordial leads showing QS complexes, ST elevation of 1 mm or more in Lead I, aVL, V5, and V6 leads showing R wave and ST depression, where ST elevation is expected, will favor the diagnosis of acute MI. The Q waves in LI, aVL, V5, and V6 in the presence of LBBB favors the old anterior wall MI. ii. Left anterior fascicular block (LAFB) may again mask inferior wall MI or mimic anterior wall MI. iii. WolffParkinsonWhite (WPW) syndrome type A may mimic lateral wall MI and type B may mimic inferior or anterior wall MI. iv. Left ventricular hypertrophy: The QS complex in V1 and V2, tall T waves seen in precordial leads, and poor R wave progression may suggest anterior wall infarction. v. Acute pericarditis : The ECG changes of acute pericarditis confuse the physicians the most with the changes with acute MI. The ECG showing ST segment elevation (though downsloping) is sometimes confused with evolving acute MI until unless properly interpreted in the light of history and looking for the subtle signs on ECG of pericarditis (Figure 1).
Pulmonary Diseases Poor R wave progression and loss of R waves in the right sided and midprecordial leads in chronic obstructive lung disease (COLD) may mimic anterior wall infarction. Vertical heart in emphysematous lung lead to Q waves in inferior leads mimicking inferior wall MI. Spontaneous pneumothorax can also mimic MI because of displacement and rotation of heart showing poor R wave progression, low voltage ECG, and symmetrical T wave inversion (Figures 2 and 3).
Intracranial Causes The intracranial (IC) bleeds are known to produce ECG changes—deep symmetrical T wave inversion, prolonged QT and Q waves, and mimic acute MI (Figure 4).
Metabolic Abnormalities Various metabolic abnormalities, especially hyperkalemia and hypothermia, show ECG changes difficult to distinguish from ACS (Figure 5).
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Figure 1: ECG in a patient of acute pericarditis mimicking acute myocardial infarction
Figure 2: Poor R wave progression mimicking anteroseptal infarction (ASMI)
Figure 3: ECG in a case of chronic obstructive pulmonary disease (COPD) mimicking anteroseptal infarction (ASMI)
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Figure 4: ECG changes in a patient of subarachnoid hemorrhage mimicking acute myocardial infarction
ABNORMAL ECG WITH NORMAL HEARTS Early repolarization syndrome (ERS) Juvenile T wave pattern Left ventricular hypertrophy (LVH) pattern Poor progression of R wave. Early repolarization is one of the most common abnormalities noted, especially in young adults. The ECG shows raised J point with notched downstroke of QRS complex, most commonly in the rightsided and midprecordial leads. It is seen in almost 1–2% of normal population. It is quite commonly confused with evolving acute MI. Historically, it is considered to be benign condition, and some recent studies have related ERS to be associated with sudden cardiac death (SCD) or VT/ ventricular fibrillation (VF).7 In children, T waves are inverted in precordial leads up to V4; while in adults, T waves are inverted up to V2 only. Sometimes, inverted T waves up to V4 continue in adulthood, and it is known as persistent juvenile pattern. Sometimes, LVH pattern is noted in thin individuals. The R wave of less than 3 mm in Lead V3 is considered as poor progression of R wave and seen in dextrocardia, pneumothorax, pectus excavatum, and as normal variant. Sometimes, it is confused with anterior wall MI. Abnormal lean Q waves can be noticed in LII and aVF and not considered as sign of old inferior wall MI.
1. Normal variants: Early repolarization syndrome is sometimes too difficult to differentiate from acute evolving MI (Figure 6). 2. Miscellaneous causes: Certain genetic conditions, such as Brugada syndrome, may mimic anterior wall MI. 3. WolffParkinsonWhite syndrome, hypertrophic cardiomyopathy, amyloidosis, myocarditis, pulmonary embolism and rarely hyperkalemia may present with Q waves and/or ST elevation mimicking acute MI. 4. One of the most confusing findings in the ECG is the STT waves changes because it may be nonspecific, may represent various medical disorders, drug side effects, or as serious as myocardial ischemia.
COMMON ARTIFACTS IN ECG INTERPRETATION The ECG artifacts are defined as ECG abnormalities recorded as cardiac potentials, but are not related to electrical activity of the heart. Normal components of the ECG are distorted because of these artifacts. These artifacts need to be recognized; else, it may lead to unnecessary testing and wrong treatment.
Causes These could be: Internal External.
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Figure 5: ECG in case of hyperkalemia mimicking extensive anterior wall myocardial infarction and ECG after correction of hyperkalemia
Figure 6: ECG showing early repolarization mimicking acute anteroseptal infarction (ASMI)
Internal
Patients’ motion: — Tremors and shiveringinduced motion artifacts — Simple movements. Muscular activity.
External
Electromagnetic interference:9 — Improper earthing
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Power line electrical disturbances Electrical cautery, other electrical devices, radiofrequency products, etc. Cable and electrode malfunction: — Insufficient electrode gel — Misplaced leads — Broken wires — Inappropriate filer settings — Loose connections. — —
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The ECG interpretation is valid only;10 If electrodes are placed in correct anatomic locations Lead wires are attached to appropriate leads The recording is of good technical quality Proper filtering Absence of extraneous electrical noise Serial ECG interpretation can be perfect only if ECG is taken with consistent technique, i.e. Electrodes in same location The patient’s body in same position Using the same lead configuration. The ECG artifacts can be due to: Inaccurate lead placement Lead wire reversals Noisy ECG signals Inappropriate filter settings Serial comparison with inconsistent lead sets. The ECG artifacts because of electrical noise (Figure 7). The ECG artifacts because of tremors: Sometimes, ECG is recorded in extreme cold conditions and the patient is shivering or the patient is having disease with tremors as Parkinsonism, giving rise to artifacts (Figures 8 to 10). The ECG wrongly interpreted at ventricular tachycardia (Figure 11). Clinical implications of wrong interpretation of ECG artifacts in one study:11
12 patients wrongly diagnosed as VT Unnecessary cardiac catheterization in 3 patients Unnecessary medical therapies including intravenous (IV) antiarrhythmic agents in 9 patients Precordial thumps in 2 patients Prosthesispatient mismatch (PPM) in 1 patient Automated implantable cardioverterdefibrillator (AICD) in 1 patient. Differentiation of electrocardiographic artifact from real disease: Absence of symptoms or hemodynamic variation during the event Normal ventricular complexes appearing among dysrhythmic beats Association with body movement Instability of baseline tracing during and immediately following the alleged arrhythmia Synchronous, visible notching consistent with the underlying ventricular rhythm marching through the pseudoarrhythmia.
LEAD MISPLACEMENTS The most common artifacts in the ECG are because of limb lead reversals:12,13 In a standard ECG, limb leads are attached as follows (Figure 12).
Figure 7: ECG artifacts because of electrical noise
Figure 8: ECG artifacts because of tremors
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Figure 9: ECG artifact because of body movement/loose connection
Figure 10: ECG artifacts because of loose connection and compared with true arrhythmia
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Figure 12: Normal electrode attachment
Figure 13: Right arm-left arm (RA-LA) limb lead reversal
Figure 14: Left arm-left leg (LA-LL) limb lead reversal
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The most common limb lead reversal is reversal of right arm (RA) with left arm (LA) (Figure 13). The P wave, QRS complex, and T wave is inverted in Lead I. Lead II and Lead III are interchanged. The aVR shows upright complexes. One gets confused with true dextrocardia. However, as compared to true dextrocardia, the precordial leads are normal with such lead misplacement.
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Other lead reversals and ECG are as shown below: When LA electrode and left leg (LL) electrode is interchanged, Lead I becomes Lead II and Lead II becomes Lead I and Lead III is inverted (Figure 14). It is difficult to diagnose unless compared with previous ECG. When LL, LA, and RA electrodes are interchanged, Lead I, Lead II, and Lead III are inverted (Figure 15).
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Figure 15: Left arm-right arm-left leg (LA-RA-LL) limb lead reversal
Figure 16: Right arm-right leg (RA-RL) limb lead reversal
Figure 17: Left arm-right leg (LA-RL) limb lead reversal
If right leg (RL) electrode (neutral electrode) is interchanged with RA or LA electrode, Lead II or Lead III becomes flat (Figures 16 and 17). ECG artifact because of change in chest lead positions: Sometimes, one may interchange the precordial electrode. It is again difficult to diagnose, unless the ECG is very
critically seen and compared with previous ECG (Figure 18). The ECG electrodes placement one space below changing morphology from right bundle branch block (RBBB) to ventricular tachycardia (Figures 19A and B):14 659
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Figure 18: ECG artifact because of changes in positions of chest leads
A
B Figures 19A and B: ECG in case of right bundle branch block (RBBB), mimicking as ventricular tachycardia because of changed position of chest leads
Figure 20A
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Figure 20B Figures 20A and B: Standard ECG leads and monitor leads show different patterns
Figure 21: Linked median ECG showing ventricular premature beats (VPBs) as ventricular tachycardia
Standard ECG and monitor ECG showing variation:15 One shall not compare the standard ECG with ECG pattern shown on the cardiac monitors (Figures 20A and B). Linked median ECG on ECG machines and on stress test machines mimicking a few ventricular premature beats (VPBs) as ventricular tachycardia: So many stress test machines have the option of linked medians and ECG
taken with that option averages out all the complexes and produces synthesized rhythm. One shall always look the raw rhythm at the bottom of record to interpret correctly (Figure 21). Similarly, most of the ECG machines have the computerized analysis and give erroneous diagnosis which not only confuses the doctor but also puts the 661
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patient under tremendous stress. The treating physician has to interpret the ECG properly and needs to explain the patient properly to alleviate his anxiety.
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CONCLUSION
6.
ECG is one of the first and important diagnostic tools in the diagnosis of cardiovascular diseases, especially for the diagnosis of ACS and arrhythmias. However, it is necessary it to diagnose correctly to come to accurate diagnosis and proper management of the case. It needs to be emphasized again that ECG shall always be interpreted in the light of history and physical findings. One should know the normal variants. To tackle the artifacts, proper ECG taking is the most important thing.
7.
REFERENCES 1. Carasso B, Gregoire F. Some limitations and pitfalls in electrocardiography, with special reference to pulmonary disease. Can Med Assoc J. 1955;72(4):26871. 2. Caceres L, Cooke D, Zalenski R, et al. Myocardial infarction with an initially normal electrocardiogramangiographic findings. Clin Cardiol. 1995;18(10):5638. 3. Francois SJ, Eme P, Urban P, et al. Impact of a normal or nonspecific admission ECG in the treatment and early outcome of patients with myocardial infarction in Swiss hospitals between 2003 and 2008. Swiss Med Wkly. 2010;140. 4. Obeyesekere MN, Klein GJ, Modi S, et al. How to perform and interpret provocative testing for the diagnosis of Brugada syndrome, long QT syndrome, and catecholaminergic
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polymorphic ventricular tachycardia. Cir Arrhythm Electrophysiol. 2011;4(6):95864. Bhatia V, Kaul U. Common errors in ECG diagnosis of coronary artery disease. J Assoc Physicians India. 2007;55:79. Sgarbossa FB, Pinski SL , Barbagelata A , et al. Electrocardiographic diagnosis of evolving acute myocardial infarction in the presence of left bundle branch block. GUSTO1 (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronaries Arteries) Investigators. NEJM. 1996;334(8):4817. Roberts JD, Gollob MH. Early repolarization: a rare primary arrhythmic syndrome and common modifier of arrhythmic risk. J Cardiovacs Electrophysiol. 2013;24(7):83743. Odman S, Oberg P. Movement induced potentials in surface electrodes. Med Biol Eng Comput. 1982;20(2):15966. Greutmann M, Horlick EM. Uncommon cause for a common electrocardiographic artefact. Can J Cardiol.2010;26(1):e30. Drew BJ. Pitfalls and artifacts in Electrocardiography. Cardiol Clin. 2006;24(3):30915. Knight BP, Pelosi F, Michaud GF et al. Clinical consequences of electrocardiographic artifact mimicking ventricular tachycardia. N Eng J Med. 1999;341:12774. Nathani PJ, R Sathish. ECG artifacts : Recognition and prevention. IJE. 2008;1:1115. Harrigan RA. Electrode misconnection, misplacement and artifact. Emerg Med Clin N Am. 2006;24:22735. Wenger W, Kligfield P. Variability of precordial electrode placement during routine electrocardiography. J Electrocardiol. 1996;29(3):17984. Drew BJ, Pelter MM, Wung SF et al. Accuracy of the EASI 12lead electrocardiogram compared to the standard 12 lead electrocardiogram for diagnosing multiple cardiac abnormalities. J Electrocardiol. 1999;32(Suppl):3847.
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Computerized ECGs: CHAPTER 79 Strengths and Limitations Kartikeya Bhargava
INTRODUCTION Since the invention of the electrocardiogram (ECG) more than a century ago,1 electrocardiography has remained as the first and universal investigation for the diagnosis of most cardiac diseases and many systemic disorders. Although ECG reading is taught in the medical curriculum at almost all levels and continuing medical education programs, many physicians still need assistance in its interpretation. Moreover, there is many a times a lack of consensus even among expert cardiologists and ECG readers when a complex ECG is presented. On top of it, measurements and calculations of common intervals and wave amplitudes in an ECG is often cumbersome and time consuming. Hence, there is always a need for computerized ECG analysis to assist the readers of ECGs including emergency physicians and technicians. Automated ECG was developed to overcome all these issues beginning in the late 1950s2 and has come a long way. However, despite a lot of advancement in technology, computerized ECG interpretation is not trusted by most experienced cardiologists who believe more in their ECG reading skills. Even the learners of ECG are always instructed not to believe the automated interpretations blindly and always carefully look at the ECG waveforms and intervals themselves. The reasons for this is often less-than-perfect interpretations provided by the computerized algorithms used in the ECG machines in the today’s world despite more than six decades of development of computerized ECG. One of the important causes of these imperfect interpretations is the lack of internationally accepted agreements and standards in the definition of waveforms, measurements of intervals and wave amplitudes, and duration and criteria for classifying normal from abnormal.3 The present chapter looks at the strengths and limitations of computerized ECG analysis.
COMPUTERIZED ECG: METHODOLOGY AND TECHNICAL ASPECTS Computerized ECG systems are of one of the following two types: 1. Computer-interpreted electrocardiograms (CIE): It comprises of computer-aided interpretation of the
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ECG that has been acquired and stored digitally and primarily involves pattern recognition techniques. The present chapter basically focuses on this type of computerized ECG. 2. Computerized electrocardiographic monitoring: It comprises of continuous online or real-time analysis of dynamic ECG signal primarily meant for prompt recognition and diagnosis of arrhythmias, but nowadays also involves continuous QT interval or ST segment deviation measurements. Examples of these include monitors in ICUs and external loop recording systems. The computerized ECG interpretation necessitates many steps4 that can be briefly summarized as below: Acquisition and digitization: Acquiring the analog ECG signals and converting them to digital signals is the first step in any ECG machine. Filtering and signal processing: The digitized signal is processed and filtered to remove noisy components such as muscle potentials, tremor or movement artifacts, respiratory phase-induced baseline drift, etc. Averaging: Most current digital ECG systems record all ECG leads simultaneously and an average template complex for each lead is derived after excluding premature complexes. Waveform recognition: The various waveforms, such as P wave, QRS complex, and T wave, are detected and recognized and their boundaries (onset and termination) are defined numerically by the rate of voltage change. The QRS complex is usually easy to recognize by the rate of voltage change compared to the P and T waves that may require additional methods. The recognition is made more accurate by superimposition of templates of each complex in various leads and their temporal alignment that is usually not easy manually. Measurements: The various interwave intervals, such as PR interval, QT interval, and RR interval, are measured and wave amplitudes and durations computed. At times, a wave (e.g. a QRS) may look deceptively narrow in one lead but broad in other lead of the 12-lead system if there is an isoelectric interval at the onset or termination of the wave. Hence, globally-derived
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interval measurements are usually longer and more accurate than single-lead derived measurements. 5,6 Some of the computerized systems also calculate the axis of the various waveforms as well as deviation of the ST segments that may provide more accurate and precise details of these parameters. Pattern recognition: After waveform recognition and various measurements, the computer programs try to simulate the pattern recognition skill of ECG readers by various mathematical techniques such as cross-correlation or by fitting a various mathematical expression such as Fourier series to the waveforms. However, as opined by many researchers, the currently used technology in the computerized ECG does not match the pattern recognition skills of human ECG readers due to remarkable and extensive capacity of the human brain.7 That, probably, is one of the major reasons for the mistakes made by computerized ECG interpretation software. Algorithmic interpretation: The processed ECG and its waveforms are subjected to various diagnostic algorithms that are proprietary and vary among different manufacturers. At the end of these processes, a computerized interpretation of the ECG is generated including various measurements. Transmission, storage and archiving: Most of these computerized machines allow transmission of the data as wells as storage and archiving in digital format.
ACCURACY OF COMPUTER-INTERPRETED ELECTROCARDIOGRAMS It is generally believed that although computerized interpretation of ECG is useful to medical students and physicians with inadequate ECG reading skills, it is often inaccurate and misguides the diagnosis and treatment of patients. The interpretation of ECG is not totally a mathematical process but rather a combination of subjective and objective parameters; and hence, there is often disagreement even among the expert cardiologists leading to interobserver variability. 8 The computerized interpretation on the other hand relies mainly on the direction of deflections, measurements of various intervals, and mathematical algorithms and lacks not only the human pattern recognition skills but also inputs from clinical and circumstantial data. Moreover, the database that have been used to devise the computer algorithms are often insufficient and may not represent the entire normal population as well as all possible disease states. It is no surprise that computer-based interpretation is often wrong and needs to be over-read before making any conclusive diagnosis. In fact, studies both old and recent have proven this fact that the overall accuracy score for computer ECG programs may vary from 80%9 to may be 94%.10,11
The accuracy of the computerized interpretation also varies according to the parameters or disease conditions being studied. It has been seen that the computergenerated measurements of various intervals are usually accurate, especially for serial measurements (Figure 1). However, in one study6 comparing interval measurements made by four different digital electrocardiographs in normal as well as patients with long QT syndrome and drug-induced QT prolongation; it was found that the mean absolute differences between algorithms were similar for QRS duration and QT interval in normal persons but were significantly larger in patients with long QT syndrome. The inaccuracies in amplitude measurements are uncommon but rate-related or day-to-day variability in amplitude are known and can result in significant differences in computer-based measurements.6 A major reason for differences in measurements among different machines and vendors is lack of standardization and recommendations for definition of waves and references that persists despite efforts being made.4,12,13 It has been seen that the computer interpretation of ECGs is often not up to the mark in diagnosis of arrhythmias, atrioventricular conduction abnormalities, and pacemaker-related abnormal rhythms.11
UTILITY OF COMPUTER-INTERPRETED ECG IN SPECIFIC DIAGNOSIS As indicated earlier, the accuracy of the computerized ECG interpretation varies depending not only on the computer program or algorithms used but also on the specific clinical condition being evaluated. The following paragraphs summarize the status of CIE in various disease states.
Myocardial Infarction and Acute Coronary Syndromes The ECG is the initial investigation in all patients suspected of acute coronary syndromes (ACS). It has retained its usefulness in not only diagnosing but also in decision making regarding the need for thrombolysis or primary angioplasty over the years despite availability of many new and sophisticated blood tests and imaging methods. Although emergency physicians are usually very good at diagnosing acute ST segment elevation myocardial infarction (STEMI), at times, the ECG may be normal or may have very subtle changes that may be overlooked by the emergency physicians or medical students. It may result in inappropriate delay in the definitive reperfusion therapy or even discharge from the emergency department with disastrous consequences. In this regard, the CIE may help with the correct diagnosis that can help in taking appropriate and timely decisions regarding not only reperfusion therapy but also need for admission
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79 Computerized ECGs: Strengths and Limitations Figure 1: Long QT syndrome in a child has been picked up by the computerized algorithm as long QT interval for rate along with diffuse T wave abnormalities. However, the presence of the P wave merging with the preceding T wave at times has resulted in the computer reading it wrongly as variability in the PR interval and atrioventricular (AV) dissociation, in an otherwise normal sinus rhythm with 1 to 1 AV conduction
and monitoring in borderline situations. Computerized automated algorithms have been specifically designed to diagnose acute STEMI and have been validated in the emergency room as well as in the prehospital phase to enable early diagnosis. These algorithms not only provide a diagnosis of acute myocardial infarction (MI) but also suggest the culprit coronary artery and identify the location of occlusion in the culprit artery. However, studies have shown that these CIE often overdiagnose (false-positive result) in up to 42% of patients leading to unnecessary catheterizations or thrombolysis and at the same time may miss the diagnosis (false-negative result) in 20–40% of patients (Figure 2).14,15 Hence, it is recommended that the interpretations provided by the computer algorithms should not be relied upon blindly to activate the cath labs but should always be used in conjunction with the cardiologist or physicians with experience in diagnosing and treating ACS and STEMI. It has been shown in a prehospital setting that technical artifacts and nonischemic causes of ST segment elevation, such as early repolarization pattern, are the common reasons for wrong diagnosis by computerized interpretation.16 It has been suggested that the clinical and demographic data including history of chest discomfort be included in the computer algorithms to increase the sensitivity of diagnosis of ACS. Also, the interpretation can include alerts: (i) to record the right-sided precordial leads
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if need be as in acute inferior STEMI, (ii) to indicate high risk and need for early reperfusion if there are findings of left main or proximal disease or multivessel disease, and (iii) to indicate possibility of improper diagnosis if the ECG shows features that may complicate ischemia interpretation such as pre-excitation, left bundle branch block, or ventricular paced rhythm. 17,18 Addition of all these features in the computer interpretation may be quite useful to the unexperienced reader and may even supplement any information overlooked by an experienced reader.
Conduction Blocks and Tachyarrhythmias Many general physicians and students of cardiology are not very confident in accurately diagnosing conduction blocks and cardiac arrhythmias on the ECG. Correct computerized interpretation, thus, is going to be useful to most of them. However, though desirable, the computerized interpretation is very frequently wrong in the diagnosis of these arrhythmias. In fact, it was found in one study that looked at more than 2,000 ECGs, the computerized interpretation was quite accurate in sinus rhythm (positive predictive accuracy 95%) but was less accurate in nonsinus rhythms (positive predictive accuracy 53.5%) and rhythm interpretation by computer was not possible in 2% of tracings.19 The main reason for
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Figure 2: Extensive acute anterior wall myocardial infarction showing marked ST elevation in precordial and lateral leads with reciprocal changes in the inferior leads is shown. Though, the ST changes are so prominent and unlikely to be missed, the computer somehow only labels as ischemia-related ST-T abnormality (and not acute infarction). An untrained reader, who completely relies on the computerized interpretation, may delay the necessary and immediately needed reperfusion therapy with such computer errors
the incorrect diagnosis of the rhythm abnormality was inability to accurately identify the P waves due to either small amplitude, varying morphology or its masking in other waveforms (Figure 3). The most common arrhythmia in general practice— atrial fibrillation is usually diagnosed accurately by the computerized interpretation. However, it may at times be overdiagnosed in 9–19% of ECGs due mostly to the presence of frequent atrial premature contractions on the background of sinus tachycardia. 20,21 Other reasons for overinterpreted atrial fibrillation can be sinus arrhythmia, sinus rhythm or atrial tachycardia (or flutter) with variable atrioventricular conduction resulting in irregular RR intervals, AV block, and frequent artifacts (Figure 4). This overdiagnosis is a major limitation of CIE as it may result in initiation of unnecessary and potentially harmful medical treatment, such as antiarrhythmic drugs or anticoagulation, in up to 10% of cases.22 At other times, the computer may miss the diagnosis of atrial fibrillation as exemplified in Figure 5. These facts and examples again emphasize that a diagnosis of atrial fibrillation by computerized interpretation should be confirmed by over-reading of ECG by cardiac experts before initiation of potentially harmful therapy or ordering additional investigations. The computer algorithms usually diagnose bundle branch blocks, fascicular blocks, and atrioventricular blocks accurately; although inability to recognize some of the P waves may result in wrong diagnosis in situations like 2 to 1 or complete AV block (Figure 6). The accurate diagnosis of wide QRS tachycardia is at times difficult even by an experienced cardiologist; and hence, computerized ECG may be useful. However, the data on accuracy of computerized interpretation of wide QRS tachycardia is limited and a few examples where the computerized interpretation was inaccurate are shown in
Figures 7 to 9. Fortunately, we know that most wide QRS tachycardias are ventricular in origin and whenever in doubt should be better treated as ventricular tachycardia rather than supraventricular tachycardia with aberrancy, making the true need for computerized interpretation in this regard uncommon.
Pacemaker Rhythms Older generation computer algorithms often failed to detect the pacemaker pulse that is usually of low voltage resulting in frequent misinterpretation and errors, such as diagnosing left bundle branch block (LBBB) or MI or left ventricular hypertrophy in patients with paced QRSithms specifically designed to amplify and recognize the pacing stimulus artifact have made tremendous improvement in diagnosing pacemaker rhythms, complex pacemaker algorithms (e.g. managed ventricular pacing mode) and recent advances in pacing technology including resynchronization therapy, newer sites of pacing like midseptal or His-bundle pacing, and multipoint pacing, are still ongoing challenges for improving the accuracy of the computerized interpretation of pacemaker rhythms.
Congenital and Acquired Long QT Syndromes Automated QT interval measurements by the computerized ECG can be quite useful for the diagnosis of congenital long QT syndromes as well as diagnosis and serial monitoring of acquired (usually drug induced) QT prolongation both with a static ECG as well as monitoring systems that provide dynamic QT interval in intensive care units. Like other fields, algorithms for QT interval measurement on ECG have also shown marked improvement from olden times; although errors still occur especially if the ECG data quality is not up to the mark.23 Automated QT measurements are also very useful for serial monitoring and comparisons of QT interval in research settings and
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79 Computerized ECGs: Strengths and Limitations Figure 3: Narrow QRS tachycardia diagnosed as junctional tachycardia by the computerized algorithm due to nonvisualization of the P waves. However, careful look at lead V1 reveals two P waves for each QRS complex—one at the end of the QRS (r’) and another exactly in between the two consecutive R waves, suggesting a diagnosis of atrial flutter with 2 to 1 atrioventricular conduction. It is difficult to categorically recognize P waves in any other leads apart from lead V1
new drug trials. It is suggested that for these purposes, either same electrocardiograph machine or different machines using the same algorithm for QT measurement be utilized since different algorithms can provide different QT interval if applied on the same ECG. 24 Some recent studies have shown that the automated QT interval measurements may not be as accurate as thought; and hence, it is recommended that the correctness of these computerized measurements should always be verified by manually measuring the QT interval by experienced readers.25-27
Chamber Hypertrophy and Enlargement The computerized ECG interpretation usually accurately identifies chamber hypertrophy based on the available clinically used criteria for the same. However, as is well known, ECG has poor sensitivity and low specificity for detected left ventricular hypertrophy. Moreover, since many criteria including simple ones like voltage criteria and complex ones like QRS area based are available and used by these computers, the final interpretation of the ECG should not only indicate the presence or absence of chamber hypertrophy or enlargement but also specify the criteria applied and the ones that were abnormal.28
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QRS Duration Measurement The measurement of QRS duration is important to classify wide and narrow QRS complex tachycardia; but more recently, it is of utmost importance in selecting patients for cardiac resynchronization therapy (CRT). Hence, automated QRS measurement in patients with heart failure and bundle branch blocks is very useful in selecting patients for and predicting the response to CRT. The various ECG systems use different methods that may result in different automated measured QRS duration in the same patient in different ECGs.29 Moreover, as stated earlier, the global QRS duration measured by computerized software is usually longer than that measured from single lead but are likely to be more accurate. Thus, it is important to measure the QRS duration manually before selecting or denying a patient resynchronization therapy based just on automated measurement by computerized ECGs.30
COMPUTERIZED ECGs: STRENGTHS AND LIMITATIONS—GENERAL COMMENTS AND CONCLUDING REMARKS The presence of computerized interpretation of ECG in most present-day systems makes it extremely important 667
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Figure 4: Sinus rhythm with complete atrioventricular (AV) block with wide QRS escape rhythm at a rate of 24 beats per minute in a middleaged patient. Although the computer algorithm has correctly identified complete AV block, it has wrongly picked up the P waves with atrial rate >220 and thus is mistaking a diagnosis of atrial fibrillation or flutter
Figure 5: Complete atrioventricular (AV) block developing after mitral valve replacement surgery in a patient with permanent atrial fibrillation is shown. The computer software has wrongly detected a ‘normal P wave’ with wrongly measured ‘short PR interval’ and interpreted it wrongly as ‘sinus rhythm’. If the ECG is not seen carefully, an important diagnosis of postoperative complete AV block in the background of atrial fibrillation diagnosed by slow regular RR intervals can be missed
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79 Computerized ECGs: Strengths and Limitations Figure 6: Sinus rhythm with 2 to 1 atrioventricular block with right bundle branch block in the conducted beats is clearly present in the ECG shown. However, the computer software fails to recognize the blocked P waves and makes an incorrect diagnosis of sinus bradycardia
Figure 7: Wide QRS tachycardia with right bundle branch block (RBBB) type pattern in lead V1 and right superior axis in a young male suggesting a diagnosis of idiopathic left ventricular (fascicular) tachycardia that was later confirmed and ablated during electrophysiology study. The computerized interpretation erroneously states sinus tachycardia, although the P waves are not clearly recognizable (probably lie at end of each QRS complex). The RBBB and left anterior fascicular block are correctly diagnosed by the computer software. The presence of rS complex in lead V6 in a RBBB type wide QRS tachycardia is also suggesting a diagnosis of ventricular tachycardia in this tracing
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Figure 8: A wide QRS tachycardia with left bundle branch block type pattern in V1 and inferior axis that is very likely ventricular tachycardia from the outflow tract region has been incorrectly labeled as sinus tachycardia and Wolff–Parkinson–White syndrome by the computer algorithm
Figure 9: A very broad QRS tachycardia with right bundle branch block pattern and northwest axis of the QRS with QS complexes in lead V6 that is clearly myocardial ventricular tachycardia is erroneously diagnosed as probable supraventricular tachycardia by the computerized software
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been recognized or thought of by the inexperienced reader. The opinion provided by the computer also helps in educating and prompting more careful and targeted reading of the ECG (Figure 10). At the same time, one needs to be aware that the computerized systems may be inaccurate in interpreting nonsinus rhythms, may misinterpret pacemaker rhythms and may not accurately diagnose arrhythmias. Also, they at times overinterpret J-point elevation of early repolarization pattern to acute MI or may miss subtle findings of acute infarctions. Rare diagnosis and clinical entities, such as QRS fragmentation due to epsilon waves in arrhythmogenic right ventricular dysplasia (Figure 11) or deWinter’s T waves, may not be known to the computer algorithms but easily recognizable by an experienced reader due to their pattern recognition skills. Since most of the times, the age is not entered by the technician recording the ECG or the algorithms of the manufacturer does not have program for children, the pediatric ECG interpretation including measurements may be incorrect. Hence, it is recommended that the computerized ECG interpretation should be considered only as an adjunct to, and not a substitute for the ECG reading skills of the clinician.25,31 All computerized ECG reports should be over-read by experienced readers before a final conclusion or report can be given. A collaboration between scientific societies of ECG, developers of algorithms and manufacturers and clinical ECG experts is needed to further improve the performance of computerized ECG.
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79 Computerized ECGs: Strengths and Limitations
to understand their strengths and limitations before following and trusting them blindly. The finish or perfectness of any product (or output) depends on the data provided or the input. The same applies to the computerized interpretation of ECGs as well. If the data provided is faulty (improper electrode placement) or has many artifacts, it is very likely that the computerized interpretation including measurements will be inaccurate. Similarly, to reduce the variations in the interpretation of ECG from different manufacturers, it is imperative that standardization of various criteria be done by the electrocardiography societies and followed rigorously by the manufacturers in developing their algorithms. Table 1 lists suggestions and recommendations at various levels to improve the accuracy of computerized ECG interpretation and to make its best use by the clinician.31 It is well know n now that the computer ized measurements of rate, intervals, and axes are usually accurate, especially if there are no artifacts. Also, the computerized interpretations are reliable in recognizing sinus rhythm and normal tracings. In fact, if the computerized interpretation of a good quality ECG suggests a ’normal ECG’; the chances of it being normal are quite high and, thus, readers can save a lot of time in reporting such ECGs. It has in fact been shown that computerized interpretation reduces the analysis time by up to 24–28% for experienced readers.3 The best advantage of a computerized interpretation for an experienced reader is that it saves time. On the other hand, for an inexperienced reader, the major advantage of computerassisted ECGs is the backup opinion that may not have
Table 1: Suggestions and actions to be taken at various levels to improve computerized ECG interpretation and its use by the clinician A. At the level of nurses and technicians 1. Proper placement of ECG electrodes 2. Use of appropriate skin preparation and use of contact gel 3. Continuous and periodic education and training of nurses and technicians involved in recording ECGs B. At the level of ECG societies 1. Development of a large database of normal parameters including all ages and both sexes representing the overall population 2. Standardization of nomenclature and uniformization of various diagnostic criteria 3. Laying down of appropriate guidelines for manufacturers to develop algorithms and testing these algorithms for their accuracy in different subsets of normal individuals and patients C. At the level of manufacturers of ECG machines 1. Development of ECG algorithms using standardized criteria as laid down by societies 2. Continuous updating of the algorithms with advancement in knowledge and technology 3. Inclusion of age, gender, and race and basic clinical information in the algorithms 4. Algorithms should specify the criteria used for diagnosing an abnormality if multiple criteria exist 5. Refinement of algorithms specific to the disease condition diagnosed, e.g. identification of culprit vessel and site of occlusion in ST elevation myocardial infarction D. At the level of ECG reader or physician 1. Learn to interpret the ECG with visual analysis and manual measurements first before looking at the computerized interpretation 2. Verify the findings interpreted manually with that of the computerized interpretation 3. Recognize any findings overlooked initially after the computerized ECG suggests or diagnoses it 4. Know the strengths and limitations of computerized interpretation to make the most use of it 5. Report any wrong interpretation provided by the computerized ECG to the manufacturer to help in subsequent improvements and correction
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Figure 10: The ECG of a 32-year-old lady with history of palpitations shows short PR interval, delta waves and widened QRS complexes. The computerized algorithm has not only correctly identified the presence of ventricular pre-excitation but also correctly localized the accessory pathway to the left side
Figure 11: The ECG showing fragmented QRS complexes with epsilon waves and marked T wave inversions in precordial and inferior leads during sinus rhythm is diagnostic of arrhythmogenic right ventricular dysplasia. However, the computer has totally missed the correct diagnosis
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REFERENCES
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1. Barold SS. Willem Einthoven and the birth of clinical e l e c t ro ca rd i o g rap hy a hu n d re d yea rs ag o. Ca rd Electrophysiol Rev. 2003;7(1):99-104. 2. Taback L, Marden E, Mason HL, et al. Digital recording of electrocardiographic data for analysis by a digital computer. IRE Trans Med Electro. 1959;6(3):167–71. 3. Hongo RH, Goldschlager N. Status of computerized electrocardiography. Cardiol Clin. 2006;24(3):491–504. 4. Kligfield P, Gettes LS, Bailey JJ, et al. Recommendations for the standardization and interpretation of the electrocardiogram. Part I: the electrocardiogram and its technology a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol. 2007;49(10):1109–27. 5. Kligfield P, Tyl B, Mareek M, et al. Magnitude, mechanism, and reproducibility of QT interval differences between superimposed global and individual lead ECG complexes. Ann Noninvasive Electrocardiol. 2007;12(2):145–52. 6. Kligfield P, Badilini F, Rowlandson I, et al. Comparison of automated measurements of electrocardiographic intervals and durations by computer-based algorithms of digital electrocardiographs. Am Heart J. 2014;167(2):150–9. 7. Alpert JS. Can you trust a computer to read your electrocardiogram? Am J Med. 2012;125(6):525–6. 8. Mele PF. The ECG dilemma: guidelines on improving interpretation. J Healthc Risk Manag. 2008;28(2):27–31 9. Hagan AD, Alpert JS, editors. Evaluation of computer programs for clinical electrocardiography. In: Cady L, ed. Computer Techniques in Cardiology. New York: Marcel Dekker, Inc; pp. 77-96. 10. Willems JL, Abreu-Lima C, Arnaud P, et al. The diagnostic performance of computer programs for the interpretation of electrocardiograms. N Engl J Med. 1991;325(25):1767–73. 11. Guglin ME, Thatai D. Common errors in computer electrocardiogram interpretation. Int J Cardiol. 2006;106(2):232–7. 12. Willems JL. A plea for common standards in computer aided ECG analysis. Comput Biomed Res. 1980;13(2):120–31. 13. Recommendations for measurement standards in quantitative electrocardiography. The CSE Working Party. Eur Heart J. 1985;6(10):815–25. 14. O’Connor RE, Al Ali AS, Brady WJ, et al. Part 9: Acute coronary syndromes: 2015 American Heart Association guidelines update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(18 suppl 2):S483–500. 15. Garvey JL, Zegre-Hemsey J, Gregg R, et al. Electrocardiographic diagnosis of ST segment elevation myocardial infarction: an evaluation of three automated interpretation algorithms. J Electrocardiol. 2016;49(5):728-32.
16. Bosson N, Sanko S, Stickney RE, et al. Causes of Prehospital Misinterpretations of ST Elevation Myocardial Infarction. Prehosp Emerg Care. 2017;21(3):283–90. 17. Wagner GS, Macfarlane P, Wellens H, et al. AHA/ACCF/ HRS recommendations for the standardization and interpretation of the electrocardiogram: part VI: acute ischemia/infarction: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol. 2009;53(11):1003-11. 18. Meissner A, Trappe HJ, de Boer MJ, et al. The value of the ECG for decision-making at first medical contact in the patient with acute chest pain. Neth Heart J. 2010;18(6):301–6. 19. Shah AP, Rubin SA. Errors in computerized electroc a rd i o g ra m i nt e r p re t at i o n o f c a rd i a c rhy t h m. J Electrocardiol. 2007;40(5):385–90. 20. Bogun F, Anh D, Kalahasty G, et al. Misdiagnosis of atrial fibrillation and its clinical consequences. Am J Med. 2004;117(9):636–42. 21. Hwan Bae M, Hoon Lee J, Heon Yang D, et al. Erroneous computer electrocardiogram interpretation of atrial fibrillation and its clinical consequences. Clin Cardiol. 2012;35(6):348-53. 22. Taggar JS, Coleman T, Lewis S, et al. Accuracy of methods for diagnosing atrial fibrillation using 12-lead ECG: a systematic review and meta-analysis. Int J Cardiol. 2015;184:175-83. 23. Tyl B, Azzam S, Blanco N, et al. Improvement and limitation of the reliability of automated QT measurement by recent algorithms. J Electrocardiol. 2011;44(3):320-5. 24. Talebi S, Azhir A, Zuber S, et al. Underestimated and unreported prolonged QTc by automated ECG analysis in patients on methadone: can we rely on computer reading? Acta Cardiol. 2015;70(2):211-6. 25. Estes NA 3rd. Computerized interpretation of ECGs: supplement not a substitute. Circ Arrhythm Electrophysiol. 2013;6:2-4. 26. Garg A, Lehmann MH. Prolonged QT interval diagnosis suppression by a widely used computerized ECG analysis system. Circ Arrhythm Electrophysiol. 2013;6:76–83. 27. Rautaharju PM, Surawicz B, Gettes LS, et al. AHA/ ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol. 2009;53(11):982–91. 28. Hancock EW, Deal BJ, Mirvis DM, et al. AHA/ACCF/ HRS recommendations for the standardization and interpretation of the electrocardiogram : part V: electrocardiogram changes associated with cardiac chamber hypertrophy: a scientific statement from the American Heart Association Electrocardiography and
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Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol. 2009;53(11):992–1002. 29. Vancura V, Wichterle D, Ulc I, et al. The variability of automated QRS duration measurement. Europace. 2017;19(4):636–43.
30. De Pooter J, El Haddad M, Stroobandt R, et al. Accuracy of computer calculated and manual QRS duration assessments: Clinical implications to select candidates for cardiac resynchronization therapy. Int J Cardiol. 2017;236:276–82. 31. Schlapfer J, Wellens HJJ. Computer-interpreted electrocardiograms: Benefits and limitations. J Am Coll Cardiol. 2017;70(9):1183-92.
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ECG Assessment of CHAPTER 80 Supraventricular Tachycardia Amit Vora, Samhita Kulkarni
INTRODUCTION
Step III: Identify the P’ Waves
Supraventricular tachycardia (SVT) originates or involves the atrium or the atrioventricular (AV) junction as essential part of the arrhythmia circuit. A careful and detailed analysis of the 12-lead ECG helps to understand the mechanism of SVT and thus guide to an appropriate acute and long-term treatment strategy. It is always prudent to interpret the ECG along with the history, clinical examination, and previous sinus rhythm (SR) or tachycardia ECG when available. In this chapter, a stepwise approach to the ECG is provided to identify the type of SVT. It is crucial to record and evaluate the 12-lead ECG and not rely on a rhythm strip to diagnose arrhythmias.
This is the most important and difficult step, but it is very useful in understanding the origin of the SVT. The morphology of the P’ wave and its relation to preceding and subsequent QRS help to identify the mechanism of SVT.
ECG ANALYSIS OF DIFFERENT SVTs
The three important steps in the ECG analysis of SVTs are as follows.
A practical, clinical classification of SVT based on AV nodal conduction for their continuation is depicted in Figure 1. Paroxysmal SVTs, such as AVNRT and AVRT, can be abruptly terminated by vagal maneuvers or AV nodal blocking drugs as the AV node is an essential part of the re-entrant circuit. The AV node-independent SVTs will only slow the ventricular rate with AV nodal block, but the atrial arrhythmia continues. Rarely, some varieties of atrial tachycardia (AT) may respond to vagal maneuvers.
Step I: Is the QRS Narrow or Wide?
Sinus Tachycardia
A narrow QRS (width 130 ms.
Atrioventricular Re-entrant Tachycardia It is mediated by accessory pathways (AP), i.e. muscular connections between the atrium and ventricle other than the AV node, breaching the fibrous AV ring. These pathways may be manifest or concealed. Manifest APs in SR will result in a pre-excitation pattern. Concealed APs will not show any pre-excitation pattern in SR and will conduct only retrogradely (from ventricle to atrium) during SVT. Almost 90% of all AP-mediated SVTs are concealed. Orthodromic AVRT is the term used when a re-entrant circuit is formed using the AP and the AV node such that antegrade conduction (from atrium to ventricle) occurs over the AV node and the retrograde (ventricle to atrium) occurs over the AP. Orthodromic AVRT presents most often as narrow QRS SVT and only in the presence of a BBB, will it be wide QRS. Antidromic AVRT is the term used when the antegrade conduction occurs via the AP and the retrograde conduction over the AV node or another AP. Antidromic AVRT, therefore, always presents as a wide QRS SVT. The orthodromic AVRTs are regular and they need to be differentiated from other regular SVT by identifying the retrograde P wave. The RP interval is shorter than the PR interval. In fact, the RP interval is generally less than 150
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ms in orthodromic AVRT. It is, therefore, relatively easy to differentiate from AT as the latter most often has a longer RP interval (at least 50% or more of the RR interval). The closest differential of narrow QRS orthodromic AVRT is AVNRT.5 However, in AVNRT, the atrium and ventricles activate simultaneously and thus has the shortest RP interval, generally 100/min and QRS width >120 ms. A narrow QRS complex is reflective of a rapid and synchronous activation sequence spreading through both ventricles through the bundle of His, bundle branches, and Purkinje network. A QRS duration >120 ms might occur in supraventricular tachycardia (SVT) with pre-existent bundle branch block (BBB) or in patients taking drugs that are capable of slowing intraventricular conduction (class IA and IC drugs, amiodarone). Conversely, in conditions such as fascicular ventricular tachycardia (VT) or VT that originates close to the His-Purkinje system, the QRS duration may be ≤120 ms. A QRS complex that is narrower during WCT than during sinus rhythm has to be VT, but this is rare. It is important that the QRS width be accurately measured on a standard 12-lead ECG, from the onset of the QRS complex to its terminal components. The lead showing the widest QRS should be measured; generally, a triphasic QRS complex, if present, will be reflective of the total QRS width. Also, measurement of the QRS duration in a single lead may be misleading (Figure 1). Evidence shows that the pre-test probability of a WQT being VT is in excess of 80% by virtue of sheer
prevalence of VT itself. The odds of WQT being VT exceed 90% if there is a history of myocardial infarction (Figures 2A and B). Figure 3 outlines a simple and quick ECG-clinical approach to unravel the etiology of WQT; this is the algorithm we have devised and follow.
TYPES OF WIDE QRS TACHYCARDIA
Ventricular tachycardia (VT) Supraventricular tachycardia (SVT) with left bundle branch block (LBBB)/right bundle branch block (RBBB) (pre-existing or rate-related) Pre-excited tachycardia [Wolff–Parkinson–White (WPW) syndrome with antidromic tachycardia or with atrial fibrillation/atrial flutter] Sinus tachycardia/SVT with myocardial delay.
STEPS FOR VENTRICULAR TACHYCARDIA DISCRIMINATION When analyzing an ECG with a wide QRS complex, a systematic approach should be used. The following steps are recommended: QRS width, regularity and its global representation should be checked in all 12 leads
Figure 1: Monomorphic ventricular tachycardia (VT). It is important to look at QRS complex width in all leads. Here, the QRS complex is relatively narrow in leads I and aVL but wide in leads V5 and V6
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81 ECG Assessment of Wide QRS Tachycardia
Figure 2A: Established/old anterior wall myocardial infarction (MI) with QR V1-V5
Figure 2B: Same patient, monomorphic ventricular tachycardia (VT), right bundle branch block (RBBB)-like pattern. The history of myocardial infarction (MI) itself is enough to diagnose VT unless proved otherwise; the north-west axis is diagnostic. The QR in V2-V5 point to this being a scar VT arising from the anterior wall
Presence and pattern of atrial activity (P wave) should be identified Relationship between atrial and ventricular activity should be determined Wide QRS complex morphology should be evaluated (particularly in leads V1 and aVR).
ASSESSMENT OF QRS REGULARITY If wide QRS is irregular, then the possibilities are: Atrial fibrillation (AFib) with WPW syndrome with anterograde conduction through accessory pathway (Figure 4). The rate and width of QRS complex is variable and depends upon competitive 685
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Figure 3: A practical approach to wide complex tachycardia (WCT) diagnosis
Figure 4: Atrial fibrillation with Wolff–Parkinson-White (WPW) syndrome. The appearance is fast, broad, irregular (FBI). Impulses from atria are conducted to the ventricle via the accessory pathway
conduction between the accessory pathway and the atrioventricular (AV) node AFib with pre-existing BBB (Figure 5) The Ashman phenomenon is an aberration of intraventricular conduction after a long/short RR
interval sequence. This is reasonably common in AFib. An aberrant conduction may disappear with normalization of QRS complex due to the occurrence of reverse Ashman phenomenon (short/long sequence) Polymorphic VT (Figure 6).
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81 ECG Assessment of Wide QRS Tachycardia
Figure 5: Atrial fibrillation with fast ventricular rate and pre-existing left bundle branch block (LBBB). The initial deflection of QRS is sharp in V1 (red box is 40 ms in duration)
Figure 6: Polymorphic ventricular tachycardia (VT). The QT interval is normal. The nonsustained ventricular tachycardia (NSVT) and the sustained VT both start with a premature ventricular contraction falling on the latter part of the T wave (R-on-T). This was from a patient with an acute coronary syndrome
Evaluation of Wide QRS Complex Capture and fusion beats are suggestive of VT. These are caused by partial (fusion) or complete (capture) activation of the ventricles by a P wave (usually a sinus complex), which is conducted antegradely over the normal AV conduction system. Capture and fusion beats usually occur in the presence of ventriculoatrial (VA) dissociation and with less rapid ventricular rates, which allow the P wave to get through the AV conduction system.
IDENTIFICATION OF P WAVE The P wave should be analyzed in all 12 leads, but especially in lead II and V1. During VT, several P wave scenarios are possible: (i) AV dissociation, wherein the
P waves may be seen intermittently, between the QRS or modifying the T wave (making it peaked in leads with a +ve T wave), (ii) 1:1 VA conduction, wherein a -ve P wave may be seen in lead II, usually in the ST segment, (iii) Variable VA conduction (Figure 7), and (iv) Atrial fibrillation.
RELATIONSHIP BETWEEN P AND QRS The relationship between atrial and ventricular activity is the key to interpret WQT. The VA dissociation or the presence of a second-degree VA block (QRS complexes geater than retrogradely conducted P waves) confirms VT (Figure 7). Conversely, if P waves are more frequent than QRS complexes, the diagnosis of SVT is confirmed (Figures 8A and B). If P waves and QRS complexes are 687
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Figure 7: Wide complex tachycardia (WCT); more QRS complexes than P waves. The P is inverted and narrow in lead II, hence retrograde. There is increasing RP interval till a P wave is dropped. This is not atrioventricular (AV) dissociation; it is ventriculoatrial (VA) Wenckebach conduction! Note also the QR in lead III, signifying a scar ventricular tachycardia (VT) from an old inferior wall myocardial infarction (MI)
equal in number, it could be SVT or VT with 1:1 retrograde conduction. Here, the P morphology is crucial; a positive P in lead II rules out VT.
MORPHOLOGIC ANALYSIS OF THE WIDE QRS COMPLEX: COMPARISON WITH SINUS RHYTHM If QRS morphology and axis is similar to that seen during sinus rhythm, this favors SVT. The exception is the rare bundle branch re-entry VT with LBBB where the patient has baseline ECG of LBBB and prolonged PR interval.
Detailed Morphologic Analysis of the Wide QRS Complex Broadly speaking, in SVT presenting as WQT, the QRS should fit into a typical BBB, both in precordial as well as in the limb leads (Figures 9A to D). In SVT with LBBB, the initial deflection of QRS complex is rapid and sharp while the terminal deflection is slurred and fragmented. By contrast, in VT with LBBB-like morphology, the initial deflection is slurred and fragmented. During VT, the initial activation takes place in the ventricle and the conduction occurs from myocyte to myocyte. Therefore, the initial deflection in VT is wide. On reaching the Purkinje network, this depolarization may become rapid, resulting in a narrow terminal deflection. The exception to this is VT originating in the Purkinje network or near the conduction system, which has narrow and rapid initial deflection. This is the
rationale behind the various proposed algorithms to identify VT. The QRS morphology based criteria are inaccurate in discriminating between V T and rare forms of supraventricular WQT, such as tachycardias with preexcitation or drug/electrolyte-induced aberrancy. In these circumstances, the QRS can be wide and bizarre, resembling that of VT.
Brugada Algorithm (Time Intervals Simplified to be Practically Useful) This is based on QRS morphology in precordial leads and the VA relationship. There are three morphologic criteria that point to the diagnosis of VT (Figure 10): 1. No RS complex in all precordial leads [specificity (100%), sensitivity (21%)]. Three possible patterns may be seen during VT: i. Positive concordance (only R waves) ii. Negative concordance (only QS waves) iii. QR morphology pattern (variant of negative concordance pattern, typically associated with an old myocardial infarction). Concordance may not always be a VT. For instance, a positive concordance is present in antidromic AV re-entry tachycardia sustained by a posterior accessory pathway. 2. At least one precordial lead showing intrinsicoid deflection >100 ms (specificity 98%, sensitivity 66%) 3. VA dissociation.
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81 ECG Assessment of Wide QRS Tachycardia Figure 8A: Wide complex tachycardia (WCT); P waves more than QRS complexes. This was a patient with recurrent pulmonary embolism. This shows a common mistake made in monitor or Holter interpretations. The WCT is usually labeled as ventricular tachycardia (VT). However, here we see an irregular narrow QRS tachycardia preceding and following the WCT; The PP interval and shortest RR intervals during this is identical to the RR during the WCT. Thus, this is atrial flutter with intermittent 1:1 conduction and bundle branch block, likely left bundle branch block (LBBB)
Figure 8B: Same patient, during electrophysiology (EP) study. Rapid atrial pacing brings out rate-related left bundle branch block (LBBB)
Figure 9A: Supraventricular tachycardia (SVT) with typical left bundle branch block (LBBB), narrow QRS and typical right bundle branch block (RBBB)
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Figure 9B: Typical atrioventricular nodal re-entrant tachycardia (AVNRT); A denotes atrial activation, which is coincident with the QRS complex
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Figure 9C: Atrioventricular nodal re-entrant tachycardia (AVNRT) with right bundle branch block (RBBB)
Figure 9D: Atrioventricular nodal re-entrant tachycardia (AVNRT) with left bundle branch block (LBBB)
Figure 10: Brugada algorithm
Morphology Criteria for VT In RBB morphology, WQT (QRS mostly positive in V1), VT is likely in the presence of: Monophasic R or biphasic qR or Rs complex in V1 RSR` pattern in V1 with the R peak being higher in amplitude than the R` peak rS complex in lead V6. In LBBB morphology, WQT (QRS mostly negative in V1), VT is likely in the presence of: Wide R wave (≥40 ms) in lead V1/V2 Slurred or notched downstroke of S wave in V1/V2 Intrinsicoid deflection ≥80 ms in V1/iV2, Q wave (QS or QR complexes) in V6.
Vereckei Algorithm 690
This algorithm uses VA dissociation together with the morphologic analysis of the QRS complex in aVR
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(Figure 11). In this algorithm, the steps detailed below are sequentially followed till the diagnosis of VT is made. Once the diagnosis is reached, points pertaining to succeeding steps need not be looked for. Step 1: Look for a dominant initial R wave which is suggestive of VT. This indicates deviation of ventricular activation sequence and is consistent with a myocardial origin. Step 2: Presence of an initial non-dominant Q or R wave > 40 ms is suggestive of VT. This occurs due to slow conduction at the beginning of ventricular depolarization, which is characteristically observed in a rhythm with ventricular origin. Step 3: Presence of a notch on the initial downstroke in a predominantly negative QRS complex (QS or QR) is suggestive of VT. This finding results from a delay in the initial ventricular activation that occurs during VT.
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81 ECG Assessment of Wide QRS Tachycardia
Figure 11: Vereckei algorithm
Step 4: Total amplitude of the QRS in the first 40 ms (Vi) less than the total amplitude of the QRS in last 40 ms (Vt) of the QRS, or Vi/Vt60 years1. Prognosis in elderly subjects is also good provided the ECG is otherwise normal (suggesting intranodal site of block)2. Atrial enlargement resulting in PR prolongation is due to conduction delay at the intraatrial level. This, usually is, accompanied by ECG markers of atrial enlargement, hence easy to identify. Localizing the site of block: The site where the delay occurs and the possible additional coexistence of second degree AVB (II-AVB) can be identified by an assessment of the duration of the PR and QRS intervals and additional examinations. Maneuvers that assist in the evaluation include responses to carotid sinus massage (CSM), 693
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Figure 4: 12 lead ECG shows third degree heart block, P waves are seen marching through QRS Table 1: ECG markers/maneuvers that assist in the evaluation of the site of block in I-AVB
Table 2: EP findings that help to identify site of delay in a patient with I-AVB and bifascicular block (Figure 2, Trifascicular block)
S. no.
S. no.
1.
2.
Maneuvers
Site of origin of block
1. Narrow QRS complexes 2. Block worsening with CSM 3. Block improving with atropine 4. Block improving with exercise
AVN
1. Wide QRS complexes 2. Block improving with CSM 3. Block worsening with atropine 4. Block worsening with exercise
Block within the HPN, an infrahisian block
Prognosis Good
Second Degree AVB (II-AVB) There are various manifestations of II-AVB: Type I, Type II, 2 to 1 AVB and paroxysmal AVB (PAVB)
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Disease site
Prognosis
1.
Prolonged A-H interval
Intranodal delay
Good
2.
Progressive increase HPN disease in the H-V interval
Bad
3.
H-V delay >100 ms
Bad. Needs permanent pacemaker implantation (PPI)
4.
Fragmentation of His-bundle electrogram (HBE)
Bad
atropine and ergometric tests (Table 1). In 85% of cases with I-AVB, the site of block is in the compact AVN. The site is infranodal in 45% of cases if the QRS is wide.1 Sudden prolongation of PR interval can be physiological and might be an expression of a jump in a very slow conducting AVN pathway and may be a substrate of an AVN reentry tachycardia.2 If ECG shows manifestation of abnormal intraventricular conduction, localizing I-AVB is complex and needs an electrophysiological (EP) study. In the presence of a bifascicular block, I-AVB may be due to an additional prolongation of AVN conduction or may be a manifestation of an extreme prolongation of HPN conduction. It is impossible to differentiate between these two entities using a 12 lead ECG. So to identify the exact site of delay, an EP study is mandatory (Table 2).
694
EPS finding
Advanced disease in the common bundle
Bad. Needs permanent pacemaker implantation (PPI)
Type I II-AVB (Mobitz I/Luciani-Wenckebach) The characteristic pattern of a typical Wenckebach block is a sequential increase in the PR interval with every cardiac cycle followed by a P that is not conducted to the ventricles. The cardiac cycle following the block has the shortest PR interval of the series and the cycle then begins all over again. This cyclical pattern repeats itself being a feature of Wenckebach periodicity. 3 The PR interval continues to widen with every subsequent beat till the P wave fails to conduct. Thus although the PR interval is widest in the cycle preceding the P that fails to conduct, the maximal perceptual increase in the PR interval occurs in the second beat of the sequence. This is because, with every cycle, the PR increases a little bit more compared to the preceding cycle but the amount of increase in comparison to that of the preceding cycle is lesser. This feature is called decremental increment. PR interval should never be shorter than the preceding one and RR interval should never be longer than the
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Table 3: Atypical Wenckebach variants S. no.
82
Atypical Wenckebach variants R-R interval of the last cycle of the sequence longer than the preceding one by ≥ 40 ms
2.
Several PR intervals in the series having the same duration
3.
The PR interval of the 2nd cardiac cycle of the sequence does not show the maximum increase
4.
PR interval decreasing unexpectedly
Atrioventricular Block: Diagnosing the Level of Block
1.
Figure 5: EPS tracing showing suprahisian block in a case of 2:1 AVB. Shown are surface ECG leads I, aVF and V1; intracardiac electrocardiograms from High right atrium (HRA), proximal, mid and distal His bundle (HIS p, HIS m and HIS d respectively). During the blocked P waves (arrow), the corresponding His bundle electrogram shows only atrial activity and absent His bundle and ventricular deflections. During conducted P waves (star), His budle electrogram shows all three components
preceding one. This is another characteristic feature of typical Wenckebach periodicity. 4, 2 Majority of type I IIAVBs follow the typical described periodicity. There are some variations that do not conform to the defined norms. These are grouped under atypical Wenckebach variants (Table 3). It is reassuring if it is a typical/atypical Wenckebach block as the block is mostly at the AVN level. Generally type I II-AVB is a supra-Hisian block and hence benign. Supra-Hisian block is identified in the His budle electrogram at EPS by the absence of His bundle and ventricular electrogram after the atrial electrogram (Figure 5). Very rarely Wenckebach can happen in the HPN and this carries an ominous prognosis. This can be predicted by small PR increments prior to the block and wide QRS in association with a bundle branch block. Although a wide QRS might be a marker of HPN disease, this is a rarer occurrence and in majority of cases, the disease is more likely to be in the AVN.5, 2 Intra-His Wenckebach phenomenon: This, unlike a block at the AVN level, worsens with exercise or atropine.
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EPS reveals a prolonged His electrogram (>30 ms) with splitting and gradual increase of the split prior to the block. In a infra-His Wenckebach, there is progressive HV delay followed by block and then the conduction resumes with a shorter HV interval.6
Type II II-AVB (Mobitz II) It is defined as the occurrence of a single non conducted p wave associated with constant PR intervals before and after a single blocked impulse as long as the sinus rate or the P-P interval is constant and there are at least 2 consecutively conducted P waves to determine the behavior of the PR interval. 7-9 Following the P wave that fails to conduct is a pause that equals the sum of the 2 previous beats (2 P-P cycles).10 The sinus rate stability/constancy is an important part of the definition because an increase in the vagal tone causes AVN block with a parallel slowing of the sinus rate. This benign block at the AVN level mimics a type II II- AVB which is always infranodal.8 The first post-block PR interval has to be of the same duration as the pre-block PR intervals and is of crucial importance
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Figure 6: EPS tracing showing infrahisian block in a case of type II-II AVB. Shown are surface ECG leads I, II, V1 and V6; intracardiac electrocardiograms from proximal and distal His bundle (HIS p and HIS d respectively) and distal coronary sinus (CS12). During the blocked P waves (arrow), the corresponding His bundle electrogram shows atrial and His activity and absent ventricular deflections. During conducted P waves (star), His budle electrogram shows all three components
for the diagnosis of type II II-AVB to be made. The 1st post block PR if shorter, can be due to AV dissociation due to an escape beat, due to improved conduction (type I II –AVB).8 80% of the patients with Mobitz II block show a wide QRS morphology and the block is in the infra-His conduction system (Figure 6). 20% cases reveal narrow QRS morphology and the block localizes to the His bundle.11, 12 There is a very high predisposition to complete heart block. Majority of patients perceive irregularities in their heart rate and complain of fatigue and intolerance to effort. Syncope and presyncope are important indicators of progressive disease worsening.13 All type II blocks are infranodal blocks but the reverse need not necessarily be true.8
2:1 AV Block
696
In this condition, there are 2 sinus P waves occurring at a constant rate for every QRS complex (Figure 7). Since this can happen due to disease at the AVN level or at the HPN level, detailed ECG interrogation is mandatory to look for specific observations that might help to localize the site of block (Table 4). Long ECG recordings may reveal a typical Wenckebach periodicity or a changing conduction ratio. This localizes the site of block to the AVN. Although not 100% diagnostic, if the ECG shows bundle branch block morphology, it is highly likely that the block is at the level of the HPN.2, 10 Occurrence of such a block during slowing of the sinus rate is reassuring and localizes the site of block to the AVN since this has happened due to hypervagotonia. As the atrial rate increases with exercise/atropine,
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infranodal block worsens while AV nodal block improves to 1:1 or 3:2 conduction. As the atrial rate decreases with vagal surge with CSM, infranodal block improves while AV nodal block worsens.7, 9 If ECG and maneuvers do not help, His bundle recordings are required for localization of site of block.
High Grade AV Block Defined as an intermittent block of 2 or more P waves (Figure 8).10 Site of block can be AVN or HPN. A narrow conducted QRS and improvement of condution with atropine or exercise suggests block at the level of AVN. Wide QRS and worsening block with atropine or on exercise localize the block to the HPN.12
Paroxysmal AV Block Third degree AVB and advanced 2nd degree AVB can occur only in paroxysms with intervening 1:1 conduction for long periods. Since recurrent syncope and brady–arrhythmias are common, permanent pacing is indicated. PAVB can follow a premature atrial or ventricular beat (APB or VPB). This bradycardia dependent block is hypothesized to be due to a local disorder at the HPN level owing to a phase-4 block occurring after a critical change of the H-H interval. The HPN fibers spontaneously depolarize and thereafter become refractory during a long pause and a long diastolic interval.12 Sodium channel inactivation at higher resting membrane potentials is hypothesized to be the cause.14
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82 Atrioventricular Block: Diagnosing the Level of Block
Figure 7:12 ECG shows 2:1 AVB, alternate P waves are conducted
Figure 8: 12 ECG shows high degree AVB. For every 3 P waves, there is only one conducted with a QRS complex
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Table 4: Localization of site of block in the setting of 2:1 AV conduction
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S. no.
Conducted PR interval
QRS width
Site of block
Prognosis
1.
Long (>200 ms)
Narrow (120 ms)
Infranodal
Poor
Third Degree AV Block (III AVB) In third degree AVB, the site of block is easy to identify from the surface ECG. If escape rhythm has a narrow QRS, then the block is at the AV nodal level. On the other hand, if the escape beat is wide the block is below the AV nodal level. The morphology of the escape rhythm depends on the site of the escape rhythm (bundle branch or the fascicles). However, irrespective of the site of block in III AVB, pacemaker is indicated because of the low rates. To conclude, site of block in AVB can be identified based on the PR interval pattern, QRS morphology, response to atropine and exercise. His bundle electrogram will give the definite proof of the site of block and should be used when appropriate.
6.
7.
8. 9.
10.
REFERENCES 1. Barrero Garcia MA, Talajic M. Atrioventricular conduction disorders. In: Barrero Garcia MA, Khairy P, Macle L, Nattel S (Eds.). Electrophysiology for clinicians. 1st edition. Minneapolis, USA: Cardiotext; 2011.pp. 44–62. 2. Bagliani G, Leonelli FM, De Ponti R, et al. Atrioventricular nodal conduction disease. Card Electrophysiol Clin. 2018;10:197–209. 3. Kinoshita S, Konishi G. Atrioventricular Wenckebach periodicity in Athletes: influence of increased vagal tone on the occurrence of atypical periods. J Electrocardiol. 1987;20(3):272–9. 4. Mond HG, Vohra J. The electrocardiographic footprints of Wenckebach block. Heart Lung Circ. 2017;26(12):1252–66. 5. Hwang HJ, Ng FS, Efimov IR. Mechanisms of atrioventricular nodal excitability and propagation. In: Zipes DP, Jalife J
11.
12. 13. 14.
(Eds). Cardiac electrophysiology: from cell to bedside. 6th edition. Philadelphia, USA:Elsevier; 2014.pp.275–85. John RM. Atrioventricular block. In: Zipes DP, Jalife J, Stevenson WG (Eds). Cardiac electrophysiology: from cell to bedside. 7th edition. Philadelphia, USA: Elsevier; 2018. pp. 1003–10. Robles de Medina EO, Bernard R, Coumel P, et al. Definition of terms related to cardiac rhythm. (WHO/ISC Task Force). Am Heart J. 1978;95:796-806. Barold SS, Hayes DL. Second-degree atrioventricular block: a reappraisal. Mayo Clin Proc. 2001;76(1):44–57. Surawicz B, Uhley H, Borun R, et al. The quest for optimal electrocardiography. Task force I: standardization of terminology and interpretation. Am J Cardiol. 1978; 41(1):130-45. Surawicz B, Knilans T. Atrioventricular block; concealed conduction; gap phenomenon. In: Surawicz B, Knilans T (Eds). Chou’s electrocardiography in clinical practice. 6th edition. Philadelphia, USA: Saunders Elsevier; 2008. pp. 456-80. Dhingra RC, Denes P, Wu D, et al. The significance of second degree atrioventricular block and bundle branch block: Observations regarding site and type of block Circulation. 1974;49(4):638-46. Laroussi L, Badhwar N. Atrioventricular conduction disease and block. Card Electrophysiol Clin. 2014;6:445-58. Schamroth L. The disorders of cardiac rhythm. Johannesburg: Blackwell Scientific Publications; 1971. Ziad IF, Miller JM, Zipes DP. Atrioventricular conduction abnormalities. In: Ziad IF, Miller JM, Zipes DP (Eds). Clinical arrhythmology and electrophysiology; a companion to Braunwald’s heart disease. 2nd edition. Philadelphia, USA: Saunders Elsevier; 2012. pp. 175–93.
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CHAPTER 83 STEMI Equivalents Arun K Chopra
INTRODUCTION The ST segment elevation (STE) is the classical ECG sign of transmural acute myocardial infarction (AMI). Though generally quite specific for STEMI, it has low sensitivity with merely 50% of patients presenting with sufficient ST elevation to enable a firm diagnosis. There are at least 5 typical variants of ECG patterns other than ST elevation, that indicate high-risk acute coronary syndromes (ACS) indicating or preceding a full blown myocardial infarction (MI). Further, isolated ST segment elevation in a single lead (aVR) may be a marker of global ischemia. Diagnosis of an MI is often masked by the pre-existing QRS and ST-T patterns in patients with left bundle branch block (LBBB) or an implanted permanent pacemaker (PPI). Knowledge of these variant patterns is important, as they facilitate quick diagnosis and prompt management of high-risk ACS patients, who could land up with serious complications later if misdiagnosed at first contact. These patterns include: 1. Isolated true posterior MI 2. Hyperacute T-waves 3. De Winter sign 4. Isolated ST segment depression in aVL 5. Wellens’ sign 6. Isolated ST segment elevation in aVR 7. MI in a patient with left bundle branch block (LBBB) or implanted pacemaker (PPI).
ISOLATED TRUE POSTERIOR MYOCARDIAL INFARCTION True posterior MI usually coexists with an inferior MI, less commonly with a lateral wall MI (15–20% of MIs). However, isolated true posterior MI is also seen, though less commonly (< 5%), and presents with tall R-waves in V1, 2, and 3 with ST depression (R/S >1 in V2) but an upright, tall T wave (Figure 1). This pattern should be confirmed by doing posterior leads (V7, 8, 9), which may reveal ST elevation, thus confirming the diagnosis.1,2 The tall R wave may not be seen in the first ECG and may evolve later, as shown in this ECG. The lack of ST elevation in the 12-lead ECG may lead to delay not only in the diagnosis of MI, but also in its appropriate management.
HYPERACUTE T WAVES These are typically seen in the first few minutes (usually 5 mm in limb leads and >10 mm in precordial leads) and usually symmetric (Figure 2). Follow-up ECGs usually reveal the classical ST elevation of STEMI, confirming the diagnosis. 3,4 Differential diagnosis includes hyperkalemia, benign early depolarization (BER) and left ventricular hypertrophy (LVH). Whereas hyperkalemia can be differentiated by tall T waves that are narrower (QT interval is shorter) and
Figure 1: Isolated true posterior myocardial infarction
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Figure 2: Hyperacute T waves
a broader QRS, LVH can be differentiated using voltage criteria. The BER is found mostly in young males with diffuse J-point elevation and tall T waves.
DE WINTER SIGN Described relatively recently (2008), this is a distinct pattern with upsloping ST elevation in aVR and ST depression with tall, peaked T waves in precordial leads (Figure 3). Found in about 2% of patients with anterior MI, here the tall T waves are persistent, and signify proximal left anterior descending artery (LAD) occlusion (Figure 3). These changes may persist throughout, evolve into an ST elevation pattern or may develop after ST elevation.5 Though the ECG is highly suggestive of an acute coronary syndrome, the lack of ST segment elevation may lead to a delay in consideration of primary percutaneous coronary intervention (PCII or thrombolysis, leading to adverse outcomes.
ISOLATED ST DEPRESSION IN aVL This may be the earliest sign of an evolving inferior MI (Figure 4), and is thought to be an early sign of right ventricular MI. A subsequent ECG reveals the inferior MI with 3:2 AV Wenchebach (Figure 5). Birnbaum et al. reported that this was the only abnormality in the presenting ECG in 7.5% patients. Further, the sensitivity of ST depression in aVL in inferior MI is very high, being 97–100% in various studies. 6,7 Therefore, a cardiology consult is merited in a patient with chest pain in the emergency room (ER) with isolated ST depression in aVL.
WELLENS’ SYNDROME This is a characteristic ST-T pattern found in the precordial leads in patients with unstable angina. The ECG shows minimal ST elevation followed by either a biphasic T-wave (Figure 6) or a deep symmetric negative T-wave (Figure 7), seen on admission in half the patients and within 24 hours of admission in the other half. Wellens and colleagues reported this in 1982, and labeled the patterns as type A and B. The patients who were catheterized all revealed tight proximal LAD stenoses. On the other hand, 75% of those who were managed conservatively developed a large anterior MI within 1–3 weeks of the appearance of this ECG pattern, even if they seemingly responded well to medical therapy. Hence, the Wellens’ sign is considered a high-risk marker suggestive of impending anterior STEMI, thus meriting an early invasive strategy. As it was found in 18% off their patients with unstable angina, this is not an uncommon finding, and needs to be remembered by ER physicians.8 Typical examples of Types A and B Wellens syndrome are shown in Figure 7.
ISOLATED ST ELEVATION IN aVR Isolated ST segment elevation in aVR (sometimes in V1 also, but in aVR > V1) combined with ST segment depression in all the other leads (8 or more leads) is a pattern strongly suggestive of extensive subendocardial ischemia (Figure 8). This pattern is described in significant stenosis of the left main stem, or a left main equivalent [tight stenoses of proximal LAD and left circumflex artery (LCx)], or severe triple vessel disease. While a recent study
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Figure 3: De Winter sign
Figure 4: Isolated ST depression in aVL—inferior myocardial infarction
found the specificity of this finding to be low at 43%, it is still suggestive of extensive ischemia, and guidelines recommend an early invasive strategy in these patients. In the setting of an STEMI, ST elevation in aVR reflects proximal vessel occlusion (LAD or LCx) and a large area at risk.9-11
NEW OR PRESUMED NEW LEFT BUNDLE BRANCH BLOCK This was one of the diagnostic criteria for diagnosis of an STEMI, and was used as an indication for thrombolysis. However, several studies13-15 published between 2007
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Figure 5: Wenckebach atrioventricular block
A
B
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Figure 6: Biphasic T wave (Panel A and B)
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Figures 7: A and B (more common) patterns of Wellens syndrome
Figure 8: Subendocardial ischemia
and 2012 showed that only 40% patients with LBBB and suspected ACS turned out to have an MI. It is a marker of LV dysfunction and does signify poor prognosis, but early angiography or lysis may not be indicated in the majority of patients and may actually cause harm. Hence, it was removed from the STEMI guidelines as an isolated marker of MI in 2013.16 However, even an ECG with LBBB, notorious for masking Q waves and ST segment deviations, can have signs highly consistent with an MI. The modified Sgarbossa criteria are (Figures 9A to C):14,15 1. Concordant ST segment elevation (5 points) 2. Discordant ST segment depression in V1-V3 (3 points) 3. Concordant ST segment elevation >5 mm, or >25% of the S wave (Smith et al) (2 points). These criteria suffer from the typical problem of high specificity with poor sensitivity. The Smith modification improves the sensitivity from 25% to 52%, while reducing the specificity from 98% to 91%.15 Hence, the diagnosis is often confirmed or refuted using other modalities,
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like cardiac biomarkers (CK-MB, Troponin’s) and echocardiography. The ECG in Figure 10 is that of a 62-year-male presenting with chest pain in ER, who was labeled as having just LBBB. The pain persisted and within 15 minutes, the patient went into VT/VF, needing defibrillation. The ECG repeated after resuscitation revealed clearer signs of a STEMI, necessitating a primary PCI that was successfully completed (Figure 11). A review of the first ECG revealed subtle but clear ST elevation in lead III and aVF.
STEMI EQUIVALENTS IN PACED PATIENTS It is very difficult to diagnose an MI in a patient who has paced complexes throughout (Figure 12). The largest series of 32 patients is from Sgarbossa et al., who applied their criteria of MI in LBBB to these patients. The comments to these criteria in LBBB patients are also relevant here.14,15
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Figures 9A to C: Sgarbossa criteria
Figure 10: Left bundle branch block
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Figure 11: Signs of STEMI
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Figure 12: Paced complexes
These are some of the patterns of ST segment deviation that can confuse an ER physician, and mask the diagnosis of an ongoing or impending STEMI, potentially causing delay in treatment (especially cath lab activation in highrisk patients). A thorough knowledge of these patterns can prevent such errors, and an early diagnosis and expeditious management leading to complete recovery of a patient may be the result.
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REFERENCES 1. Oraii S, Maleki M, Tavakolian AA, et al. Prevalence and outcome of ST-s egment elevation poster ior electrocardiographic leads during AMI. J Electrocardiol. 1999;32(3):275-8. 2. vanGorselen EO, Verheugt FW, Meuring BT, et al. Posterior myocardial infarction: the dark side of the moon. Neth Heart J. 2007;15(1):16-21. 3. Goldberger AL. Hyperacute T waves revisited. Am Heart J. 1982;104(4 Pt 1):888-90. 4. Morris F, Brady W. ABC of clinical electrocardiography:Acute myocardial infarction-Part 1. BMJ. 2002;324(7341):831-4. 5. de Winter R. Verouden N, Wellens HJ, et al. A New ECG sign of Proximal LAD occlusion. N Engl J Med. 2008; 359(19):2071-3. 6. Birnbaum Y, Sclarovsky S, Mager A, et al. ST segment depression in aVL: a sensitive marker for acute inferior myocardial infarction. Eur Hear J. 1993;4(1):4-7. 7. Turhan H, Yilmaz MB, Yetkin E, et al. Diagnostic valve of aVL derivation for right ventricular involvement in patients with acute inferior myocardial infraction. Annals of Noninvasive Electrocardiology. 2003;8(3):185-8. 8. deZwaan C , Bar F W, Wellens HJ. Character istic electrocardiographic pattern indicating a critical stenosis high in left anterior descending coronary artery in patients admitted because of impending myocardial infraction. Am Heart J. 1982;103(4 pt 2):730-6. 9. Angul N, Ozdemir K, Tokac M, et al. Value of lead aVR in predicting acute occlusion of proximal left anterior descending coronary artery and in-hospital outcome in STelevation myocardial infraction:An electrocardiographic
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p re d i c a t o r o f p o o r p ro g n o s i s. J E l e c t ro c a rd i o l . 2008;41(4):335-41. O’Gara PT, Kushner FG, Ascheim DD , et al. 2013 ACCF/ AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines . J AM Coll Cardiol. 2013; 61:e78-140. Lopes RD, Siha H, Fu Y, et al. Diagnosing acute myocardial infarction in patients with left bundle branch block. Am J Cardiol. 2011;108(6):782-8. Jain S, Ting HT, Bell M, et al. Utility of left bundle branch block as a diagnostic criterion for acute myocardial infarction. Am J Cardiol. 2011;107(8):1111-6. Larson DM, Menssen KM, Sharkey SW, et al. “False -positive” cardiac catheterization laboratory activation among patients with suspected ST-segment elevation myocardial infarction. JAMA. 2007;298(23):2754-60. Sgarbossa EB, Pinski SL , Barbagelata A , et al. Electrocardiographic diagnosis of evolving acute myocardial infraction in the presence of left bundle-branch block. GUSTO-1 (Global Utilization of streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) Investigators. N Engl J Med. 1996;334(8):481-7. Smith SW, Dodd KW, Henry TD, et al. Diagnosis of ST-elevation to S-Wave ratio in the presence of left bundle branch block with the ST-elevation to S-Wave ratio in a modified Sgarbossa rule. Ann Emerg Med. 2012;60(6):766-76. Wong CK, Gao W, Stewart RA, et al. The prognostic meaning of the full spectrum of aVR ST-segment changes in acute myocardial infraction. Eur Heart J. 2012;33(3):384-92. Yamaji H, lwasaki k, Kusachi S, et al. Prediction of acute left main coronary artery obstruction by 12-lead electrocardiography. ST segment elevation in lead aVR with less ST segment elevation in lead V (1). J Am Coll Cardiol. 2001;38(5):1348-54. Ne e l a n d IJ, Ko nt o s M C , d e L e m o s JA . Ev o l v i n g considerations in the management of patients with left bundle branch block and suspected myocardial infarction. J Am Coll Cardiol. 2012;60:96-105.
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Let’s Face the Viva Recent Advances in Echocardiographic
Strain Imaging
Nobuyuki Kagiyama, Yuko Soyama, John Gorcsan III Hemodynamic Assessment in the Cardiac Catheterization Laboratory
Jaganmohan A Tharakan, Sanjay G Interpretation of Catheterization Traces
Sriram Rajagopal, Lakshmi Gopalakrishnan Interpreting a Nuclear Stress Test
Girish Kumar Parida, Abhinav Singhal, Chetan D Patel Cardiac Tumors: Practical Approach and Management
Kewal C Goswami, Preetam Krishnamurthy
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Recent Advances in Echocardiographic Strain CHAPTER 84 Imaging Nobuyuki Kagiyama, Yuko Soyama, John Gorcsan III
FUNDAMENTALS OF STRAIN IMAGING Echocardiographic strain imaging has made great advances due to emerging clinical applications. The process of determining strain is based on speckle tracking echocardiography. This is a process where a computer algorithm analyzes the reflected B-mode ultrasound data frame by frame to determine patterns of spectacles that move through the echocardiographic image. A region of interest is placed on the image; and from this, physiologic mechanical information regarding myocardial deformation is obtained. Although 3-dimensional strain algorithms are advancing, most clinical applications currently utilize 2-dimensional strain imaging.1,2 There are three basic applications of strain imaging: Longitudinal strain, circumferential strain, and radial strain. There have been many interesting studies using circumferential and radial strain; however, this review will focus on longitudinal strain which has the greatest representation in the literature, currently.
GLOBAL LONGITUDINAL STRAIN Longitudinal strain or deformation is determined from the apical views to focus on longitudinal shortening of the left ventricle. The myocardium in 3-dimensions shortens, thickens, and twists; however, longitudinal strain isolates longitudinal deformation. A region of interest is placed on the myocardial wall and the strain is calculated as the change in length/original length (Figure 1). The three standard views are apical 4 chamber, apical 2 chamber, and apical long axis views. Longitudinal strain analysis is applied to each of these views with the standard being 6 segments: basal, mid, and apical segments (Figure 2). From these 18 segments, an average value is displayed which is known as global longitudinal strain (GLS).1 Our technical approach involves placing the region of interest on the endocardial and epicardial surfaces and playing the cine loop to ensure tracking of the myocardial wall. Often, slight adjustments are made to the region of interest after this visual inspection of the tracking. From this, time strain curves are displayed individually and as an average time-strain curve. This measure of GLS has been a stable and reproducible measurement, with acceptable
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Figure 1: Principle of longitudinal strain by speckle tracking echocardiography Schematic measurement of longitudinal strain from the apical 4-chamber view. Using speckle tracking echocardiography, strain values are calculated as change in length divided by original length and expressed as percentage
interobserver variability. The GLS measures longitudinal shortening; so, accordingly, it is expressed with a minus sign. This has been confusing to many clinicians; because, mathematically, a larger GLS value representing better myocardial function is actually a smaller number with a minus sign. Accordingly, it is useful to consider the absolute values of GLS with larger numbers representing better ventricular function and smaller GLS numbers representing poorer ventricular function. Some authors have adopted presenting GLS as absolute values, but a common format has not been agreed upon.
NORMAL LONGITUDINAL STRAIN VALUES At this point in technological development, there are still differences in vendors’ approach for measuring GLS. Accordingly, there have been documented slight but significant differences in GLS values.3 Furthermore, there have been documented differences in GLS with gender and age.4-6 Taking all of these things into consideration, it is still useful to have a normal range of values for GLS. Metaanalyses have been published showing the average value for GLS, of approximately 19.7% (in absolute values). 7 Taking many different publications into consideration, the threshold for abnormal GLS is below 17%, and clearly abnormal is below 15% (in absolute values).
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Figure 2: Segmental and global longitudinal strain by standard apical views The left panel shows quantification of longitudinal strain from 3 standard apical views. Segmental strain from each 6 segment is represented as each curve in 4-chamber (top), 2-chamber (middle), and apical-long view (bottom). Polar plot on the right panel shows color coded peak segmental longitudinal strain with higher appearing as dark red. Global longitudinal strain is determined as the average from 3 apical views Abbreviation: GLS, global longitudinal strain
RELATIONSHIP OF GLS TO EJECTION FRACTION Most clinicians would consider left ventricular (LV) ejection fraction (EF) the standard reference value for LV function. There must be a linear relationship between LVEF which measures blood displacement within the LV cavity and GLS which measures the longitudinal deformation of the cavity wall. Comparative studies of GLS with LVEF are done by the gold standard of cardiac magnetic resonance (CMR) imaging (Figure 3).8 They have demonstrated a significant linear relationship, with some variations in individual patients. Interestingly, several studies have shown that GLS adds clinical utility to LVEF. 9-12 There has been a computer modeling study showing that wall properties, such as hypertrophy, influence on the relationship between GLS and LVEF, and in particular imaging studies with late gadolinium enhancement demonstrating scar showed that GLS had some important physiological information.14 Because LV hypertrophy and in particular myocardial fibrosis and scar are associated with more advanced disease processes, it is logical that GLS adds functional information to LVEF.15
GLS IN HEART FAILURE WITH REDUCED EJECTION FRACTION Several interesting studies have reported GLS as an important prognostic marker in patients with reduced LVEF.9,16,17 Stanton et al.16 initially studied 546 consecutive
patients who were referred for assessment of LV function by echocardiography. They showed that GLS was predictive of all-cause mortality additive to LVEF and visual wall motion assessment. Sengelov et al.9 collected GLS data on 1,065 heart failure clinic patients with reduced LVEF and followed them for up to 8 years. When dividing the baseline GLS tertiles, they observed a highly significant association with all-cause mortality. Furthermore, when performing multivariable analysis with clinical characteristics and routine echocardiographic measurements, such as LVEF and echo Doppler measures of diastolic function, they found GLS of additive prognostic value. In particular, a 1% (GLS unit) decrease in absolute values was associated with an increase in mortality (p 50% that GLS was impaired and a risk marker for all-cause mortality over 1.9 years, using a cut-off of -16%.
GLS IN ACUTE HEART FAILURE Park et al.10 made a recent significant contribution to the medical literature by studying GLS in 4,172 patients with acute heart failure. Patients were categorized as either heart failure with reduced (LVEF 50%). Patients were also classified as having mildly (GLS >12.6%), moderately (8.1% < GLS 8 WU.m and PVR/SVR >0.5: consider pH specific therapy (sildanefil/bosentan) for 6 months and repeat hemodynamic study. Pulmonary vasoreactivity testing: The following agents can be used for acute pulmonary vasoreactivity testing: Epoprostenol Intravenous: Starting at 2ng/kg/min, with increments of 2 ng/kg/min every 10 min to maximum 12 ng/min
Adenosine Intravenous : 50 mic./kg/min, with increments of 50 mic./kg/min every 2 min. to maximum 350 mic/kg/min Nitric oxide Inhaled: 10–20 ppm—5 min. (some recommend increments of 20 ppm every 5 min to maximum 80 ppm). A positive response to vasoreactivity testing is defined as a reduction of mPAP ≥ 10 mm Hg to reach an absolute value of mPAP ≤ 40 mm Hg with an increased or unchanged CO, for purpose of initiation of oral calcium channel blocker in idiopathic PAH
Assessment of PVR after Balloon Occlusion of the Defect In patients with increased pulmonary blood flow due to L>R shunt, elevation of PA pressure is contributed by the increased pulmonary blood flow, elevated PV pressures (in posttricuspid shunts such as VSD, AP window and PDA) and pulmonary vascular resistance. Limitation in determining the left-to-right shunt leads to error in estimation of PVR. Occlusion of the defect by a balloon or by a device cuts off the L>R shunt and the PA pressure thus obtained truly reflects severity of PVR. PVR is calculated using mPAP, PAWP and the CO. Simultaneous administration of 100% O2 reduces the PA pressure and PVR contributed by hypoxic vasoconstriction. PVR values obtained after trial occlusion of the defect is used to decide on device closure or surgical closure. PVRI more than
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7 Wood units.m2 will preclude closure of the defect as the PVR is unlikely to regress and may even progress.
Other Indications Univentricular repair: Invasive studies are indicated to assess the mPAP and PVR in patients planned for conversion of Glenn procedure to Fontan (Figure 9). MPAP of 15 mm Hg or LVEDP > 16 mm Hg during catheterization is suggestive of left heart disease. Vasoreactivity tests are not advised in patients with PAH and left heart disease (elevated PA wedge or LVEDP), or in a rare patient with pulmonary veno-occlusive disease,2 as administration of pulmonary vasodilators in these conditions can worsen pulmonary venous hypertension and precipitate pulmonary edema.
TRANSPULMONARY GRADIENT, DIASTOLIC PULMONARY GRADIENT The difference between the ‘driving’ pressure in the pulmonary vasculature and the ‘filling pressure of the left heart’ (mPA-mPAWP) is useful to suspect pulmonary vascular disease in the presence or absence of left heart disease and can be termed as transpulmonary gradient (TPG).3 TPG > 12 in the absence of a high cardiac output or
Figure 10: Simultaneous PA and LA pressure trace in a patient with ASD and severe PAH. Transpulmonary gradient = mPA – mLA = 58–7 = 51 mm Hg. DPG = PA(diastolic) – mean LA = 40–7 = 33 mm Hg. This suggests presence of pulmonary vascular disease. It is also essential to calculate pulmonary vascular resistance as discussed. [PVR = (mPA- mLA)/pulmonary blood flow]. In the provided example, the calculated Qp was 4 L/min and calculated PVR = 51/4 = 12.75 Wood Units
left to right shunt signifies underlying pulmonary vascular disease. Substituting with examples, if TPG = 12 and CO =4, PVR = 3 Wood Units. Considering another situation of a patient with atrial septal defect and significant left to right shunt, if TPG = 16 and Qp = 8, then PVR = 2 Wood Units. The limitation of this generalisation value of TPG is evident in another example in a patient with low CO (as in patients with advanced HF): TPG = 10, CO = 2, calculated PVR = 5 Wood Units. In this context, the diastolic pulmonary gradient (DPG) (PA diastolic to PA wedge pressure gradient) can be a useful indicator to suspect underlying pulmonary vascular disease. At end diastole, the blood flow in the pulmonary circuit is the least; a difference between diastolic PA pressure and mean LA (or PAWP) >5 mmHg suggests pulmonary vascular disease even in presence of left to right shunt lesion (Figure 10). In our catheterisation laboratory, DPG is used to screen for presence of pulmonary vascular disease (increase in pulmonary vascular resistance) to plan for pulmonary vasodilator challenge. The concept of passive pulmonary hypertension (PH), reactive PH and fixed PAH due to established pulmonary vascular disease is explained in Figures 11A and B.
Hemodynamic Assessment in the Cardiac Catheterization Laboratory
Figure 9: PA pressure trace accessed from right internal jugular vein during cardiac catheterization in a patient with bidirectional Glenn shunt (end-side anastomosis of superior caval vein with ipsilateral right pulmonary artery). Since the PA is disconnected from RV, there is loss of phasic waveforms. Only respiratory variation is evident
HEART FAILURE AND TRANSPLANTATION Apart from establishing the diagnosis of overt or latent HF (discussed in the section exercise testing), invasive catheterization provides important prognostic information such as filling pressures, PVR, CO and also helps to guide therapy by an analysis of preload and afterload (e.g. response to vasodilators). In patients being considered for advanced therapy, the ISHLT guidelines recommend right heart catheterization, once in 3–6 months in patients 721
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A
B
Figures 11A and B: Figure A shows simultaneous LV, LA and PA pressure recording in a patient with severe MS before PTMC; PA= 90/40 (mean 60 mm Hg), LA mean 28 mm Hg. The panel in the right shows the same after a successful PTMC, with mean LA pressure decreasing to 14mmHg and significant reduction in transmitral gradient. The PA pressure has decreased to 69/30 (mean 46 mm Hg), immediately post procedure. The component of ‘passive PH’ contributed to by elevated LA pressure regresses first. However the remainder (indicated by the elevated PA systolic pressure and the remarkable difference between the diastolic PA and LA mean pressure) is due to variable combinations of ‘reactive’ pulmonary hypertension due to pulmonary arteriolar vasoconstriction which declines over weeks to months and the ‘fixed pulmonary arterial hypertension ‘due to established pulmonary vascular disease, which usually does not regress. If the PA pressure remains elevated during long-term follow-up, without any residual mitral valve disease, it is likely that the patient has significant fixed component of PAH at the outset
listed for heart transplantation. During RHC, vasodilator challenge is recommended, if PASP > 50 mm Hg and either the transpulmonary gradient is > 15 or the PVR is > 3 WU while maintaining systemic arterial blood pressure > 85 mm Hg. If medical stabilization does not lower PVR to < 3 WU, the patient should be considered for mechanical adjuncts such as LVAD and re-assessed after 3–6 months for reversibility of PH.
PERICARDIAL DISEASES Patients with pericardial diseases benefit from invasive catheterization. Checking right heart filling pressures in a patient after relieving tamponade helps to identify underlying constriction, if present (Figure 12).
Constrictive Pericarditis versus Restrictive Cardiomyopathy Hemodynamic study is useful to differentiate chronic constriction from restrictive cardiomyopathy. Typically, in constrictive pericarditis, the RA mean, RVEDP, PA diastolic, PAW mean and LV EDP are all elevated and within 5 mm Hg of each other. The RVEDP is more than one third of the RV systolic pressure. The RA pressure is elevated and shows very little respiratory variation due to the thickened pericardium preventing transmission of intrathoracic pressure to cardiac chambers. The RV systolic pressure rises in inspiration due to better RV filling as well as diminished LV filling from the pulmonary veins resulting in reduced LV systolic pressure leading to discordance in the systolic pressure due to ventricular interdependence (Figure 13A). In restrictive cardiomyopathy, ventricular interdependence is absent (Figure 13B). LVEDP is often
5 mm Hg or more than RVEDP and RVEDP is less than one-third RV systolic pressure. Simultaneous recording of PAWP and LVEDP demonstrates the phenomenon of dissociation of intrathoracic and intracardiac pressures in constriction. During inspiration, the pressure in the pulmonary veins fall much more than the LVEDP. This results in decreased filling of LV during inspiration. However, during expiration, the increase in PV pressure is not offset by a proportionate increase in LV filling because of the limitation imposed by rigid pericardium. Hence there is widening of early diastolic gradient between PAWP and LV during expiration and narrowing of the same during inspiration. This phasic change in the gradient is not seen in restrictive cardiomyopathy (Figure 13C).
EVALUATION OF OBSTRUCTIVE LESIONS Recording of Pressures and Pressure-gradients This requires recording pressures from the two chambers simultaneously using two transducers which are equisensitive and have identical frequency response. Simultaneous recording is recommended to demonstrate small gradients which can be phasic, e.g. tricuspid valve stenosis, anastomotic site obstruction in Glenn shunt, pulmonary vein ostial stenosis, IVC stenosis, etc. However, using two equi-sensitive transducers simultaneously can be cumbersome and often error prone, if frequency response and damping characteristics of the two recording systems are different. More commonly, one records pressure while withdrawing catheter from one chamber to the other and analyzing the superimposed tracings of
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A
Hemodynamic Assessment in the Cardiac Catheterization Laboratory
Figure 12: RA pressure before (upper panel) and after (lower panel) pericardiocentesis in a patient presenting with tamponade. Upper panel shows elevated RA pressure with blunted v wave and y descent (solid arrows) with respiratory variation of atrial pressure. Lower panel: after pericardiocentesis, reveals persistent elevation of RA pressure with prominent x and y descents suggesting underlying constrictive pericarditis (e.g. of effusive constrictive pericarditis)
B
C Figures 13A to C: (A) Constrictive pericarditis: Area between LV and RV pressure trace, markedly altered by respiratory phase: Typical ventricular interdependence; (B) Restrictive cardiomyopathy: The RV and LV pressures show concordance: absence of interventricular dependence; (C) Demonstration of intra-thoracic intracardiac dissociation (see text)
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the two chambers using ECG as the time marker. When obstruction or stenosis is very severe, a catheter across the stenosis itself increases the gradient as in severe valvar aortic stenosis. To measure gradient in severe aortic stenosis accurately, one catheter is placed in LV antegrade across mitral valve through trans-septal route and another catheter in aortic root. To identify multiple levels of gradient, a pull back from one chamber to the other should be done carefully using end hole catheter or an equally effective diagnostic Goodale-Lubin catheter (end hole with proximal side holes very close to the tip and functions effectively as an end-hole catheter, without problem of wall-sucking during catheter aspiration, and pressure damping often seen with end hole catheters). However an over the wire catheter system with side holes is best suited to demonstrate multiple gradients in LV/RV outflow, permitting multiple controlled pullbacks retaining guidewire access in the distal chamber. Fluoroscopic guidance complemented by angiography is required to demonstrate site of gradients in great vessels, e.g. peripheral PS, coarctation of aorta.
Mitral Stenosis Hemodynamic studies are useful to assess severity of the mitral stenosis (MS) as well as to guide intervention. Invasive hemodynamic assessment in patients with MS involves calculation of transmitral gradient (TMG), cardiac output and mitral valve area (MVA) using the Gorlin’s formula, along with assessment of pulmonary hypertension and pulmonary vascular resistance (Figure 14). Trans-septal puncture allows simultaneous recording of LA and LV pressures. In a symptomatic patient, If the resting TMG is low, he is subjected to exercise to check for increase in gradient and pulmonary artery pressures (Figures 4A and B). The adequacy of PTMC is gauged using several hemodynamic criteria: (i) at least 50% decline in LA mean pressure without any fall in CO (ii) 50% decline in transmitral gradient without any fall in cardiac output. The various echocardiographic criteria used include final MVA (planimetry) > 1.5 cm2, increase in MVA by at least 25% without an increase in MR by more than one grade out of 4. Severe MR occurs in < 4% of patients.4 Patients who
Figure 14: Calculation of mitral valve area using Gorlin’s formula
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develop significant MR have mean LA pressure above preprocedure levels, with the amplitude of LA ‘v’ wave > 50% of the LV systolic pressure, increase in PA pressures, rise in LVEDP and drop in forward CO (Figure 15).
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Fixed versus dynamic left ventricular outflow tract obstructive lesions (LVOTO): One of the important uses of hemodynamic studies in patients with LVOTO is to distinguish, if the obstruction is anatomically fixed or if the segment of narrowing in the outflow varies according to the underlying hemodynamic status of the patient. The commonest etiology of fixed LVOTO is valvular AS in an adult patient, whereas HOCM accounts for the most cases of dynamic LVOTO. Figures 16A and B illustrate some of the methods used to distinguish between the two entities in the catheterization laboratory. It should be noted that the absence of these signs do not exclude the diagnosis of HOCM, especially if the substrate for obstruction is mild. Low gradient A Sitr: In the current era, the diagnosis and decisions about management of AS is principally based on echocardiographic assessment. However, since the utility of percutaneous aortic valve interventions is on the rise, one has to differentiate various types of low-gradient aortic stenosis in the catheterization laboratory, especially in a patient with depressed systolic function.5 According to Gorlin’s equation, valve area is directly proportional to flow and inversely to square root of gradient across it. In patients with depressed LV function and very low cardiac output, the calculated aortic valve area might be lower than the actual anatomical narrowing, since the forward momentum might not be sufficient enough to maintain the aortic valve open fully for sufficient period. These patients can be differentiated into true critical AS and pseudo-AS based on their response to increased stroke volume consequent to dobutamine infusion. In patients with true critical AS, the calculated valve area remains low, with increase in gradient whereas the calculated AVA increases by >0.2 cm2 in patients with pseudo-AS. In 30% of patients with low flow low-gradient AS the dobutamine test is inconclusive as they fail to augment their cardiac output by at least 20% after dobutamine due to poor contractile reserve and this group has adverse outcome after surgery. Concomitant coronary angiography helps to
Figure 15: Simultaneous LA and LV pressure trace in a patient after PTMC revealing severely elevated LA pressure, tall V wave which is almost 80% that of the amplitude of peak LV systolic pressure and elevated LVEDP indicating severe MR
identify, if coronary artery disease is the reason for lack of contractile reserve in these patients. In patients suspected of severe AS with normal LV function, but low gradient due low stroke volume due to high afterload, the calculated aortic valve area may be spuriously low (paradoxical low flow low gradient AS with normal LV function) and the response to arterial vasodilators in catheterization laboratory might help to re-categorize them into true or pseudo-AS.
Hemodynamic Assessment in the Cardiac Catheterization Laboratory
Left Ventricular Outflow Tract Obstructive Lesions
EVALUATION OF PATIENTS WITH ISCHEMIC HEART DISEASE Physiological Assessment of Coronary Stenosis Fractional Flow Reserve One of the major applications of assessment of vascular physiology in contemporary clinical practice is in patients with ischemic heart disease. Assuming that a steady state of maximal coronary blood flow is attained, it is now possible to assess the physiological significance of coronary lesions by estimating the fractional flow reserve (Box 1 and Figure 17). Sensor-tipped guidewires are introduced distal to the lesion during coronary angiography and maximal coronary blood flow is induced by administering
Box 1: Fractional flow reserve estimation FFR = =
Maximum flow in presence of stenosis Normal maximal flow
(QS max) (Pd – Pv)/R Pd – Pv Pd = ≈ = N (Q max) (Pa – Pv)/R Pa – Pv Pa
Pa = Aortic pressure, Pd = Pressure distal to stenosis, Pv = Mean pressure in right atrium Assuming: Maximal vasodilatation, low myocardial resistance (R), normal right heart pressures (negligible Pv)
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A
B Figures 16A and B: (A) Contour of aortic pressure wave in HOCM (A) and that in severe valvular AS in figures; (B) Also illustrates the effect of PVC in fixed LVOTO (ref. Table 2) Table 2: Features of fixed and dynamic LVOTO
Parameter
Severe AS
HOCM
Contour of aortic waveform
Slow rising (arrowhead), late peaking, prominent anacrotic notch in the upstroke (Figure 10B)
Rapid upstroke (arrow-head) with ‘spike and dome’ appearance or double peak in systole (Figure 10A)
Effect of a premature ventricular complex (PVC)
In the sinus beat after PVC, the aortic valve gradient increases with an increase or no change in aortic pulse pressure (Figure 10B)
In the sinus beat after an appropriately timed PVC, the LVOT gradient increases with a ‘reduction’ in the aortic pulse pressure (Figure 6)
Valsalva – strain phase (phase2)
Gradient decreases due to decreased flow across the aortic valve (decreased ventricular filling)
Gradient increases in strain phase (Figure 6)
a combination of epicardial vasodilator (nitroglycerin) with coronary microvascular dilator (adenosine). A value of 5 segments). Also, perfusion defects can be categorized as small, medium, and large if 20% of the LV myocardium is involved, respectively.23 In addition to the individual segmental scores, it is recommended that summed scores and percent myocardium involvement be calculated. The summed stress scores equal the sum of the stress scores of all the segments, and the summed rest score equals the sum of the rest scores of all the segments. The summed difference score equals the difference between the summed stress and the summed rest scores. This is a measure of perfusion defect reversibility, reflecting stressinduced ischemia.24-27
Quantitative Quantitative analysis of static perfusion images is useful to supplement visual interpretation.28,29 This quantitative analysis is typically displayed as a ‘bullseye’ or polar plot. The quantitative programs provide an objective interpretation that is obviously more reproducible than visual analysis. It is particularly helpful in identifying subtle changes between two studies in the same 739
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Figure 3: A medium-sized fixed perfusion defect seen in the mid and proximal inferior wall of LV; consistent with scarred myocardium, displayed in SA, VLA, and HLA slices and as polar maps Abbreviations: SA, short axis; VLA, vertical long axis; HLA, horizontal long axis; LV, left ventricle
patient. 30-32 Initial defect size and reversibility can be quantitatively expressed as a percentage of the entire LV, or as a percentage of individual vascular territories. Like semiquantitative visual scoring, segmental scores also can be computed automatically. Despite these advantages, quantitative programs have certain limitations. They rely on adequate myocardial contours, which can sometimes be challenging in scans with very severe perfusion defects or with excess sub-diaphragmatic activity. Therefore, quantitative analysis should only be used as an adjunct to, and not a substitute for, visual analysis.
Reversibility Reversibility of perfusion defects may be categorized qualitatively as partial or complete. If an area of infarcted myocardium with a fixed defect has perfusion greater than 50% of the database norm, it is at least partially viable.33 Reversibility on a quantitative polar plot will depend on the specific software in routine use and the normal reference databases used in the program (Figure 4). 34 ‘Reverse redistribution/distribution’ may be seen on delayed Tl201- and 99mTc-labeled imaging.35 Reverse redistribution is a pattern in which the severity of perfusion defect on
stress images worsens on rest images. It is reported to occur in myocardial segments with a mixture of viable and nonviable myocardium that are supplied by patent infarct-related arteries, postrevascularization and postthrombolysis.36
Interpretation of Attenuation-corrected SPECT Studies Attenuation correction (AC) is performed using CT transmission images in a hybrid SPECT-CT system. Though interpretation of AC-SPECT images follows a similar approach to that used for nonattenuationcorrected (NAC) myocardial perfusion images, normal distribution of perfusion tracers may be significantly different in the AC images compared to NAC ones. Coregistration of the transmission images (or mu maps) with the emission images must be ensured, because artifacts can result from patient movement, that might lead to misregistration of the transmission and emission images. While artifacts related to respiratory motion can be corrected using software methods, those due to patient motion may be more challenging to correct and at times require repeat imaging. It should be remembered that if
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87 Interpreting a Nuclear Stress Test
Figure 4: A large reversible perfusion defect seen in the inferolateral wall and adjacent inferior wall of LV; consistent with stress-induced ischemia, displayed in SA, VLA, and HLA slices and as polar maps Abbreviations: SA, short axis; VLA, vertical long axis; HLA, horizontal long axis; LV, left ventricle; LAD, left anterior descending
perfusion defects are seen only on the AC images (with normal NAC images), AC-related artifacts need to be considered and excluded first. Intense extracardiac activity may scatter counts into the inferior wall causing masking/overcorrection of inferior wall perfusion in AC images and make the anterior wall appear hypoperfused. Normal variant apical thinning can be more pronounced with AC. Fixed apical perfusion defects should be considered abnormal when defects are severe enough and have a corresponding wall motion abnormality or associated perfusion abnormalities in LAD territory.37
Interpretation of Gated MPS A systematic approach to the display and interpretation of the ventricular function derived from gated MPS is important.
Gated SPECT Display Multiple slices of LV should be displayed for visual assessment of regional wall motion and systolic wall thickening. At least, a display of apical, mid, and basal short-axis and mid-ventricular horizontal as well as vertical long-axis slice(s) should be viewed. Each of the above-mentioned views need to be normalized to the series of end-diastolic to end-systolic slices so that the apparent count density changes during the cardiac cycle will reflect myocardial wall thickening. Software algorithms automatically define epicardial and endocardial borders and calculate ventricular volumes and left ventricular ejection fraction (LVEF). The physician should review the assigned endocardial and epicardial contours to ensure accuracy of the volumes and LVEF and may use these contours to analyze wall motion (Figure 5).
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GATED SPECT PARAMETERS There are standard nomenclatures for regional wall motion: normal, hypokinesis, akinesis, and dyskinesis. Hypokinesis can be further graded as mild, moderate, or severe. A semiquantitative scoring system is also recommended where 0, 1, 2, 3, 4, and 5 respectively represents normal, mild hypokinesis, moderate hypokinesis, severe hypokinesis, akinesis, and dyskinesis. Nuclear medicine physicians can take help of software algorithms in semiquantitative scoring of wall motion and thickening.38 Wall motion and wall thickening are generally concordant except in patients with left bundle branch block (LBBB), RV pacing, or after cardiac surgery where septal wall motion is frequently abnormal (paradoxical), with normal wall thickening. Along with noting LV wall motion, wall thickening, and LVEF, the function of the RV should also be noted. Normal databases are available for regional wall thickening, LVEF, and volumes. The LVEF may be categorized as normal (>55% to Atria> Ventricles
Occasional
Atria> Ventricles
Unusual
Adults
88 Cardiac Tumors: Practical Approach and Management
(A) Benign tumors 1. Congenital tumor +
2. Acquired tumor Myxoma
+/–
Papillary fibroelastoma Hemangioma
+
Myocardium, endocardium
Lipomatous atrial hypertrophy
+
++
Myocardium of atrial septum
Lipoma
++
Myocardium, endocardium, pericardium
All sites
Rare
Valves> Atria
Occasional
Inflammatory myofibroblastic tumor
+
++
+
+/–
Endocardium
Teratoma
++
+
+/–
Pericardial cavity, ventricular septum (rare)
No
Yolk sac tumor
++
+
Pericardial cavity, ventricular septum (rare)
No
3. Germ cell tumor
(B) Malignant tumors Angiosarcoma
+/-
Myxofibrosarcoma
+/–
Leiyomyosarcoma Rhabdomyosarcoma
+/–
Lymphoma Source: Adapted from Burke et al.
++
RA, pericardium
Occasional
+/–
++
Endocardium
LA
Rare
+/–
++
Endocardium
LA
No
++
+
Myocardium
Ventricles
No
+/–
++
Myocardium
RA
Occasional
16
can also infiltrate into the myocardium increasing the propensity for arrhythmia. The usual manifestations of the most common tumor—cardiac myxoma are listed in Table 3. Cardiac myxoma is the most common tumor and will be discussed in detail in the next section.
Cardiac Myxoma Myxomas most commonly occur in the left atrium though they can occur in any chamber. The myxoma is usually attached to the fossa ovalis part of the inter-atrial septum (Figures 1, 4 to 6, 8, 9, 11). They form a pedunculated mass with a pedicle (85%) (Figure 5) but sessile forms also occur (Figure 11).19 The external surface of the cardiac myxoma is usually globular and smooth (60%) (Figures 4 and 11) though their surfaces can be irregular with frond like mass and friable margins (Figures 5 and 6) predisposing them to embolization.5 These tumors can occasionally be encapsulated (2.8%) (Figures 6 and 11) (Goswami et al.5).
HISTOPATHOLOGY Multipotent mesenchymal stem cells are the likely origin of cardiac myxoma. The occasional finding of bone and
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marrow tissue in myxomas support their origin from mesenchymal cells.20 An alternative hypothesis is their origin from endocrine sensory tissues as suggested by Krikler et al. based on neuroendocrine markers in 24 excised atrial myxomas.21 Additionally, resembling tumors of neural origin, cardiac myxoma is often associated with cutaneous leiomyomatosis, systemic findings like fever, weight loss and hypergammaglobinemia. Cardiac myxomas in general are benign tumors though there are multiple case reports of local recurrence and distant emboli invading vessel walls and having independent growth.6,22
CLINICAL FEATURES Constitutional Symptoms Constitutional symptoms may be the only manifestation of the myxoma in up to 30% patients.23 Elevated gamma globulins, inflammatory chemokines produced by the myxoma and antibodies against the myxoma cells can elicit systemic response that may produce constitutional symptoms.24 Isolated right atrial cardiac myxomas usually do not produce constitutional symptoms. This probably
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Symptoms Obstructive symptoms
56 (80%)
104 (84.5%)
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Table 3: Clinical manifestation of cardiac myxoma in Indian population (Goswami et al.(5,17)
1. Dyspnea
56 (80%)
98 (79.6%)
2. Syncope
11 (15.7%)
18 (14.6%)
3. Pedal edema
11 (15.7%)
20 (16.2%)
7 (10%)
10 (8.1%)
4. Postural symptoms
No. of patients (N = 70) 5
No. of patients (N = 123)17
Embolism
21 (30%)
32 (26%)
1. Cerebral artery
14 (20%)
23 (18.7%)
2. Retinal artery
4 (5.7%)
4 (3.3%)
3 (4.3%)
5 (4.1%)
Constitutional
3. Pulmonary artery
32 (45.7%)
51 (41.5%)
1. Fever
32 (45.7%)
48 (39%)
2. Weight loss
7 (10%)
11 (8.9%)
3. Arthralgia
4 (5.7%)
4 (3.3%)
Miscellaneous
25 (35.7%)
60 (48.7%)
1. Palpitation
18 (25.7%)
41 (33.3%)
2. Chest pain
7 (10%)
19 (15.4%)
Asymptomatic
4 (5.7%)
6 (4.9%)
may be because the chemokines produced by the tumor that are responsible for the constitutional symptoms are metabolized in the pulmonary circulation before they reach the systemic circulation.5 The constitutional symptoms are more common in larger myxomas as compared to smaller myxomas and could be because larger myxomas produce more chemokines.5 In patients with murmur and constitutional symptoms, a close differential diagnosis will be infective endocarditis.
Obstructive Symptoms Obstructive symptoms (syncope, dyspnea, systemic congestion) of myxoma is the most common presentation in Indian population.5 The tumor in its usual location in the atria impairs the flow across the atrioventricular valves (Figures 6 and 11). The obstruction is characteristically progressive.25 Intermittent obstruction may present as posture related syncope, or even sudden death. The larger the myxoma, there is an increased tendency to present with obstructive symptoms as compared to smaller myxoma.5 The obstructive and other symptoms observed in myxoma will be similar to symptoms seen in patients with hypertrophic obstructive cardiomyopathy, valvular heart disease with ball-valve thrombus and dilated cardiomyopathy.
Embolism Systemic embolization can occur in 26–30% of Indian Population (Goswami et al).5,17 Systemic embolization is more commonly seen in smaller myxomas. These myxomas are usually small and do not cause obstruction
nor produce enough chemokines to cause constitutional symptoms and hence more often end up presenting in a rather catastrophic manner as systemic embolization. Myxoma with friable and irregular surface predispose to thrombus formation which are prone to embolize (Figure 5). About 50% of total embolic presentations involve embolization to central nervous system.26 Patients with embolism usually had smaller myxomas and this association could be because of: (1) Patients with embolisms seek medical attention much earlier because of the acute presentation of an embolic event. (2) Myxomas with embolism are gelatinous and friable and may give rise to multiple systemic embolisms and may never become large enough to give rise to obstructive or constitutional symptoms. The association between the size of the left atrial myxoma, the incidence of embolization and other clinical presentations have been reported by Fyke et al,27 Xie et al. 28 and Goswami et al. 5 Pulmonary embolism can occur in isolated right sided myxomas or bi-atrial myxomas. These can cause fatal pulmonary obstruction in up to 10% cases.29 The differential diagnoses that have to be suspected in patients presenting with systemic embolization in normal sinus rhythm include intermittent atrial fibrillation, multivalvular heart disease (murmur will be present) and infective endocarditis (constitutional symptoms will be present).
Miscellaneous Symptoms Cardiac myxoma patients may have nonspecific symptoms like chest pain (typical angina, atypical angina and pleuritic chest pain), palpitations and giddiness, etc.5
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Location of Myxoma Cardiac myxomas usually arise from the fossa ovalis in the left atrium. Most common location of myxoma is the left atrium (79–96%) followed by right atrium (7.2–15%) and very rarely in both atrium and ventricle. The table below summarizes the sites of origin of cardiac myxoma from various cardiac tumor series (Table 5). Figure 1: Autopsy specimen showing left atrial myxoma attached to the inter-atrial septum. The mass has a smooth and globular surface. The mass is impinging on the mitral valve (not seen in the picture)
EXAMINATION Mitral diastolic murmur is the most common clinical finding on auscultation indicating the mitral inflow obstruction by the tumor. Apical systolic murmur and diastolic murmur were audible in 37.4% and 47.2% patients in the Indian population resulting in misdiagnosis of mitral stenosis and mitral regurgitation. 17 The characteristic “tumor plop” of cardiac myxoma—produced by the sudden prolapse of the tumor into the mitral valve—is not a common finding (5.7%—Goswami et al.5). Unlike mitral stenosis, the mid-diastolic murmur of cardiac myxoma does not start with the opening of the mitral valve but starts only after the tumor plop. It is to be noted that the tumor plop and late diastolic murmur can vary in intensity with change of posture. The tumor plop is usually misdiagnosed as opening snap in the presence of a diastolic murmur leading to a mis-diagnosis of mitral stenosis. Differentiating this finding from the diastolic murmur of mitral stenosis is often difficult (Table 4). More commonly, the first heart sound is accentuated and pulmonary component of the second heart sound is loud.17 In the presence of regurgitation, systolic murmur can occur.
CLINICAL DIAGNOSIS Cardiac myxomas are rarely diagnosed based on the history, physical findings, electrocardiogram and chest
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X-ray. This is because there are no specific symptoms or signs based on which the diagnosis of myxoma can be made. Cardiac myxomas are notorious to mimic many cardiovascular diseases.5,17 Mitral valve disease is the most common clinical diagnosis (70–72.4%) before echocardiography was performed.5,17 Only in 5.7–6.5% cases left atrial myxoma was clinically diagnosed before echocardiography and 4.8–5.7% were identified on family screening of the patients who presented with bi-atrial myxoma.5,17 Table 4 shows the suspected clinical profile of patients before echocardiography in Indian patients. In a given patient presenting with typical signs and symptoms of mitral stenosis, who is found to be in sinus rhythm and has constitutional symptoms and/ or peripheral embolization, a diagnosis of cardiac myxoma should always be suspected.
Atrial Myxoma Atrial myxomas, whether right or left or bi-atrial, arise from the interatrial septum usually from the region of the limbus of the fossa ovalis (Figures 1, 4 to 6, 8 to 11). About 10% arise from other sites other than fossa ovalis, especially the posterior, anterior part of the inter-atrial septum and the LA appendage. In Indian population most of the myxomas (80–90%) arise from the left atrium.5,33 RA myxoma tends to be more solid and sessile than the LA myxomas, with a wider attachment to the inter-atrial septum or atrial wall. Calcifications are more commonly seen in right atrial myxomas (Figures 8 and 9). Myxoma may be multicentric within a single chamber or bi-atrial.34 The most common arrangement of bi-atrial myxoma involves attachment of two stalks to opposite sides of the same area of the interatrial septum resembling dumb-bell (Figure 8). 35 In the Indian Population, the size of atrial myxoma ranged from 2.0 cm to 9.5 cm on echocardiography (Goswami et al.)5 which correlated very well with the size at the time of surgery.
Right Atrial Myxoma Right atrial myxomas (Figure 9) are rare compared to their left atrial counterpart (16% vs 80% respectively). Right atrial myxomas observed over a period of 16 years from All India Institute of Medical Sciences, New Delhi has been summarized in the table below (Table 6).18 Right atrial myxomas frequently produce symptoms and signs of right heart failure. The constitutional symptoms were absent in patients with isolated RA
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Table 4: Clinical diagnosis before echocardiography in Indian patients5,17
11 Let’s Face the Viva
Clinical diagnosis
No. of patients (n = 70)
No. of patients (n = 123)
1. Mitral valve disease
49 (70%)
89 (72.4%)
a. MS
14 (20%)
30 (24.4%)
11 (15.7%)
17 (13.8%)
c. MR
14 (20%)
23 (18.7%)
d. MS+TR
7 (10%)
14 (11.4%)
e. MR+TR
3 (4.3%)
5 (4.1%)
2. Tricuspid valve disease
7 (10%)
14 (11.4%)
a. TS+TR
5 (7.1%)
9 (7.3%)
5 TR
2 (2.9%)
5 (4.1%)
3. Ischemic heart disease
4 (5.7%)
8 (6.5%)
4. Left atrial myxoma
4 (5.7%)
8 (6.5%)
5. Family screening and follow up
4 (5.7%)
6 (4.8%)
6. Dilated cardiomyopathy
2 (2.9%)
2 (1.6%)
b. MS+MR
Abbreviations: MS, mitral stenosis; MR, mitral regurgitation; TS, tricuspid stenosis; TR, tricuspid regurgitation)
Table 5: Myxoma distribution in various cardiac chambers Bhan et al, 1998
2
Bjessmo and Ivert, 199730 Bortolotti et al, 199031 Centofanti et al, 199932 Goswami et al, 19985 Goswami et al, 200317 Aggarwal et al, 200715
LA
RA
Biatrial
RV
LV
55
10
1
0
0
(83.3%)
(15.2%)
(1.5%)
56
6
1
0
0
(88.9%)
(9.5%)
(1.6%)
46
6
0
2
0
(85%)
(11%)
77
6
(92.8%)
(7.2%)
(4%) 0
0
0
0
0 0
58
9
3
(82.9%)
(12.9%)
(4.2%)
103
15
3
2
(83.7%)
(12.1%)
(2.4%)
(1.6%)
151
23
6
3
6
(80%)
(12%)
(3.2%)
(1.6%)
(3.2%)
myxoma though were present in patients who presented with bi-atrial tumors (67%). Patients who presented with pulmonary embolism had myxoma that were smaller and had irregular, friable and papillary surface as compared to those that did not embolize. Larger right atrial myxomas, on the other hand, presented predominantly with obstructive symptoms like congestive heart failure and syncope. It is interesting to note that there is increased mortality with RA myxoma compared to LA myxoma, but the reason remains unclear.
Ventricular Myxoma Myxomas in ventricles are more commonly found in the right ventricle. These tend to be attached to the right ventricular free wall or the ventricular septum.
Total 66 63 54 83 70 123 189
15% of reported ventricular myxomas are associated with multiple myxomas. There is significant association of ventricular myxomas with familial myxomas. Left ventricular myxomas are very rare (Figure 12). Ventricular myxoma tend to present more commonly with embolic manifestations.36
Myxomas in Childhood Myxomas are rarely reported in pediatric age group including infancy.37 Obstructive symptoms are uncommon in the paediatric age group and hence high index of clinical suspicion is necessary to identify patients with cardiac myxoma. First presentation usually is an embolic episode and often catastrophic. Children are also more prone to develop multiple myxomas.17
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Table 6: Summary of RA myxoma 130
RA myxoma
21 (16%)
Gender distribution
Male = 6; Female = 14
Symptoms 1. Mean duration of symptoms
8.8 months
2. Obstructive symptoms
14 (70%)
3. Constitutional symptoms*
2 (10%)
4. Pulmonary embolism
5 (25%)
5. Syncope
3 (15%)
Multiplicity of tumor 1. Isolated
15 (75%)
2. Bi-atrial
3 (15%)
3. Associated RV myxoma
2 (10%)
Attachment of tumor 1. Fossa ovalis
9 (44%)
2. Inferior part of IAS
9 (44%)
3. Free wall of RA
1 (4%)
4. Inferior part of CS
2 (8%)
Presence of stalk
17 (85%)
Prolapse into RV
16 (80%)
Recurrence after surgery
1 (5%)
Mortality
2 (10%)
Abbreviations: RA, right atrium; RV, right ventricle; IAS, interatrial septum; CS, coronary sinus *Constitutional symptoms were seen in patients with bi-atrial myxomas
Familial Myxomas The non-familial myxoma is the most common, are usually solitary, seen mostly in left atrium and rarely recur after surgery compared to their familial counterparts. These are most commonly seen in middle aged females.38 In comparison, myxoma have familial occurrence in about 5% of patients and are primarily disorders of young men.39 Multiplicity, tendency to recur after surgery and extracardiac manifestations are common with familial variants (Figure 8). 40 Histologically, they are like the non-familial variant though aneuploidy is seen in most cases of familial myxomas. Familial myxoma present at a younger age, are more likely to be multiple and are found in atypical locations. There is also increased risk of recurrence after resection.41 In the clinical and echocardiographic series published from AIIMS, New Delhi, India (Goswami et al.),5 3 out of 70 patients were identified to have familial myxoma in one family. Out of the three, two had bi-atrial myxoma (Figure 8) and one had left atrial myxoma. Multiple instances of recurrences of myxoma after surgery were seen in two patients. The mother of the index patient with bi-
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88 Cardiac Tumors: Practical Approach and Management
Total myxoma
atrial myxoma was found to have bi-atrial myxoma which recurred as bi-atrial myxoma 24 months after surgery and second recurrence as a solitary left atrial myxoma 12 years after surgery. She was successfully reoperated twice for the recurrence. The brother of the index patient had left atrial myxoma which recurred 10 years after surgery as left atrial myxoma and was successfully re-operated. It is to be noted that in this series, the recurrence in the non-familial group was seen only in 2 patients and this was attributed to the earlier practice of incomplete resection of the inter-atrial septum surrounding the attachment of myxoma during surgery.17 The common syndrome described with myxomas is the “Carney syndrome” (Table 7). Carney complex is an autosomal dominant syndrome, rare in incidence, and is characterized by pigmented lesions of the skin and mucosa, cardiac and cutaneous myxomas and multiple endocrine tumors. The disease is caused by inactivating mutations or deletions of the PRKAR1A gene located at 17q22-24 coding for the regulatory subunit type 1 alpha of protein kinase A (PKA) gene.42
DIAGNOSTIC EVALUATION Cardiac tumors are often misdiagnosed in a clinical examination. In an initial 11 years experience and subsequently 16 years updated data from All India Institute of Medical Sciences, New Delhi (Goswami et al.),5,17 it was observed that only 5.7–6.5% had clinical suspicion of myxoma before confirmation by echocardiography.5 Most often malignant cardiac tumors are diagnosed at very late stages when they become clinically apparent.
Echocardiography Echocardiography, with its wide availability, is the screening and diagnostic tool of choice in patients with suspected cardiac tumor. We will discuss a step by step approach of describing cardiac tumor in this section.
Malignant vs Benign Cardiac Tumor Certain characteristics of a tumor helps to identify the malignant cardiac tumor. These are listed below (Table 8). Pericardial effusion in association with a cardiac tumor usually suggests a malignant cardiac tumor (Figure 2) though can be present in patients with right heart failure secondary to myxomas.
Neoplastic vs Non-neoplastic Masses Cardiac tumors can often be difficult to differentiate from other masses like vegetations and thrombus. Thrombi are found in the presence of valvular disease, akinesia or severe hypokinesia of ventricular walls or in the presence of atrial fibrillation/flutter. They have a predilection for left atrial appendage (Figures 3 and 11). 751
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Table 7: Carney complex features42
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1. Lentigines
Table 8: Echocardiographic parameters to differentiate between benign and malignant cardiac tumors43,44
2. Blue nevus
Echocardiographic parameter
Benign
3. Myxoma
Location outside right atrium
+++
4. Adenoma 5. Pancreatic cancer 6. Adrenocortical cancer 7. Prolactinoma
Location outside atria and ventricles
+
Malignancy
+++
Non-mobility
++
Pericardial effusion
+++
Assessment of Obstruction Intra-cardiac tumors often prolapse through the valve to cause obstruction. The larger the size of the tumor, the higher the degree of obstruction. The size and the degree of obstruction directly correlate with the symptoms of the patient (Figure 12).5
Catheterization and Angiography With improvements in imaging using computed tomography and magnetic resonance imaging, there is little role for catherisation and angiography. However, pre surgical coronary angiography can reveal the dense vascularisation of cardiac tumours (Figure 13). Figure 2: Apical 4 chamber view: Right atrial mass prolapsing into ventricle through the tricuspid valve in diastole mimics myxoma. Note that the mass lacks any attachment to the interatrial septum compared to cardiac myxoma. Mild pericardial effusion is present. Histopathology of the mass revealed diffuse large B cell lymphoma
On the contrary, calcification (Figures 8, 10 and 11) and echolucency (Figures 4, 5 and 11) are characteristic of cardiac myxoma.5 If further ambiguity persists, cardiac MRI can provide certainty in the diagnosis. Vegetations may become very large especially in fungal endocarditis and can be difficult to differentiate by echocardiography.
Surface Characteristics of the Cardiac Tumor Smooth surface of cardiac tumors (Figure 3) is less frequently associated with embolic manifestations compared to the tumors with variegated surface (Figure 5). The latter provides nidus for thrombus formation and are also more friable in nature making them more prone for embolism.5
Multiplicity of the Cardiac Tumor
752
Cardiac tumor can occur in solitary or as multiple tumors in various chambers of the heart. Multiplicity are characteristically seen in rhabdomyoma (Figure 7) and rarely seen in myxoma in benign cardiac tumors (Figure 8). Familial cardiac myxoma can present with multiple tumors. Multiple masses are often present in malignant cardiac tumors.
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Computed Tomography Computed tomography (CT) can be used to accurately image the heart and surrounding mediastinum. Cardiac CT provides better soft-tissue contrast than echocardiography, can depict calcification and fat, and may allow tissue diagnosis of some masses such as lipomas. Cardiac CT images can be reconstructed to provide 3D models that allow for better understanding of the surgical anatomy. CT also provides sufficiently accurate information regarding coronary arteries especially as part of preoperative evaluation. Although spatial resolution of CT has improved with the development of faster imaging techniques, particularly electron beam CT, this modality is still inferior to echocardiography in the depiction of small moving structures such as the cardiac valves. 45 Unlike echocardiography, CT does not allow for true real-time imaging. The most common primary cardiac tumor—cardiac myxoma, can be safely operated based on echocardiographic diagnosis (Figure 14).
Magnetic Resonance Imaging MRI has emerged as a useful tool for detailed evaluation of cardiac masses. It is noninvasive, has a large field of view and allows for direct multi-planar imaging capability. A distinct advantage of MRI over echocardiography is the ability to obtain histopathological characteristics of a cardiac mass.46,47 In one of the studies from All India Institute of Medical Sciences, it was shown that MRI was complementary to echocardiography and was able to detect additional tumors. It also provided information
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88
C
to reclassify atypical findings in echocardiography like asymmetric hypertrophy of ventricular septum to more appropriate diagnosis like fibroma and lipoma. Cardiac MRI imaging also helped delineating the intramural component extension into inflow or outflow, outflow tract obstruction and associated pericardial or extracardiac masses better than echocardiography. 48 It is to be noted that cardiac MRI imaging takes longer times for acquisition and in a critically ill patient it is often difficult to obtain.
Positron Emission Tomography 18-FDG positron emission tomography (PET) can provide additional information regarding the activity of tumor, recurrence after surgery and metastasis. This is not a widely used modality in cardiac tumors but has shown promise to provide incremental information over and above other cross section imaging modalities.49,50
MANAGEMENT General The key to management of cardiac tumors is early diagnosis and management. The consequences of
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A
B
Figures 3A to C: (A) Parasternal short-axis at aortic level: The leftatrial thrombus seen extending into the left atrial appendage (arrow); (B) Left-atrial thrombus attached to the lateral wall of the atrium—note the absence of attachment to the interatrial septum; (C) Parasternal long-axis: Note the arrow pointing at the diseased mitral valve
complications of cardiac tumors are often catastrophic. Any patient suspected to have cardiac tumor should be immediately screened with echocardiography and further imaging to characterize the tumor and defining its extent should be expedited for early intervention.
BENIGN CARDIAC TUMORS Cardiac Myxoma Cardiac myxoma, the most common benign cardiac tumor, has very good prognosis after surgery with survival like the general population.1,2,30,51-54 Recurrences for the tumor should be carefully monitored during the initial years especially in patients with familial type of cardiac myxoma. Improved surgical techniques like removal of the atrial septum along with the base of the tumor have reduced recurrences secondary to residual tumor.
Papillary Fibroelastoma Papillary fibroelastoma is a benign cardiac tumor notorious for its embolic manifestations. These tumors rarely cause obstructive symptoms. Surgery can be considered in young patients with low surgical risk or when there is associated cardiovascular condition requiring surgery.
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A
B Figures 4A and B: Myxoma in a patient who presented with cerebrovascular accident with 2 different surfaces in different phases of the cardiac cycle (A) Apical 4 chamber: Left atrial myxoma arising from the interatrial septum with broad base. The mitral valve is normal. There are echoluscent areas within tumor suggestive of hemorrhage; (B) Apical 4 chamber view of the same patient
The tumor is usually shaved off from its base when attached to the ventricle, atrium or aortic valve. 55 The chance of recurrence of the tumor is rare .56 Valve-sparing surgery is preferred since recurrence even from a partially resected tumor is rare.57
Rhabdomyoma Rhabdomyomas are the most common childhood cardiac tumor and commonly located in the ventricles.58 They are usually multiple (cf. fibroma—usually solitary) (Figure 7). These tumors are strongly associated with tuberous sclerosis and incidence is as high as 48% in patients with tuberous sclerosis. Most often, these patients
are asymptomatic, although some patients may present with arrhythmias and heart failure. These tumors often regress with age but they can sometimes grow or develop during puberty. There is an increasing role of mTOR (mechanistic target of rapamycin) inhibitors like sirolimus, everolimus being used in rhabdomyoma that have shown accelerated regression.59 Surgery is usually avoided and is reserved for patients with features of obstruction and arrhythmias not controlled with antiarrhythmic drugs.
Cardiac Fibroma Cardiac fibroma (Figure 15) typically occurs in childhood and most commonly located in the ventricles and the
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B
Figures 5A and B: (A) Apical 4 chamber view: Left atrial myxoma—note the variegated surface of the myxoma. The myxoma is attached to the lower part of the left side of the inter-atrial septum and is prolapsing into the left ventricle. There is significant right atrial and ventricle enlargement secondary to pulmonary hypertension; (B) Parasternal long axis view of same patient—the variegated surface (small arrow) of the cardiac myxoma is more marked. This patient presented with previous history of transient ischemic attack
interventricular septum. 60 Their intramural location predisposes to cardiac arrhythmias. The tumors are usually single and often calcified. It is the most common resected neoplasm in children and the second most common benign primary cardiac tumor found at
A
autopsy in children.58 Fibroma needs to be operated in symptomatic patients. In asymptomatic patients with large tumors, surgery should be considered for preventing progressive cardiac deformity and valve dysfunction.61 During surgery, the tumor is usually enucleated from the
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A
B Figures 6A and B: (A) Parasternal long axis view: Large left atrial myxoma attached to the interatrial septum prolapsing into the left ventricle (arrow); (B) Apical 4 chamber view of the same patient
myocardium. When there is a large tumor and complete removal seems impossible, even partial removal provides good palliation. 62 Cardiac transplantation needs to be considered in the presence of unresectable tumor.
MALIGNANT CARDIAC TUMORS
Figure 7: Apical 4 chamber view: Hyperechogenic mass seen in right atrium (arrow) and right ventricle in a neonate—rhabdomyoma
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These are exceedingly rare tumors. Only 15% of primary cardiac tumors are malignant. The majority (95%) represent sarcoma with remaining 5% is made up of primary cardiac lymphoma and mesothelioma. Metastatic cardiac tumors are 30 times more common than primary cardiac tumors.55 Primary cardiac sarcomas constitute approximately 1% all soft tissue sarcomas.63 Angiosarcoma is the most common sarcoma in adult. Rhabdomyosarcoma is the
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Figure 8: Apical 4 chamber view: Bi-atrial myxoma (dumb-bell appearance) in both right and left atrium attached to the interatrial septum (oblique arrow). Note the calcification (horizontal arrow) in the right atrium and multiple areas of echolucencies suggestive of haemorrhage—Goswami et al.5 Courtesy: From IJC
Figure 10: Apical 4 chamber view: Large left-atrial myxoma is attached to the interatrial septum (horizontal arrow) with normal mitral valve. The tip of the myxoma shows heavy calcification
most common sarcoma in children. Leiomyosarcoma, synovial sarcoma, osteosarcoma, fibrosarcoma, myxoid sarcoma, liposarcoma, mesenchymal sarcoma, neurofibrosarcoma and malignant fibrous histiocytoma are other cardiac sarcomas observed. Angiosarcoma are found predominantly on the right side or the pericardium whereas other sarcomas are found predominantly on the left side of the heart. Pericardial angiosarcoma are extremely rare. On echocardiography, it demonstrates a broad based atrial mass near the inferior vena cava. Epicardial, endocardial and intracavitary extension is common. On CT and MRI they have avid, arterial phase enhancement permitting a definitive diagnosis. Pulmonary metastasis is frequent and survival after diagnosis rarely exceeds 6 months.55
Figure 9: Apical 4 chamber view: Large right atrial myxoma prolapsing into right ventricle presented with history of recurrent syncope. Note the attachment to the interatrial septum (horizontal arrow) and calcification (vertical arrow)
Undifferentiated pleomorphic sarcoma with variable degrees of myofibroblastic differentiation include a spectrum of high grade sarcoma that have been left unclassified and malignant fibrous histiocytoma is re garde d as synonymous w ith undifferentiate d pleomorphic sarcoma.16 The majority arises from the left atrium and is usually endocardial based. Usual presentation is dyspnea which is related to the obstruction of the mitral valve. Clinically they mimic cardiac myxoma. On imaging, multiple attachment sites, mitral valve involvement or infiltration into the atrial or ventricular walls are seen which are not seen with cardiac myxoma. Prognosis is very poor and survival beyond a few months is rare. Leiomyosarcoma constitute approximately 10% of cardiac sarcomas. These are most commonly seen in left atrium. Rhabdomyosarcoma is usually a multisite tumor without any predilection to a cardiac chamber. It is more common in males. Primary cardiac lymphoma is rare accounting for only 1.3% of primary cardiac tumors and 0.5% of extranodal lymphomas. There is significant male predominance (male to female ratio 3:1). The incidence of cardiac lymphoma is increasing and may be due to Ebstein-Barr related lymphoproliferative disorder in AIDS and posttransplant patients. In among post-transplant lymphoma the incidence is greater in patients with cardiac and lung transplants than those with renal transplants. It should be noted that majority of primary cardiac lymphoma are diagnosed in immunocompetent patients and these do not contain the Ebstein-Barr DNA. Lymphomas are medically managed with typical chemotherapy used for lymphoma.
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B
Figures 11A and B: (A) Apical 4 chamber view: Large left atrial myxoma prolapsing into the left ventricle. The myxoma is attached to the left side of the interatrial septum (right arrow) around fossa ovalis and is encapsulated; (B) Parasternal short-axis at aortic level of the same patient: The left atrial appendage is normal. There are multiple areas of echolucency suggestive of hemorrhage
A
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B
Figures 12A and B: Left ventricular cardiac myxoma: (A) Parasternal long axis view: Large LV myxoma attached to the left ventricular outflow tract is seen (arrow); (B) Parasternal short axis: Mass prolapsing through the aortic valve during systole. Patient had sudden cardiac death
Figure 13: Coronary angiography: RAO caudal view showing contrast enhancement of the left atrial cardiac myxoma in the delayed phase due to neovascularization (circle)
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Figure 14: Computed tomography—axial section of the heart: Large left atrial myxoma (6.7 cm along the longitudinal axis) prolapsing into left ventricle. Note the absence of contrast enhancement of the tumor in the arterial phase
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Figure 15: Parasternal short axis view at mitral valve level: Echogenic mass just below the posterior mitral leaflet invading the inferoseptal part of left ventricle myocardium—cardiac fibroma
Pericardial mesothelioma is a rare malignant tumor of the pericardium. It is more commonly seen in males (male to female ratio 2:1). There is no clear association of the tumor with asbestos exposure unlike pleural mesothelioma. Unlike the tumors of the myocardium, this tumor hardly project into the cardiac chambers. These encase the heart and present with tamponade features. The tumor has a poor prognosis.64
CONCLUSION Primary cardiac tumor is a relative rare entity. Majority of primary cardiac tumor are benign and most of the benign tumors are cardiac myxoma. The most common presentation of myxomas are obstructive symptoms followed by constitutional symptoms and embolization of the tumor. In a given patient presenting with typical signs and symptoms of mitral stenosis, who is found to be in sinus rhythm and has constitutional symptoms and/or peripheral embolization, a diagnosis of cardiac myxoma should always be suspected. Increasing use of echocardiography has increased the antemortem diagnosis of these tumors. Benign tumor especially cardiac myxoma have excellent prognosis and early diagnosis by 2D echocardiography offers a definitive treatment with good surgical outcomes. Malignant tumors are rare but have a very poor prognosis. Clinical presentation is usually during the late stages at a point where further treatment is not helpful. Novel surgical approaches like cardiac auto-transplantation may allow for excision of unapproachable tumors. Palliation is the mainstay of treatment.
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23. Fyke FE 3rd, Seqard JB, Edwards WD, et al. Primary cardiac tumors: experience with 30 consecutive patients since the introduction of two-dimensional echocardiography. J Am Coll Cardiol. 1985;5(6):1465-73. 24. Currey HL, Mathews JA, Robinson J. Right atrial myxoma mimicking a rheumatic disorder. Br Med J. 1967;1(5539): 547-8. 25. Greenwood WF. Profile of atrial myxoma. Am J Cardiol. 21(3):367-75. 26. Meller J, Teichholz LE, Pichard AD, et al. Left ventricular myxoma: echocardiographic diagnosis and review of the literature. Am J Med. 1977;63(5):816-23. 27. Earl Fyke F, Seward JB, Edwards WD, et al. Primary cardiac tumors: Experience with 30 consecutive patients since the introduction of two-dimensional echocardiography. J Am Coll Cardiol. 1985;5(6):1465. 28. Xie S. Cardiac tumors: clinical and echocardiographic diagnosis of 65 cases. Zhonghua Xin Xue Guan Bing Za Zhi. 1990;18(1):17-9, 61. 29. Percell RL, Jr., Henning RJ, Siddique MP. Atrial myxoma: case report and a review of the literature. Heart Dis. 2003;5(3):224-30. 30. Bjessmo S, Ivert T. Cardiac myxoma: 40 years’ experience in 63 patients. Ann Thorac Surg. 1997;63(3):697-700. 31. Bortolotti U, Maraglino G, Rubino M, et al. Surgical excision of intracardiac myxomas: a 20-year follow-up. Ann Thorac Surg. 1990;49(3):449-53. 32. Dein JR, Frist WH, Stinson EB, et al. Primary cardiac neoplasms. Early and late results of surgical treatment in 42 patients. J Thorac Cardiovasc Surg. 1987;93(4):502-11. 33. Blondeau P. Primary cardiac tumors—French studies of 533 cases. Thorac Cardiovasc Surg. 1990;38(Suppl 2):192-5. 34. O’Neil MB Jr, Grehl TM, Hurley EJ. Cardial myxomas: a clinical diagnostic challenge. Am J Surg. 1979;138(1):68-76. 35. Imperio J, Summers D, Krasnow N, et al. The distribution patterns of biatr ial myxomas. Ann Thorac Surg. 1980;29(5):469-73. 36. ElBardissi AW, Dearani JA, Daly RC, et al. Analysis of benign ventricular tumors: long-term outcome after resection. J Thorac Cardiovasc Surg. 2008;135(5):1061-8. 37. Reddy DJ, Rao TS, Venkaiah KR, et al. Congenital myxoma of the heart. The Indian J Pediatr. 1956;23(6):210-2. 38. Kotylo PK, Kennedy JE, Waller BF, et al. DNA analysis of atrial myxomas. Chest. 1991;99(5):1203-7. 39. Carney JA. Differences between nonfamilial and familial cardiac myxoma. Am J Surg Pathol. 1985;9(1):53-5. 40. Carney JA, Hruska LS, Beauchamp GD, et al. Dominant i n h e r i t a n c e o f t he c o mp l e x o f my xomas, sp ott y pigmentation, and endocrine overactivity. Mayo Clin Proc. 1986;61(3):165-72. 41. Carney JA, Swee RG. Carney complex. Am J Surg Pathol. 2002;26(3):393. 42. Correa R, Salpea P, Stratakis CA. Carney complex: an update. Eur J Endocrinol. 2015;173(4):M85-97. 43. Patel R, Lim RP, Saric M, et al. Diagnostic performance of cardiac magnetic resonance imaging and echocardiography in evaluation of cardiac and paracardiac masses. Am J Cardiol. 2016;117(1):135-40.
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Index Note: Page numbers followed by f, t, or b represent figures, tables, or boxes respectively.
A ‘a’ waves, 7–8, 7f Abatacept, 584 Abdominal aortic aneurysms, 600–601 Abnormal coagulation factors, in Eisenmenger syndrome, 388 Absent ‘a’ wave, 8, 8f Accessory pathway-induced cardiomyopathy, 486, 487f AccuCinch system, 225 ACE inhibitors, 455 and dilated cardiomyopathy, 452, 453
collagen autoimmunity hypothesis, 49
MRI, 362, 363f
epitope spreading, 49
overview, 360
humoral immune response and endothelial injury, 47
radiography, 361
molecular mimicry, 47 noncardiac manifestations, 49 overview, 74 pathogenesis, controversies in, 49–50 endothelial heterogeneity, 49 healing ability, 49 myocardial damage in, 50
Acquired ASOVs, 352
valve involvement, 50
Acquired methemoglobinemia, 379
vicious inflammatory cycle, a, 49
Acrocyanosis, 439
Adenosine, 736–737
ACS. See Acute coronary syndrome (ACS)
Adults, CoA in, 360–366
Acute aortic regurgitation, 69, 69t Acute aortic syndrome, 601 aortic dissection, 601, 610–611
cardiac catheterization and angiography, 362 classification, 360
acute type A, 602–603
clinical presentation, 360–361
acute type B, 603, 603t
CT, 362, 363f
classification of, 601, 602f
diagnostic evaluation, 361–362, 361f, 362f, 363f
natural history, 601–602 treatment of, 602–603 intramural hematoma, 601, 603 penetrating aortic ulcer, 604 Acute coronary syndrome (ACS), 644 diagnosis, computer-interpreted ECG in, 664–665, 666f Acute glomerulonephritis (AGN), 46 Acute mitral insufficiency BMV and, 103–104, 104t Acute myocardial infarction (AMI), 640 Acute phase reactants, 581 Acute rheumatic fever (ARF), 46. See also Rheumatic fever (RF)
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balloon coarctoplasty for, 364
native, 360
recurrent, 360 stent implantation, 364, 365f Adults, cyanosis in, 378–383 differential diagnosis, 379, 380t with clinical features of ASD, 381 with continuous murmur, 381 cyanotic heart disease with cardiomegaly on X-ray, 381 cyanotic heart disease with relatively normal sized heart on X-ray, 381 differential cyanosis, 379–380, 381f hemoglobin work-up in cyanotic patient approach to, 381 investigations, 381–382, 382f methemoglobinemia acquired, 379 congenital, 379
ECG, 361, 361f
methemalbuminemia, 379
echocardiography, 361–362
methemoglobin, 379
indications of intervention, 362–366
pseudocyanosis, 379
endovascular strategies, 364, 365f evaluation and follow-up, recommendations, 366 medical management of systolic arterial hypertension, 365–366 outcomes and late complications, 364–365
immunological mechanisms, 47–49, 48f
recommendations for interventional and surgical treatment, 363–364
cellular immune response in, 47–49
surgical treatment strategies, 364
sulfhemoglobinemia, 379 overview, 378 pathophysiology central cyanosis, 378–379, 378f peripheral cyanosis, 379 treatment strategy, 382–383 Adults, with repaired TOF aortic root enlargement after, 398 arrhythmias, 398 cardiac catheterization and angiography, 401 complications on follow-up, predictors of, 401 computed tomography, 399–400, 400f
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ECG, 398, 399f echocardiography, 398–399, 399f electrophysiology study for risk stratification, 401 long-term follow-up, 397 long-term follow-up, issues on, 398–399 magnetic resonance imaging, 400, 400f nuclear scintigraphy, 400 optimal frequency of clinical followup, 398 other cardiac comorbidities, 398 overview, 397 percutaneous pulmonary valve replacement/implantation, 401–402 periodic holter monitoring, 399 pregnancy and, 401 pulmonary regurgitation, 398 reoperations in, 401 residual ventricular septal defects, 398 right ventricular outflow tract obstructions, 398 serial estimation of brain natriuretic peptide, 401 standardized clinical assessment and management plans, 401 surgical repair of unoperated TOF, 397 Adventitia, 598 AF. See Atrial fibrillation (AF) Age, Eisenmenger syndrome pathophysiology and, 385–386 Airway diseases central cyanosis in newborn and, 372 AL amyloidosis, 553 decrease in production of amyloid, 556–557, 556t diagnosis of, 553, 554f, 554t, 555f Alcoholic cardiomyopathy, 483 Alfred de Musset sign, 19 AMBITION trial. See Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial Ambrisentan, 630 Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial, 630
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Ambulatory blood pressure monitoring, 14 Amend mitral annuloplasty ring, 224, 224f American College of Rheumatology (ACR) classification criteria for Takayasu arteritis, 577, 578, 579t American Heart Association (AHA), 204 Amplatzer duct occluder I (ADO I), 344, 345, 345f Amplatzer duct occluder II (ADO II), 344, 345, 346f Amplatzer duct occluder II additional size (ADO II AS), 344, 345–347, 347f Amplatzer vascular plugs, PDA, 347, 347f–348f Amyl nitrite, 36 Amyloidosis, 472–474, 473f AL amyloidosis, 553, 554f, 554t, 555f cardiac biomarkers, 554, 555 cardiac magnetic resonance imaging, 553, 555f cardiac magnetic resonance imaging in, 474, 474f clinical features, 552–553 familial, 553 longitudinal strain in, 712–713, 712f nuclear imaging in, 474, 475f pathophysiology, 552 radio-nuclear testing, 553 and restrictive cardiomyopathy, 540, 541, 542 senile systemic, 553 transthyretin-related, 557 Anatomic repair (double-switch operation), in CCTGA, 260 Anatomical errors, CHD echocardiography, 289–294 anomalous pulmonary venous drainage, 292, 293f aortic arch interruption, 290, 290f aortopulmonary window, 291 coarctation of aorta, 289–290, 290f muscular ventricular septal defects, 294, 294f peripheral pulmonary artery stenosis, 290–291, 290f, 291f pulmonary vein stenosis, 292, 292f sinus venosus defects and coronary sinus ASD, 293–294
supravalvar aortic stenosis, 291 venous anomalies leading to cyanosis, 292, 293f venous anomalies without clinical findings, 293, 294f Anderson-Fabry disease, 476 cardiac magnetic resonance imaging in, 476, 476f echocardiography in, 476 nuclear imaging in, 476 Anemia, 441 Aneroid manometers, 12 Aneurysms of the sinuses of Valsalva (ASOVs), 351–359 acquired, 352 arterial pulse in, 352 clinical presentation, 352 congenital form, 351–352 diagnosis cardiac catheterization and angiography, 357 chest radiograph, 355, 355f computed tomography, 356 echocardiography, 355–356, 355f–356f electrocardiogram, 354–355 history, 352 physical examination, 352–354, 353f epidemiology, 351 JVP in, 352–353, 353f management, 357–359, 358f pathological anatomy and etiology, 351, 351f ruptured, 352 sinuses involved in order of frequency, 352 types, based on etiology, 351–352 unruptured, 352 Angiocardiography, in CHD, 309 Angiography, 587, 752. See also Cardiac catheterization in adults with repaired TOF, 401 ASOVs, 357 CoA in adults, 362 in LS, 342 Angioplasty balloon, 591–592, 594f carotid, 589, 591–592f, 591t pulmonary artery, 592, 595t, 596f renal. See Renal angioplasty Angiotensin-converting enzyme (ACE), 561, 562
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AngioVac cannula, 621 Annular modification techniques for MR, 186
traumatic aortic injury, 604, 604t steno-occlusive lesions of, 608, 608f, 609f Aortic aneurysm, 599–601, 599f, 600t
heart sounds, 67–69 ejection sounds, 67 first heart sound, 67 fourth heart sound, 67
abdominal, 600–601
second heart sound, 67
Annulus reversus, 516
arch, 600
Anomalous origin of left coronary artery from pulmonary artery (ALCAPA), 25
third heart sound, 67
of ascending aorta, 599, 600t
Anomalous pulmonary venous drainage, 292, 293f Antenatal natural history, of VSD, 320 Anthracyclines, 455 Anti-TNF agents, 584 Anticoagulants, oral imatinib, 632 macitentan, 631
descending thoracic, 600 natural history, 599 thoracic, timing for intervention, 599–601, 599f, 600t thoracoabdominal, 600 Aortic arch interruption, 290, 290f Aortic dissection, 593, 596f, 601, 610– 611 acute type A
investigations, 20 murmur, 67–69, 68t natural history, 81–83, 82t, 83t overview, 17 peripheral signs, 67, 67t peripheral signs of aortic runoff, 18–20 physical examination and assessment of severity, 66–69
ranolazine, 631–632
subacute and chronic, 603
riociguat, 630–631
postnatal natural history of VSD and, 321
surgery for, 602–603
precordium, 67
selexipag, 631
acute type B
spironolactone, 632
management of, 603, 603t
treprostinil, 631
subacute and chronic, 603, 603t
Anticoagulated patients, secondary prophylaxis in, 122 Anticoagulation AF in RHD, 116 Anticoagulation management in pregnancy, recommendations, 255–256, 256f Antimicrobial therapy infective endocarditis bacterial resistance, 207 general trends, 207 specific recommendations, 207–208 Antioxidants, 642 Antirheumatic drugs, 582–583, 584 Antistreptococcal vaccine, 120–121 Antitubercular drugs, 525, 533 Antiviral therapy, 495, 497f Aorta, 598, 607 ascending. See Ascending aorta branches of, 598f chest X-ray in CHD, 284 diseases, 607t acute aortic syndrome. See Acute aortic syndrome
classification of, 601, 602f
severe, 68, 68b Aortic regurgitation (AR), VSD with, 326–330 clinical presentation, 327–328
natural history, 601–602
cardiac catheterization, 328
treatment of, 602–603, 603t
chest X-ray, 328
Aortic ejection click in AS, 70 Aortic regurgitation (AR), 66–69, 73, 130–131, 138–141 acute, 69, 69t arterial pulse, 17–18 bisferiens pulse, 18 wide pulse pressure, 18 arterial pulse in, 66 assessment of color flow doppler evaluation, 172–173, 173f diastolic flow reversal, 175, 175f M-mode color flow propagation velocity, 176–177 pressure half-time, 175–176, 176f proximal isovelocity surface area flow convergence method, 174–175, 174f
ECG, 328 echocardiogram, 328, 328f, 329f epidemiology, 326 history, 326 morphology, 327 natural history, 327 pathogenesis, 326–327 physiological effects, 327 treatment, 328–330, 330f Aortic root, 598 diseases specific to, 611–613, 613f Aortic root enlargement, after TOF repair in adults, 398 Aortic runoff, peripheral signs of, 18–20 Aortic stenosis (AS), 69–71, 71t, 73, 129–130, 138–141 causes, 138t ECG findings, 277
by vena contracta, 173–174, 173f, 174f
echocardiographic findings, 138– 141, 138t–141t
volumetric severity, 172, 173f
physical findings and assessment of severity
aneurysmal disease, 599–601, 599f, 600t
bisferiens pulse in, 66 blood pressure in, 66
arterial pulse, 70
aortitis, 609–610
chronic, 69, 69t
clinical features, 70–71, 70b
arteritis, 604–605
echocardiographic findings, 138– 141, 138t–141t
heart sounds, 70–71
imaging of, 607–608
KG-Index.indd 763
clinical manifestations, 599
Index
Angiotensin receptor-neprilysin inhibitor (ARNi), 449, 453
precordium, 70
763
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Essentials of Postgraduate Cardiology
Aortic valve, assessment of, 165–172
Arterial pulses
remodeling, 115
combined AS and MS, 172
in AS, 70
management, 116
data acquisition optimization, 166– 169, 167f–169f
in AR, 66
overview, 115
in ASOVs, 352
pathophysiology, 115
low-gradient, low-flow rheumatic aortic valve stenosis, 170, 170f
in LS, 341
pulmonary veins, electrical remodeling and stretch, 115–116
low-gradient low-flow severe AS, types of, 170–171, 171f, 172f paradoxical low-flow as with preserved ejection fraction, 171–172 Aortic valve, RHD of, 75
in MS, 61 Arteritis, 604–605 Arthralgia, 41
rhythm control, 117
Arthritis, 39
thromboembolism, 116
management, 43, 43t Artifacts attenuation, 742, 743f
ventricular rate control, 116–117 symptoms, 21 systemic examination, 22–23
of left bundle branch block, 742–743
Atrial flutter, ECG analysis, 677, 678f
AS. See Aortic stenosis (AS)
motion, 742
Atrial septal defect (ASD), 4, 420, 429
AR. See Aortic regurgitation (AR)
reconstruction, 742
Aortic valve disease
assessment, in LS, 341–342
Aortitis, 609–610
ARTO system, 222–223, 223f
BMV and, 104
Aortography, 576, 576f
aRV. See Atrialized right ventricle (aRV)
Aortopathy
ARVC. See Arrhythmogenic right ventricular cardiomyopathy (ARVC)
cyanosis with clinical features of, 381
indications of surgery for, 196 pathophysiology of, 192, 193f Aortopulmonary collaterals (APCs), 303f, 304
AS. See Aortic stenosis (AS) Ascending aorta, 598
Aortopulmonary window, 291
aneurysms of, 599, 600t
Aortopulmonary window (AP window), 25, 28
diseases specific to, 611–613, 613f ASD. See Atrial septal defect (ASD)
Apparatus factors, blood pressure measurement, 13
Ashman phenomenon, 686
AR. See Aortic regurgitation (AR)
ASOVs. See Aneurysms of the sinuses of Valsalva (ASOVs)
Arch artery interventions, 589 subclavian artery, 589, 589t, 590f
Ashrafian sign, 19
Aspirin, 642
ECG findings, 277 JVP and, 9, 9f Atrial septal defect (ASD), imaging of, 332–339 echocardiographic imaging transesophageal echocardiography (TEE), 335–336, 335f, 337f transthoracic echocardiography (TTE), 333–335, 334f embryology of interatrial septum, 332
ARF. See Acute rheumatic fever (ARF)
Asymptomatic murmur, 404
Arm position, in blood pressure measurement, 13
Asymptomatic severe MR, outcome of, 80–81, 80t, 81t
ostium secundumatrial septal defect, anatomy of, 332, 333f
Arrhythmia, 21
Atherosclerosis, 609
overview, 332
Arrhythmia-induced TCMP, 503
Atrial fibrillation (AF), 675, 685, 686, 687f
three-dimensional transesophageal images, 336, 337f
Arrhythmia-mediated TCMP, 503 Arrhythmias, 416, 420–421, 426
ECG analysis, 677, 678f
intracardiac echocardiography, 336–339, 338f, 339t
in adults with repaired TOF, 398
effects of, JVP and, 111
blood pressure measurement and, 15
hypertension and, 22 incidence, 23
Atrial septostomy, 432
supraventricular, 503–504
overview, 21
Atrial tachycardia (AT)
and tachycardiomyopathy, 503
physical examination, 21
types of, 332–333, 333f
ECG analysis, 675, 676–677, 677f
blood pressure, 22
Atrialized right ventricle (aRV), 419
Arrhythmogenic right ventricular cardiomyopathy (ARVC), 462
jugular venous pulse, 22
Atriopulmonary connection, 414, 414f
neck examination, 22
Arrhythmogenic right ventricular dysplasia (ARVD), 477–478
pulse, 21–22
Atrioventricular block (AVB), 692–693, 692–693f, 694f
ventricular, 504
in RHD, 115–117
Arrhythmogenic RV dysplasia, 421
anticoagulation, 116
Arterial pulse, AR and, 17–18 bisferiens pulse, 18
correction of underlying disorder, 116
wide pulse pressure, 18
inflammation and structural
764
KG-Index.indd 764
first degree, 693–694, 694t second degree, 694–696, 695f, 696f, 697f, 698t third degree, 698 Wenckebach, 700, 702f
09-11-2018 14:51:10
Atrioventricular nodal re-entrant tachycardia (AVNRT), 21, 677, 678–679, 679f
methods of crossing mitral valve, 95, 95f
in AR, 66
pre-evaluation, 92
Atrioventricular re-entrant tachycardia (AVRT), 21, 679, 680f
auscultatory gap, 14
technique, 93–96
measurement, 11–15
Auscultation, tricuspid valve disease, 111–112 Auscultatory gap, 14 Austin flint murmur, in AR, 68–69, 68t Autoimmune myocarditis, 492 Autoimmunity, and dilated cardiomyopathy, 484–485 AV canal defect, ECG findings, 275, 276f AVB. See Atrioventricular block (AVB) AVNRT. See Atrioventricular nodal reentrant tachycardia (AVNRT)
landmarks for, 93, 94f
ambulatory blood pressure monitoring, 14
technique for, 93–94
arrhythmias, 15
Balloon valvuloplasty BAV anomalies, 194–196
children, 14–15
Basal ventriculoplasty, 225
chronic kidney disease (CKD), 15
Baseline reference, 730
diabetes mellitus, 15
BAV. See Bicuspid aortic valve (BAV)
elderly, 15
Becker sign, 19
historical perspectives, 11, 11f
Bedrest, in rheumatic fever, 42
mercury use in, 11
Benign cardiac tumors
noninvasive techniques, 11–12, 12f
cardiac fibroma, 754–755
AVRT. See Atrioventricular re-entrant tachycardia (AVRT)
cardiac myxoma. See Cardiac myxoma
obese patient, 15
Azathioprine, 495, 583
papillary fibroelastoma, 753–754
practical points in, 13
rhabdomyoma, 754
pregnancy, 15
B Bacterial endocarditis, 443 Balloon angioplasty, 591–592, 594f Balloon catheter, for BMV, selection of, 95, 95t Balloon coarctoplasty for native coarctation of aorta, 364 for recurrent coarctation of aorta, 364 Balloon dilatation, 432 Balloon mitral valvotomy (BMV), 92. See also Percutaneous transvenous mitral commissurotomy
Beta-blockers, 455
process, 13–14
and dilated cardiomyopathy, 452–453 Beta-myosin heavy chain (MYH7), 461 Bicuspid aortic valve (BAV), 190–197, 611 anatomy, 190–191, 191f–192f anomalies of aorta, 192, 193f balloon valvuloplasty, 194–196 diagnosis, 193–194, 194f dysfunction of, 192 embryology, 190, 190f exercise and, 197
balloon catheter selection, 95, 95t
indications of surgery for aortopathy, 196
complications acute mitral insufficiency, 103– 104, 104t
self monitoring, 14 sources of error in, 14 in special populations, 14–15 physical examination in AF, 22 systolic, 13 BMV. See Balloon mitral valvotomy (BMV) BNP. See Brain natriuretic peptide (BNP) BNPs. See Brain natriuretic peptide (BNPs) Body posture, in blood pressure measurement, 13 Borderline RHD, 76
intervention, 194
AV regurgitation (subcategory C), 76
natural history, 192–193
management of, 77
overview, 190
morphological features of MV (subcategory A), 76
atrial septal defect, 104
pathophysiology of aortopathy, 192, 193f
cardiac tamponade, 104
pregnancy and, 196–197
MV regurgitation (subcategory B), 76
Bidirectional Glenn (BDG) operation, 412
Bosetan, 630
dilatation of IAS puncture site, 94–95
Biomarkers, 494, 638
Bradyarrhythmias, 299
echocardiography in, 92–93 indications for, 92
Birth, normal cardiopulmonary adaptation at, 371–372
in juvenile MS, 102
Bisferiens pulse, 18
death, 103 embolism, 104
in Lutembacher’s syndrome, 99–104, 100f
KG-Index.indd 765
present-day methods, 12–13
genetics, 192
gaint left atrium, 96, 96f
overview, 11
Berheim phenomenon, 7
approach, 93 complex anatomy and, 96
Index
Attenuated/absent ‘x’ wave, 7f, 8
trans-septal puncture (TSP), 93
Hypertension
and amyloidosis, 554, 555
in AR, 66 Blood pressure, 11. See also
Bozzolo sign, 19 Brain abscesses, 440–441 Brain natriuretic peptide (BNP), 554 serial estimation of, in adults with repaired TOF, 401 Breastfeeding secondary prophylaxis, 121
765
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Essentials of Postgraduate Cardiology
Brugada algorithm, 688, 690f Bulboventricular foramen (BVF), 404
C
advantages, 311–312, 312f
CABG. See Coronary artery bypass graft (CABG) CAD. See Coronary artery disease (CAD) Calcific MS, PTMC and, 98, 99f Cannon waves, 8, 8f Cardiac amyloidosis. See Amyloidosis Cardiac biopsy, 555 Cardiac catheterization, 405, 406f, 407f, 423. See also Angiography in adults with repaired TOF, 401
in Anderson-Fabry disease, 476, 476f basic sequences, 309–310, 310f
clinical diagnosis, 749–751 clinical manifestation of, 748t constitutional symptoms, 747–748 diagnostic evaluation angiography, 752 catheterization, 752 computed tomography, 752
bright-blood sequences, 310, 310f
echocardiography, 751–752, 752t
dark-blood or black blood sequences, 310, 310f
magnetic resonance imaging, 752–753
in cardiac amyloidosis, 474, 474f in cardiac sarcoidosis, 475 in CHD, 309–314
positron emission tomography, 753 embolism, 748 familial, 751
in CHD, 309 CoA in adults, 362
advantages, 311–312, 312f
location of, 749–750, 750t
in Eisenmenger syndrome, 390, 390f
comprehensive assessment of complex CHD, 312
miscellaneous symptoms, 748
laboratory, provocative maneuvers in fluid challenge, 717–718
decision-making for singleventricle versus biventricular repair, 312–313
premature ventricular contractions, 718, 718f
physiological and blood-flow assessment, 313
valsalva maneuver, 718–719, 719f
postoperative assessment of tetralogy of fallot, 312, 313f
exercise, 717, 718f
in LS, 342, 342b prophylaxis before, IE and, 213–214
specific applications, 312–314, 313f, 314f
histopathology, 747
obstructive symptoms, 748 Cardiac position-related QRS changes, ECG, 274 Cardiac resynchronization therapy (CRT), 453 Cardiac sarcoidosis. See Sarcoidosis Cardiac situs assessment of, chest X-ray in CHD, 281–282 Cardiac tamponade, BMV and, 104
total anomalous pulmonary venous connection and, 432, 433b
in constrictive pericarditis, 517
Cardiac transplantation. See Heart transplantation
VSD with AR, 328
disadvantages, 312
Cardiac troponin T (TNNT2), 462
in endomyocardial fibrosis, 477
Cardiac tumors, 746–758
Cardiac computed tomography (CCT), 467, 472, 517 Cardiac devices, IE after implantation of, 208 Cardiac diseases. See also specific entries central cyanosis in newborn and, 372 Cardiac examination in MS, 61 precordium, 61 right ventricular impulse, 61 Cardiac fibroma, 754–755 Cardiac imaging challenges to, 302 Eisenmenger syndrome, 390 technical improvements, 302 Cardiac Insufficiency Bisoprolol StudyIII (CIBIS-III) trial, 453
KG-Index.indd 766
in amyloidosis, 553, 555f
in childhood, 750
3-D printed models of complex cardiac lesions, 314f
ASOVs, 357
766
Cardiac magnetic resonance imaging (CMRI), 309, 466–467, 472. See also Magnetic resonance imaging (MRI)
in hypertrophic cardiomyopathy, 469–470, 470f, 506, 507f
benign. See Benign cardiac tumors
methods of tissue characterization, 511–512
epidemiology, 746
in MR, 185
malignant, 755–756, 758
in myocarditis, 494, 494f other pulse sequences
classification of, 746–747, 747t examination, 749 management of, 753 timeline in, 746t
MR angiography (MRA), 311, 311f
Cardio ankle vascular index (CAVI), 19
myocardial delayed enhancement (MDE) sequence, 311
Cardiological Society of India (CSI), 204
myocardial perfusion imaging, 311 phase contrast MRI (PC-MRI), 310, 311f overview, 309 Cardiac myxoma, 746, 747, 749f, 754f, 755f, 756f, 757f
Cardioband, 223, 223f Cardiomegaly, cyanotic heart disease with, 381 Cardiomyopathies, 460–463 accessory pathway-induced, 486, 487f alcoholic, 483 dilated. See Dilated cardiomyopathy (DCM)
09-11-2018 14:51:11
Catheter ablation, 456
left atrium, 283–284, 283f
genes causing, 460–461, 462t
Catheter angiography, in CHD, 302–303
left ventricle, 284
hypertrophic. See Hypertrophic cardiomyopathy (HCM)
Catheter-based therapy (CBT), 616
right atrium, 283, 283f
idiopathic dilated cardiomyopathy, 450, 462 imaging modalities cardiac computed tomography, 467 cardiac magnetic resonance imaging, 466–467 echocardiography, 464–466 nuclear cardiac imaging, 467 objectives of, 464 Indian context, 462–463 ischemic, 481–482 medications related, 484 MOGE(S) classification, 464 noncompaction, 470–471, 471f radiation-induced, 478 restrictive. See Restrictive cardiomyopathy (RCM) reversible, 478 suspected, noninvasive evaluation of, 464–478 Takotsubo, 487–488 uremic, 488 viral, 484 Cardiopulmonary adaptation, normal, at birth, 371–372 Cardiotoxicity, 455 Cardiovascular CT, of CHD, 303 Cardiovascular drugs, in pregnancy, 255, 255t Cardiovascular MRI, in CHD, 303 Cardiovascular system (CVS), 11 Carditis, 39, 40–41 diagnosis-related challenges, 41 management, 42–43, 43t Care in puerperium, pregnancy and, 257 Carillon (pseudoannuloplasty), 222, 222f
aspiration/suction/vortex embolectomy, 621 caution, 621 consensus statements, 622 devices utilized for, 617, 618f embolus fragmentation/ dissolution, 621 postintervention, 622
right ventricle, 284 Chemotherapy, 478 cardiotoxicity for, GLS in monitoring, 713 Chest radiograph in ASOVs, 355, 355f cyanosis in newborn, 374, 375f Chest X-ray, 404–405, 405f
potential indications for, 617
in aortic dissection, 611
procedure, preparation for, 618, 619–620, 620f, 620t
in chronic constrictive pericarditis, 527
rheolytic embolectomy, 621
in Ebstein’s anomaly, 422, 422f
techniques, 617b
in endomyocardial fibrosis, 548
Catheter-directed extraction embolectomy, 621 Catheter-directed thrombolysis (CDT), 616, 617–618, 619f ultrasound-facilitated, 620–621
in Kawasaki disease, 638 pulmonary arteriovenous malformation, 436, 437f in pulmonary hypertension, 626 for restrictive cardiomyopathy, 471
CBT. See Catheter-based therapy (CBT)
in Takayasus’s arteritis, 575, 575f
CCHD. See Cyanotic congenital heart disease (CCHD)
total anomalous pulmonary venous connection, 430–431, 431f
CCP. See Chronic constrictive pericarditis (CCP)
tricuspid valve disease, 113
CCT. See Cardiac computed tomography (CCT) CCTGA. See Congenitally corrected transposition of great arteries (CCTGA) CDT. See Catheter-directed thrombolysis (CDT) CECT. See Contrast-enhanced computed tomography (CECT) Celiac disease, 485 Cellular immune response in RHD, 47–49 Central cyanosis, 378–379, 378f in adults, 378–379, 378f in newborn, causes of, 372 airway diseases, 372
Carney syndrome, 751, 752t
cardiac diseases, 372
Carnitine deficiency, 485
lung diseases, 372
VSD with AR, 328 Chest X-ray, in CHD, 281–288 and CHD classification, 284–288 coarctation of aorta, 288 left-to-right (acyanotic) shunt, 284–285, 285f, 285t right-to-left (cyanotic) shunt, 285–288, 285t, 286f overview, 281 sequential approach for interpretation, 281–284 aorta, 284 cardiac situs assessment, 281–282 chamber enlargement assessment, 283–284, 283f pulmonary vascularity assessment, 282–283 technical consideration, 281
Carotid angioplasty, 589, 591–592f, 591t
Cerclage annuloplasty, 224
Carotid intima medial thickness (CIMT), 582
Cerebrovascular events
Carpentier’s classification, mitral valve anatomy, 180
Chagas disease, 484
Chorea, 39
Chamber enlargement, assessment, chest X-ray in CHD, 283–284, 283f
Chronic alcoholism, and dilated cardiomyopathy, 454–455
CARPREG (CARdiac disease and PREGnancy) risk score, 253
Index
general principles, 460–461
Eisenmenger syndrome and, 389
Children, blood pressure measurement in, 14–15 Chordal implantation, 225, 225f
Chronic aortic regurgitation, 69, 69t
767
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Chronic constrictive pericarditis (CCP), 526 clinical challenge, 526–529 clinical course of, 529
chest X-ray in CHD, 288
in CoA in adults, 362, 363f
ECG findings, 277
contrast-enhanced, 436, 437f
Coarctation of aorta (CoA), in adults, 360–366
overview, 302
diagnostic dilemma of, 526–529
balloon coarctoplasty for, 364
in pulmonary hypertension, 627– 628
effusive-pericarditis, 531–532 etiology, 526
cardiac catheterization and angiography, 362
in Takayasus’s arteritis, 576–577, 577f, 587
management of, 532
classification, 360
technical improvements, 302
pericardiectomy for, 528–529
clinical presentation, 360–361
post-pericardiectomy low cardiac output syndrome, 530–531
CT, 362, 363f
restrictive cardiomyopathy vs., 540, 543t surgical techniques and results, 530–531f treatment of, 532–533 Chronic kidney disease (CKD), 442 blood pressure measurement and, 15 Chronic RHD, evolution into, 50
diagnostic evaluation, 361–362, 361f, 362f, 363f ECG, 361, 361f echocardiography, 361–362 indications of intervention, 362–366 endovascular strategies, 364, 365f evaluation and follow-up, recommendations, 366
Chronic thromboembolic pulmonary hypertension (CTEPH), 627
medical management of systolic arterial hypertension, 365–366
CIBIS-III trial. See Cardiac Insufficiency Bisoprolol Study-III (CIBIS-III) trial
outcomes and late complications, 364–365
CIE. See Computer-interpreted electrocardiograms (CIE) CIMT. See Carotid intima medial thickness (CIMT) Cine angiography, 587
recommendations for interventional and surgical treatment, 363–364 surgical treatment strategies, 364
Computed tomography angiogram (CTA), 433 Computed tomography (CT) angiography of CHD, 302–307 aortic arch anomalies and airway compression, 304, 304f aortopulmonary collaterals, 303f, 304 associated findings (pre-and postoperative), 306, 307f cardiovascular CT, 303 cardiovascular MRI, 303 catheter angiography, 302–303 challenges, 302 clinical applications, 303–306 coronary arteries, 303, 304f echocardiography, 302 limitations, 306
CKD. See Chronic kidney disease (CKD)
MRI, 362, 363f
optimal imaging modality selection, 302–303
native, 360
overview, 302
Classical (reduced left ventricular ejection fraction) low-flow, low-gradient aortic stenosis
overview, 360 radiography, 361
postoperative evaluation, 305– 306, 306f
recurrent, 360
situs evaluation, 303, 303f
stent implantation, 364, 365f
systemic and pulmonary veins, 304, 305f
definition and pathophysiology, 200 LV contractile and/or flow reserve, 200–201, 200f–201f
Cocaine, 484
outcomes and risk, 201
Collagen autoimmunity hypothesis, RHD/ARF and, 49
severity, 200 therapeutic management, 201–202, 202f Clinical follow-up optimal frequency of, adults with repaired TOF and, 398
Color flow jet area in left atrium, 150– 151, 151f Combination therapy, 630 Eisenmenger syndrome, 393
Clinical RHD, prevalence, 74
Combined systolic and diastolic murmurs, 26, 26f, 26t
Clopidogrel, 642
Computed tomography (CT), 405
Clubbing, 442–443 CMRI. See Cardiac magnetic resonance imaging (CMRI) Coarctation of aorta (CoA), 28–29, 29f
768
KG-Index.indd 768
CHD echocardiography, 289–290, 290f
in adults with repaired TOF, 399– 400, 400f in aortic dissection, 611, 611f ASOVs, 356 cardiac, 467, 472, 517 in cardiac myxoma, 752
technical improvements, 302 ventricular size and function evaluation, 304–305, 305f in LS, 342 Computer-interpreted electrocardiograms (CIE), 663 Congenital ASOVs, 351–352 Congenital heart disease (CHD), 319 angiocardiography in, 309 assessment with left-to-right shunts, 243–250 cardiac catheterization in, 309 cardiac MRI (CMRI) in, 309–314. See also Cardiac magnetic resonance imaging (CMRI)
09-11-2018 14:51:11
advantages, 311–312, 312f comprehensive assessment of complex CHD, 312 decision-making for singleventricle versus biventricular repair, 312–313 physiological and blood-flow assessment, 313 postoperative assessment of tetralogy of fallot, 312, 313f specific applications, 312–314, 313f, 314f chest X-ray in, 281–288. See also Chest X-ray, in CHD and CHD classification, 284–288 overview, 281 sequential approach for interpretation, 281–284 technical consideration, 281 CT angiography of, 302–307
anatomical errors, 289–294 common errors, 289, 289t
challenges, 302 clinical applications, 303–306 coronary arteries, 303, 304f
fetal echocardiography and prenatal diagnosis of, impact of, 297–300 early prenatal screening, 297– 298 planned peripartum care, 298– 299, 299f structural heart defects, 299–300 in utero therapy for rhythm disorders, 299
systemic and pulmonary veins, 304, 305f technical improvements, 302 ventricular size and function evaluation, 304–305, 305f cyanosis in newborn and, 373–374,
medical management anatomic repair (double-switch operation), 260 conventional repair (physiological repair), 260 RV dysfunction management, 262–263
anticoagulation management, recommendations, 255–256, 256f
care in puerperium, 257 genetic counseling, 257 high-risk anatomic lesions, 255 high-risk pathophysiologic states, 254–255 maternal risk, 253–254 mode of delivery, 257 overview, 252 percutaneous intervention/ surgery during, 257
thrombolytic therapy, 256
situs evaluation, 303, 303f
management, 259–263, 261f
PA band, 260, 262f
limitations, 306
postoperative evaluation, 305– 306, 306f
heart block in, 263
pregnancy and, 252–257
physiological changes during, 252–253, 254t
overview, 302
clinical presentation, 259
JVP and, 9–10
echocardiography, 302 optimal imaging modality selection, 302–303
single ventricle. See Single ventricle (SV) Congenitally corrected transposition of great arteries (CCTGA), 259–263
fetal risk, 254
catheter angiography, 302–303
shunt lesions, assessment of, 719–721, 719t
overview, 289 echocardiography in, 309
aortopulmonary collaterals, 303f, 304
cardiovascular MRI, 303
evaluation of patients with
Congenital methemoglobinemia, 379
cardiovascular drugs in, 255, 255t
cardiovascular CT, 303
Congenital heart diseases (CHD)
functional errors, 294–295
aortic arch anomalies and airway compression, 304, 304f
associated findings (pre-and postoperative), 306, 307f
KG-Index.indd 769
373t–374t echocardiography, 289–295. See also Echocardiography, CHD
premature death due to, 320 Congenital heart disease (CHD), epidemiology, in India, 235–241 current status of care in, 239–241 improvement strategies of cardiac care for children, 240–241
Index
3-D printed models of complex cardiac lesions, 314f
tricuspid valve repair/ replacement, 260, 262 univentricular palliation, 260 natural history, 259 overview, 259 pregnancy in, 263 Congestive cardiac failure (CCF), 6, 22, 23 Constrictive pericarditis (CP), 514, 514t cardiac computed tomography, 517 cardiac magnetic resonance, 517 chronic. See Chronic constrictive pericarditis (CCP) Echo signs of, 515–517, 516–517f, 518f, 518t invasive hemodynamic criteria for, 520–521, 520f, 520t, 521f multimodality imaging, 517, 519f pathophysiology of, 514–515, 515f restrictive cardiomyopathy vs., 722, 723f Contemporary era, unselected MS in, 88–89 Continuous murmur in ASOVs, 353, 354f
incidence and prevalence, 235–237, 236t, 237t, 238t
cyanosis with, 381
overview, 235
differential diagnosis, 26, 26f, 26t
defined, 25
prevention, 237–239
aortopulmonary window, 28
risk factors, 235
coarctation of aorta, 28–29, 29f
769
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Essentials of Postgraduate Cardiology
coronary cameral fistula, 27–28, 28f in cyanotic congenital heart disease, 30–31, 31f extracardiac arteriovenous fistula, 30 mammary soufflé, 29 patent ductus arteriosus (PDA), 26–27, 27f pulmonary arteriovenous fistula, 29, 30f ruptured sinus of valsalva aneurysm, 27, 28t venous hum, 29 overview, 25 physiologic classification, 25 Contraception Eisenmenger syndrome and, 391 Contrast echocardiography, 436, 466 Contrast-enhanced computed tomography (CECT), 436, 437f Conventional repair (physiological repair), in CCTGA, 260 Conventional therapy Eisenmenger syndrome
CP. See Constrictive pericarditis (CP)
acquired, 379
CRT. See Cardiac resynchronization therapy (CRT)
congenital, 379
CT. See Computed tomography (CT)
methemoglobin, 379
CT angiography (CTA), 587
pseudocyanosis, 379
CTA. See Computed tomography angiogram (CTA)
sulfhemoglobinemia, 379
methemalbuminemia, 379
overview, 378
CTEPH. See Chronic thromboembolic pulmonary hypertension (CTEPH)
pathophysiology central cyanosis, 378–379, 378f peripheral cyanosis, 379
Cuff inflation hypertension, 14
treatment strategy, 382–383
Cyanosis, 404, 416, 430, 439–444 and anemia, 441
Cyanosis, in newborn, 371–377 central, causes of, 372
and brain abscesses, 440–441 and clubbing, 442–443
airway diseases, 372
and cyanotic spell, 440
cardiac diseases, 372 lung diseases, 372
and dental abnormalities, 444 differential, 439
chest radiograph, 374, 375f
and erythrocytosis, 441
congenital heart disease and, 373– 374, 373t–374t
failure to thrive, 439–440
echocardiography, 374–375
and gallbladder stones, 443–444
electrocardiography, 374
and hemoptysis, 443
hyperoxia test, 373
and hemostatic complications, 441
initial evaluation, 372
pathophysiology, 440
exercise conditioning, 391
peripheral, 439
iron supplement, 390–391
and polycythemia, 441
oxygen therapy, 391
pregnancy and CHD, 255
phlebotomy, 390
pseudocynosis, 439
initial management prostaglandin E1, role of, 375 supplemental oxygen, role of, 376f, 377
Coronary angiogram, 640
and pulmonary hypertension, 443
Coronary angiography, indications for, 645–646, 645t
and renal problems, 442
normal cardiopulmonary adaptation at birth, 371– 372
and stroke, 442
overview, 371
Coronary arteries, 420
systemic problems with, 439
pulse oximetry, role of, 374
Coronary artery bypass graft (CABG), 592
and thrombosis, 441–442
Coronary artery disease (CAD), 22, 481–482, 635, 640–641, 641f diagnosis on ECG, 652, 653–654f, 655f Coronary artery lesions (CAL), 637, 638–639, 639t abnormal, 639 classification according to diameter, 639t Z-score classification, 639 Coronary cameral fistula, 27–28, 28f Coronary sinus atrial septal defect, 333 Corrigan, Dominic, 18 Corrigan pulse, 18
and ventricular dysfunction, 444 Cyanosis, in adults, 378–383
continuous murmur in, 30–31, 31f
differential diagnosis, 379, 380t
source of, 30
with clinical features of ASD, 381 with continuous murmur, 381
surgically created shunts, 30–31 Cyanotic heart disease
cyanotic heart disease with cardiomegaly on X-ray, 381 cyanotic heart disease with relatively normal sized heart on X-ray, 381 differential cyanosis, 379–380, 381f hemoglobin work-up in cyanotic patient
Corrigan sign, 18
approach to, 381
Corticosteroids, 486, 495, 525, 533
investigations, 381–382, 382f
and nonspecific aortoarteritis, 582
Cyanotic congenital heart disease (CCHD), 397
methemoglobinemia
with cardiomegaly, 381 with relatively normal sized heart, 381 Cyanotic spell, 440 Cyclophosphamide, 583 Cyclopsprine A, 642 Cyclosporine, 495
D 3D/4D STIC fetal echocardiography, 296–297, 298f Damping, 730–731
770
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09-11-2018 14:51:12
autoimmunity and, 484–485
DS1000, 225, 225f
chronic alcoholism and, 454–455
DCM. See Dilated cardiomyopathy (DCM)
ECG findings, 279, 279f
DSA. See Digital subtraction angiography (DSA)
epidemiology, 449
2DTTE/TEE
De Winter sign, 700, 701f
mitral valve morphology assessment in MS by, 134t
Death, BMV and, 103
etiological classification of, 450–451, 451f
DeBakey system, 601
evaluation of, 451–452, 452f, 452t
Duroziez, Paul, 18
Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE), 453
familial/genetically determined, 450
Duroziez sign, 18
Definite RHD, 75–76 management of, 77 multivalvular RHD (subcategory C), 75 RHD of aortic valve (subcategory C), 75 RHD of MV with stenosis (subcategory B), 75 RHD of the mitral valve with regurgitation (subcategory A), 75 Definitive therapy natural history of MS in era prior to, 87–90 clinical course after relief of severe valvular obstruction, 89–90, 89t, 90t unselected MS in contemporary era, 88–89 Dennison sign (Shelly sign), 19 Descending thoracic aortic aneurysm, 600 Desrazoxane, 455 Dextrocardia, PTMC and, 99 Diabetes mellitus (DM), 483 blood pressure measurement, 15 Diastolic murmur, 26 in AR, 68 tricuspid valve disease, 113, 113t
Dynamic auscultation
idiopathic, 450
classification of techniques, 32, 32t
immunosuppressive therapy in, 453
overview, 32
management of, 452–454, 453f
pharmacological maneuvers
device therapy in heart failure, 453–454
amyl nitrite, 36 methoxamine, 36
heart transplantation, 454
phenylephrine, 36
mechanical circulatory support, 454
physiological maneuvers clinical implications, 32–33, 34f
regenerative therapy, 454
isometric exercise, 35–36
natural history, 449–450
Müller maneuver, 33–34
peripartum cardiomyopathy and, 455
passive leg elevation or sudden lying down, 34–35, 35f
poor prognostic factors, 450, 450t
rapid standing from squatting or lying posture, 33
sarcoidosis and, 455–456 stress-induced cardiomyopathy/ Takotsubo cardiomyopathy and, 455–456 tachycardiomyopathy and, 456 DILV. See Double inlet left ventricle (DILV) Dipeptidyl peptidase-4 (DPP-4) inhibitors, 483
sudden squatting, 35, 35f valsalva maneuver, 32, 33f, 33t Dysplastic tricuspid valve, 421 Dystrophin gene (DMD) mutation, 450
E Ebstein’s anomaly, 419–426
Dipyridamole, 736
anatomy, 419, 420f
Direct (true) annuloplasty, 223–225, 224f
classification, 420, 420t
Disease modifying anti-rheumatic drug (DMARD), 582, 583–584
ECG findings, 276, 277f
DM. See Diabetes mellitus (DM) DMARD. See Disease modifying antirheumatic drug (DMARD)
differential diagnosis, 421 embryology, 419–420 etiology, 421 examination
Dobutamine, 737
ECG, 422, 422f
Doppler echocardiography, 471–472
fetal echocardiography, 423
Differential cyanosis, 379–380, 381f, 439
Doppler ultrasound, 586, 586f
Diflunisal, 557
Double inlet left ventricle (DILV), 403–404
magnetic resonance imaging, 423, 423f
Diastolic pulmonary gradient (DPG), 721
DIG trial. See Digitalis Intervention Group (DIG) trial Digital sphygmomanometer, 13 Digital subtraction angiography (DSA), 587, 591f, 594f, 595f Digitalis Intervention Group (DIG) trial, 453 Dilated cardiomyopathy (DCM), 449– 456, 460, 461–462, 467–468 anthracyclines and, 455
KG-Index.indd 771
Index
Data sources, for estimation of burden of RF/RHD, 53–54
Double outlet right ventricle, ECG findings, 277
3D echocardiography, 422–423, 424f 2D echocardiography, 422, 423f
DPG. See Diastolic pulmonary gradient (DPG)
natural history, 421–422
Drugs. See also specific drugs
presentation of, 421–422
pathophysiology, 421
antirheumatic, 582–583, 584
and sudden cardiac death, 421
antitubercular, 525, 533
treatment for
and cardiomyopathy, 484 Drummond sign, 19
Starnes procedure, 424 surgery, 424–426, 425f
771
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Essentials of Postgraduate Cardiology
ECG. See Electrocardiogram (ECG); Electrocardiography (ECG) Echo signs, 515–517, 516–517f, 518f, 518t Echocardiographic strain imaging. See Strain imaging Echocardiography, 133–147, 405, 406f, 471, 506, 613. See also Fetal echocardiography of AS, 138–141, 138t–141t adults with repaired TOF, 398–399, 399f in AL amyloidosis, 553, 555f in Anderson-Fabry disease, 476 of AR, 138–141, 138t–141t ASD transesophageal echocardiography (TEE), 335–336, 335f, 337f transthoracic echocardiography (TTE), 333–335, 334f ASOVs, 355–356, 355f–356f in cardiac myxoma, 751–752, 752t in cardiac sarcoidosis, 475, 476f in cardiac tumors, 746 for cardiomyopathy, 464–466 CHD, 302 in CHD, 309 CoA in adults, 361–362 contrast, 436, 466 cyanosis in newborn, 374–375 Doppler, 471–472 in endomyocardial fibrosis, 477, 549 exercise, MR and, 184–185 fetal echocardiography, 423 in Kawasaki disease, 638–639, 639t in LS, 341 percutaneous intervention vs. surgical management and, 342 M-mode evaluation, 465 mitral regurgitation (MR), 183 MR assessment by, 137t MS diagnosis by, 133, 133t in myocarditis, 493–494 overview, 133 of PR, 145–146, 145t–146t of PS, 145–146, 145t–146t in pulmonary hypertension, 626, 626f, 627t in restrictive cardiomyopathy, 536, 540f
role in BMV, 92–93 3D, 422–423, 424f, 466
Eisenmenger syndrome (ES), 340, 384–393
total anomalous pulmonary venous connection, 431–432, 431t, 432f
cardiac catheterization, 390, 390f
of TR, 141–145, 143t–144t transesophageal, 607
classification, 384–385, 385t, 386t, 387t
transthoracic, 607
clinical features, 388–389
of TS, 141–145, 143t–144t 2D, 422, 423f, 465, 471, 472f, 527 VSD with AR, 328, 328f, 329f Echocardiography, CHD, 289–295 anatomical errors, 289–294 anomalous pulmonary venous drainage, 292, 293f aortic arch interruption, 290, 290f aortopulmonary window, 291
cardiac imaging, 390 cerebrovascular events, 389
abnormal coagulation factors, 388 erythrocytosis, 388 platelet abnormalities, 388 thrombosis, 388–389 conventional therapy exercise conditioning, 391 iron supplement, 390–391 oxygen therapy, 391 phlebotomy, 390
coarctation of aorta, 289–290, 290f
defined, 384
muscular ventricular septal defects, 294, 294f
exercise testing, 390
peripheral pulmonary artery stenosis, 290–291, 290f, 291f
history, 243
pulmonary vein stenosis, 292, 292f sinus venosus defects and coronary sinus ASD, 293–294
epidemiology, 384 future perspectives, 393 infective endocarditis prophylaxis and prevention of infections, 391 laboratory investigations, 389 management strategy, 390–391 natural history, 387–388, 388f
supravalvar aortic stenosis, 291
other miscellaneous organ involvement, 389
venous anomalies leading to cyanosis, 292, 293f
overview, 384
venous anomalies without clinical findings, 293, 294f common errors, 289, 289t functional errors, 294–295 valvar quantifications, 295, 295f ventricular, 294–295 overview, 289
pathophysiology, 385 age, 385–386 cardiac lesion, types of, 386 environmental factors and comorbidities, 387 genetic and epigenetic factors, 387 pregnancy and contraception and, 391
Eddy sounds, 26–27
pulmonary dysfunction, 389
Edge-to-edge mitral leaflet repair
renal function and uric acid clearance, 389
MitraClip, 220–221, 221f PASCAL mitral valve repair system, 222, 222f Efficacy and Survival Study (EPHESUS) trial, 453 Effusive-constrictive pericarditis, 531–532 treatment for, 533
surgical management heart and lung transplant, 393 treat-repair-treat, 393 targeted therapy, 391 combination therapy, 393 endothelin receptor antagonist, 391–392, 392f
772
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common AV canal defect, 275, 276f
prostanoids, 392–393
corrected transposition of great arteries, 276
Ejection fraction (EF) GLS to, relationship of, 710 preserved, GLS in heart failure with, 712
dilated cardiomyopathy, 279, 279f
tricuspid valve disease, 113 VSD with AR, 328
Index
phosphodiasterase type 5 inhibitors, 392
Electrophysiology study for risk stratification, adults with repaired TOF and, 401
double outlet right ventricle, 277
EMB. See Endomyocardial biopsy (EMB)
Ebstein’s anomaly, 276, 277f
Embolism, BMV and, 104
Ejection sounds, in AR, 67
major cardiac mass, position of, 275
Embryology, bicuspid aortic valve, 190, 190f
EJV. See External jugular vein (EJV)
pericarditis, 279f, 280
Elderly, blood pressure measurement in, 15
Pompe’s disease, 277, 278f
Embryology, of interatrial septum, ASD, 332
Electrocardiogram (ECG), 405, 406f, 471
single ventricle, 277
reduced, GLS in heart failure with, 710, 711f
pulmonary stenosis, 277 situs identification, 275
abnormal with normal hearts, 654, 655f
tetralogy of fallot, 275, 275f–276f
adults with repaired TOF, 398, 399f
ventricular septal defects, 277, 278f
in AL amyloidosis, 553, 554f
tricuspid atresia, 275
EMF. See Endomyocardial fibrosis (EMF) Endomyocardial biopsy (EMB), 494, 549 Endomyocardial fibrosis (EMF), 477, 546–550 clinical presentation, 548
artifacts, 654, 655–656, 656–658f
in Ebstein’s anomaly, 422, 422f
epidemiology, 546–547, 547f
ASOVs, 354–355
in endomyocardial fibrosis, 548
etiology of, 548
automated, 663
in Kawasaki disease, 638
imaging modalities, 548, 549f
axis detection, 267, 267b
lead misplacements, 656, 658–661f, 658–662
chest x-ray, 548
cardiac position-related QRS changes, 274
echocardiography, 549
limitations, 651
electrocardiogram, 548
in cardiac sarcoidosis, 475
in LS, 341
endomyocardial biopsy, 549
in chronic constrictive pericarditis, 527
in myocarditis, 493
fluoroscopy, 548
CoA in adults, 361, 361f computerized, 663–672 accuracy of, 664, 665f acquired long QT syndromes, 666, 667 and acute coronary syndrome diagnosis, 664–665, 666f congenital long QT syndromes, 666, 667 methodology, 663–664
normal in pathological conditions, 651–652
incidence and prevalence of, 550
normal variations and related abnormalities, 267–270, 267f–270f
management of, 549–550
overview, 267 P wave, analysis, 271, 271f left atrial enlargement, 271 right atrial enlargement, 271 PR segment, analysis, 271–273, 272f short PR interval, causes, 272– 273, 272f
and myocardial infarction diagnosis, 664–665, 666f
in pulmonary hypertension, 626
pacemaker rhythms, 666
QRS complex, analysis, 272–274
QRS duration measurement, 667
bundle branch blocks, 273
tachyarrhythmias, 665–666, 667f, 668–670f
left ventricular hypertrophy, 273–274, 274f
technical aspects, 663–664
right ventricular hypertrophy, 273, 273f
in India, 547–548 natural history, 549–550 Endothelial heterogeneity, 49 Endothelial injury, in RHD, 47 Endothelin receptor antagonist, Eisenmenger syndrome and, 391–392, 392f Endovascular strategies, for CoA in adults, 364, 365f Environmental factors, Eisenmenger syndrome pathophysiology and, 387 Environmental risk factors, rheumatic fever pathogenesis, 47 EPHESUS trial. See Efficacy and Survival Study (EPHESUS) trial
diagnosis of CAD on, 652, 653–654f, 655f
recording and interpretation, basics of, 267
Epigenetic factors, Eisenmenger syndrome pathophysiology and, 387
disease-specific changes
ST segment, analysis, 274
Epistaxis, 41
T wave, analysis, 274–275
Epitope spreading
cyanosis in newborn, 374
aortic stenosis and coarctation of aorta, 277 atrial septal defects, 277
total anomalous pulmonary venous connection, 431
ARF, 49 RHD, 49
773
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Essentials of Postgraduate Cardiology
Erythema marginatum, 39, 41 Erythrocytosis, in Eisenmenger syndrome, 388
Fetal heart. See also Fetal echocardiography concept of universal screening, 296
ES. See Eisenmenger syndrome (ES)
Fetal risk, CHD and, 254
European League Against Rheumatism (EULAR), 582
Fibrosis, 115
Exercise, 717, 718f BAV and, 197 Exercise conditioning Eisenmenger syndrome, 391 Exercise echocardiography MR and, 184–185 Exercise testing in Eisenmenger syndrome, 390 External jugular vein (EJV) examination of, 3–4, 3f Extra-cardiac conduit-TCPC (ECTCPC), 414–415, 414f Extracardiac arteriovenous fistula, 30 Extracorporeal membrane oxygenator (ECMO), 495
F
First degree atrioventricular block (I-AVB), 693–694, 694t
G Gaint left atrium, BMV of, 96, 96f Gallavardin phenomenon, 23 Gallbladder stones, 443–444 Genetic counseling, pregnancy and CHD, 257
in AS, 70
Genetic factors, Eisenmenger syndrome pathophysiology and, 387
in AR, 67
Genetics, bicuspid aortic valve, 192
in MS, 61–62
Genotyping, 460, 461
in tricuspid valve disease, 111
Gerhardt sign (Sailer’s sign), 19
First heart sound
FK506 (Tacrolimus), 633
Giant ‘a’ wave, 7–8, 7f
Floppy mitral valve/mitral valve prolapse, 180–181
Gibson, George Alexander, 26
FlowTriever device, 621 Fluoroscopy, in endomyocardial fibrosis, 548 Follow-up
Gibson’s murmur, 26 Glenn shunt, 406, 407 Global longitudinal strain (GLS), 709, 709f, 710f in acute heart failure, 712
in CoA, recommendations, 366
in heart failure
predictors of complications on, in adults with repaired TOF, 401
with preserved ejection fraction, 712 with reduced ejection fraction, 710, 711f
Fontan circulation, 410
18f-Fluorodeoxyglucose [18f ]FDG, 467, 475–476 18
f-fluorodeoxyglucose–positron emission tomography (FDGPET) scanning, 577
clinical effects of, 415
relationship to ejection fraction, 710, 710f
late complications systemic complications, 415–416
Familial/genetically determined dilated cardiomyopathy, 450
ventricular dysfunction, 415
FDG-PET scanning. See 18 f-fluorodeoxyglucosepositron emission tomography (FDG-PET) scanning
normal values, 709
indications for, 410–411
Familial amyloidosis, 553
Familial myxomas, 751
in monitoring cardiotoxicity for chemotherapy, 713
early postoperative complications, 415
in valvular heart disease, 713
patient selection for, 411
GLS. See Global longitudinal strain (GLS)
physiology, 410
Glucocorticoids, 582
preparation for, 411–412 ‘Ten Commandments’ for, 411, 412t
Glutamine-NMDA (N-Methyl-Daspartate), 633
types of, 414–415, 414f
Granulomatous myocarditis (GM), 486
Feasibility test, for device closure in PDA, 348–349, 349f, 350t
45 degrees inclination, patient positioning, 4–5, 5f
Great Ormond Street Echo (GOSE) score, 422, 424t
Fetal echocardiography, 296–300, 423. See also Echocardiography
Fourth heart sound
Group A Streptococcus (GAS), 39, 40, 42, 46, 119
3D/4D STIC, 296–297, 298f
in AR, 67
indications, 296, 296t
in tricuspid valve disease, 111
overview, 296 and prenatal diagnosis of CHD, impact of, 297–300 early prenatal screening, 297– 298 planned peripartum care, 298– 299, 299f structural heart defects, 299–300
774
KG-Index.indd 774
in AS, 70
in utero therapy for rhythm disorders, 299
Fractional flow reserve, 725–726, 725b, 726f Frank-Starling law, 3 FRV. See Functional RV (FRV) Functional errors, CHD echocardiography, 294–295 valvar quantifications, 295, 295f ventricular, 294–295 Functional RV (FRV), 419, 421 Functionally single ventricle, 411t
H Hales, Stephen, 11 HCM. See Hypertrophic cardiomyopathy (HCM) Health care-associated IE, prevention of, 205 Health system-related challenges secondary prophylaxis, 44 Heart block, in CCTGA, 263 Heart failure (HF), 404, 481 acute, GLS in, 712
09-11-2018 14:51:13
alcoholic cardiomyopathy and, 483 cocaine and, 484
pregnancy and CHD, 254–255
I IABC. See Intra-aortic balloon counterpulsation (IABC)
device therapy in, 453–454
LV/RV dysfunction and heart failure, 255
IAS puncture site, in BMV, dilatation of, 94–95
diabetes mellitus and, 483
pulmonary hypertension, 254
and heart transplantation, 721–722
univentricular heart and fontan operation, 255
ICD. See Implantable cardioverter defibrillator (ICD)
hypertensive heart disease and, 482–483, 483f
Hill’s sign, 18–19
management of, 555–557
HJR (hepatojugular reflux), 6
pregnancy and CHD and, 255
HOA. See Hypertrophic osteoarthropathy (HOA)
valvular heart disease and, 483 Heart muscle disease. See Cardiomyopathies Heart sounds. See also specific entries in AS, 70–71 aortic ejection click, 70 first heart sound, 70 fourth heart sound, 70 second heart sound, 70 third heart sound, 70 in AR, 67–69
management of combination therapy, 630 oral anticoagulants. See Anticoagulants, oral pharmacotherapy, 630 Potts shunt, 632
Hospital admission data
pulmonary artery denervation, 632
epidemiological trends of burden of RHD in India, 54, 54t rheumatic fever, pathogenesis, 46–47 Humoral immune response, in RHD, 47
first heart sound, 67
Hyperacute T waves, 699–700, 700f
fourth heart sound, 67
Hyperoxia test, cyanosis in newborn and, 373
third heart sound, 67
Idiopathic pulmonary arterial hypertension (IPAH), 630
Home-based BP monitoring, 14
ejection sounds, 67
second heart sound, 67
Idiopathic dilated cardiomyopathy, 450, 462
HOCM. See Hypertrophic obstructive cardiomyopathy (HOCM); Mitral valve prolapse (MVP)
Host susceptibility
Hypertension. See also Blood pressure
in Lutembacher’s syndrome, 341
concept, 11
in MS, 61–64
cuff inflation hypertension, 14
Index
cyanosis, 255
coronary atherosclerosis and, 481–482
stem cell therapy, 632 IE. See Infective endocarditis (IE) iFR. See Instantaneous wave-free reserve (iFR) IJV. See Internal jugular vein (IJV) Image acquisition protocol, 737 Imatinib, 632 IMH. See Intramural hematoma (IMH) Immunosuppressive therapy, 495, 495b, 496t, 566 Implantable cardioverter defibrillator (ICD), 453–454
first heart sound (S1), 61–62
diagnosis, 11
murmur, 62–64, 63t
with LVH, 22
opening snap, 62, 62t, 63t
masked, 14
In utero therapy, for rhythm disorders, 299
prevalence, 11
Incomplete KD (ICKD), 640, 641f
risk factor for AF, 22
India
Heart transplantation, 449, 454, 557 Eisenmenger syndrome (ES) and, 393 heart failure and, 721–722 Hemodynamics, 729 of Lutembacher’s syndrome, 340 Hemoglobin work-up, in cyanotic patient approach to, 381 investigations, 381–382, 382f Hemoptysis, 443 Hepatic dysfunction, 416 Hepatojugular reflux (HJR), 6 Hereditary hemochromatosis (HH) and restrictive cardiomyopathy, 544–545 Hibernating myocardium, 481 High-risk anatomic lesions pregnancy and CHD, 255
KG-Index.indd 775
High-risk pathophysiologic states
Hypertensive heart disease, 482–483, 483f Hypertrophic cardiomyopathy (HCM), 23, 460, 461, 462, 468–470, 469f, 506–512
CHD epidemiology in, 235–241 current status of care in, 239–241 improvement strategies of cardiac care for children, 240–241
cardiac magnetic resonance imaging in, 469–470, 470f, 506–507, 507f
incidence and prevalence, 235– 237, 236t, 237t, 238t
late gadolinium enhancement in. See Late gadolinium enhancement (LGE)
prevention, 237–239
tissue characterization in, 507–508, 510f Hypertrophic obstructive cardiomyopathy (HOCM) valsalva maneuver, 33, 34f Hypertrophic osteoarthropathy (HOA), 443
overview, 235 risk factors, 235 epidemiological trends of burden of RHD in, 54 hospital admission data, 54, 54t population-based survey studies, 54, 55t school-based surveys, 54–56, 55t prophylaxis for infective endocarditis in, 212–215
775
09-11-2018 14:51:13
antibiotic regimens, 214, 214t
Essentials of Postgraduate Cardiology
before cardiac catheterization and therapeutic cardiac procedures, 213–214
antimicrobial therapy bacterial resistance, 207
nonspecific prevention measures, 214, 214t
specific recommendations, 207–208
general trends, 207
overview, 212
diagnosis, 205
rationale for, 212
health care-associated IE, prevention of, 205
recommended procedures before, 213, 213t valvular heart disease (VHD)
imaging, 205–206
Internal jugular vein (IJV), 3 examination of, 3–4, 3f Interpretation, procedural steps, 729 Interventricular communication, 403–404 Intra-aortic balloon counterpulsation (IABC), 531 Intracardiac echocardiography of ASD, 336–339, 338f, 339t Intramural hematoma (IMH), 601, 603 Intravenous immunoglobulin (IVIg), 495
impact of guideline change, 204–205
concerns regarding, 642 mechanism of KD, 641
management, 207 microbiology, 206
aortic valve disease, 129–131
overview, 204
case scenarios, 131–132
postnatal natural history of VSD and, 322–323
combined valvular and multivalvular heart diseases, 131
prevention, 204
evaluation, 127–128
prognostic assessment, 206–207, 206t
future perspectives, 132
prophylaxis for, in India, 212–215
therapy, 453 Invasive hemodynamic criteria for constrictive pericarditis, 520– 521, 520f, 520t, 521f Invasive hemodynamic study, 716 Investigations of pregnancy associated cardiomyopathy (IPAC) study, 455 IPAH. See Idiopathic pulmonary arterial hypertension (IPAH)
incidences, 127
antibiotic regimens, 214, 214t
mitral valve disease, 128–129, 129f, 130f
before cardiac catheterization and therapeutic cardiac procedures, 213–214
IRIS Millipede complete annuloplasty ring, 224, 224f
cardiac conditions at risk for, 212–214, 212t
Iron supplement
nonspecific prevention measures, 214, 214t
Ischemic cardiomyopathy, 481–482
overview, 127 perspective, 127 tricuspid valve disease, 131 Indian Council of Medical Research (ICMR), 53 Indirect (pseudo) annuloplasty, 222– 223, 222f–223f Infectious cardiomyopathy, 484–488 accessory pathway-induced cardiomyopathy, 486, 487f celiac disease, 485 Chagas disease, 484 granulomatous myocarditis, 486 left apical ballooning syndrome, 487–488 Lyme disease, 484 myocardial tuberculosis, 484 nutritional deficiencies, 485
overview, 212 rationale for, 212 rationale for change in recommendations, 212–213, 213t recommended procedures before, 213, 213t
Eisenmenger syndrome, 390–391 Ischemic heart disease evaluation of patients with, 725–728 Ischemic mitral regurgitation (MR) dynamic nature of, 182 mitral valve distortion in, 184 quantitation of, 183–185
in special subgroups, 208 surgical indications, 208
Isolated ST depression in aVL, 700, 701f
Infective endocarditis prophylaxis Eisenmenger syndrome and, 391 Inflammation and structural remodeling, AF in RHD and, 115 Inoue, Kanji, 92
peripartum cardiomyopathy, 484
Inspection, tricuspid valve disease, 111
systemic lupus erythematosus, 485
Instantaneous wave-free reserve (iFR), 726–728, 727f
thyroid dysfunction, 485
Iron deficiency anemia, 441
Ishikawa criteria for Takayasu arteritis, 576, 577t, 579t
obstructive sleep apnea, 485
tachycardiomyopathies, 485–486, 486f
KG-Index.indd 776
after implantation cardiac devices, 208
cardiac conditions at risk for, 212–214, 212t
rationale for change in recommendations, 212–213, 213t
776
Infective endocarditis (IE), 204–208, 443
Interatrial communication, 404 Interatrial septum (IAS)
trace elements, 484
embryology of, in ASD, 332
viral cardiomyopathy, 484
formation of, 332
Isolated ST segment elevation in aVR, 700, 701, 703f Isometric exercise dynamic auscultation, 35–36 IVIg. See Intravenous immunoglobulin (IVIg)
J Japanese Kawasaki Disease Research Committee (JKDRC) criteria, 636 Jones criteria, RF and, 39 clinical features not included in, 41
09-11-2018 14:51:13
Jugular venous pulse/pressure (JVP) ‘a’ waves, 7–8, 7f
K
Large ‘v’ waves, 7f, 9
Kawasaki disease (KD), 635–646 acute myocardial infarction in, 640
atrial septal defect, 9, 9f
cardiovascular manifestations in
congenital heart disease, 9–10
chest X-ray, 638
pericardial disease, 9
echocardiography, 638–639, 639t
pulmonary artery hypertension, 9
electrocardiography, 638
‘v’ waves, 7f, 9
physical findings, 638
‘x’ descent, 7f, 8–9
coronary artery disease in, 640–641, 641f
‘y’ descent, 7f, 9 in ASOVs, 352–353, 353f
diagnosis of, 636–637
atrial fibrillation, effects of, 111
differential diagnosis, 637, 638t
examination of, 3
epidemiology, 635–636, 635f
external and internal jugular veins, 3–4, 3f
historical perspective, 635
jugular venous pressure, 3
interventions in
incomplete/atypical, 640
jugular venous waveforms, 3–4, 3f
acute coronary syndrome, 644 chronic CAD, 644
interpretation of, 4–5, 5f
laboratory evaluation
hepatojugular reflux, 6
biochemistry, 638
jugular venous pressure, 4–5, 5f
biomarkers, 638
measurement, 5
blood counts, 637
patient positioning, 4–5, 5f
long-term management, 643
respiratory variation, 5–6
natural history, 645
right atrial pressure, calculation of, 5 sternal angle, locating, 5 waveforms, 6, 6f, 7t
cyclopsprine A, 642
respiration, effects of, 110–111
intravenous immunoglobulin, 641–642
in TR, 110 in TS, 110
pentoxyphylline, 642
waves, identification, 4–5, 5f
pharmacological agents doses, 643
correlation with clinical findings, 7
protocol for, 644
tips for board examination, 6–7
steroids, 642
Jugular venous waveforms examination of, 3–4, 3f external jugular vein (EJV), 3–4, 3f internal jugular vein (IJV), 3–4, 3f
Leflunomide, 583–584 Left apical ballooning syndrome, 487–488 Left atrial thrombus, MS with (case study), 131 Left atrium, 283–284, 283f Left atrium clot Manjunath’s classification of, 97f, 98 PTMC in, 96–98, 97f Left bundle branch block (LBBB), 703, 704f artifacts of, 742–743 Left-sided prosthetic valve thrombosis (PVT)
management of, 217, 217f
aspirin, 642
in AF, 22
and systolic dysfunction, 512 Lateral tunnel, variant of TCPC, 414, 414f
prevalence, 635
antioxidants, 642
physical examination
and sudden death risk, 508–510, 510f, 511f
incidence of, 216
abciximab/tPA/streptokinase, 642
overview, 3
quantification of, 512
pathology, 636, 636t, 637f
treatment of
in MS, 61
pattern of, 510, 511, 511f
clinical presentation and diagnosis, 216–217
refractory, 643
maneuvers to augment, 111
in hypertrophic cardiomyopathy, 507–508, 510f
new strategy in, 643–644f
recurrence, 636
in Lutembacher’s syndrome (LS), 341
Late gadolinium enhancement (LGE)
Index
abnormal contours
ticlopidine/clopidogrel, 642 Korotkoff sounds, 13, 14 Kyphoscoliosis, PTMC in, 102, 103f
L
Left-to-right (acyanotic) shunt, chest X-ray in CHD, 284–285, 285f, 285t large aorta, 284 normal aorta, 284–285, 285f post-tricuspid L-R, 285, 285f Left-to-right shunts, 243 CHD assessment with, 243–250 Left ventricle, 284 Left ventricular dysfunction, rheumatic aortic stenosis with (case study), 131–132 Left ventricular end-diastolic pressure (LVEDP), 23 Left ventricular hypertrophy (LVH), 22 Left ventricular outflow tract obstructive lesions (LVOTO), 725, 726f, 726t Left ventricular remodeling, MR and, 186 LFT. See Liver function test (LFT)
Juvenile MS, BMV in, 102
Landmarks, for TSP in BMV, 93, 94f
Lighthouse sign, 19
JVP. See Jugular venous pulse (JVP)
Landolfi sign, 19
Lincoln sign, 19
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Essentials of Postgraduate Cardiology
Lipid profile, 640 Liver function test (LFT), 629 Locomotor brachii, 18 Loeys Dietz Syndome, 612, 613f Löffler’s endocarditis, 477 Long-term follow-up adults with repaired TOF, 397 issues on, 398–399 Low-dose thrombolysis, 617–618, 619f Low-gradient aortic stenosis, 199–203 classical (reduced left ventricular ejection fraction) low-flow definition and pathophysiology, 200 LV contractile and/or flow reserve, 200–201, 200f–201f outcomes and risk, 201 severity, 200 therapeutic management, 201– 202, 202f normal-flow definition and pathophysiology, 202–203 outcomes and risk stratification, 203 severity, 203 overview, 199, 199f paradoxical (preserved left ventricular ejection fraction) low-flow definition and pathophysiology, 202 outcomes and risk stratification, 202 severity, 202 therapeutic management, 202 technical pitfalls and measurement errors, 199–200 LS. See Lutembacher’s syndrome (LS) Lung diseases central cyanosis in newborn and, 372 Lung transplantation Eisenmenger syndrome (ES) and, 393 Lutembacher’s-ASD/RHD severe MS with severe submitral disease, 99–104, 100f Lutembacher’s syndrome BMV in, 99–104, 100f Lutembacher’s syndrome (LS), 340–343
778
KG-Index.indd 778
atrial septal defect assessment in, 341–342
cardiac catheterization, 342, 342b
Ebstein’s anomaly, 423, 423f
clinical features, 340–341
in LS, 342
CT angiography and cardiac MRI, 342
in Takayasus’s arteritis, 576–577, 577f, 587
ECG, 341
total anomalous pulmonary venous connection, 433
echocardiography, 341 percutaneous intervention vs. surgical management and, 342
Major cardiac mass, position of, ECG findings, 275 Malignant cardiac tumors, 755–756, 758
epidemiology, 340
Mammary soufflé, 29
hemodynamics, 340
Maneuvers, effect of
history, 340 investigations, 341–343 management of, 342–343
tricuspid valve disease decreased murmur intensity, 112
mitral stenosis assessment in, 341, 341f
diastolic murmur, 113, 113t
overview, 340
murmur of MR, differentiating from, 112
physical examination, 341
increased murmur intensity, 112
auscultation (heart sounds), 341
Manjunath’s classification, of left atrium clot, 97f, 98
jugular venous pulse, 341
Marey’s modification, 12f
precordium, 341
Masked hypertension, 14
arterial pulses, 341
pulmonary artery hypertension assessment in, 342 LV internal diameter at end-diastole (LVIDD), 465 LV internal diameter at end-systole (LVIDS), 465 LV/RV dysfunction pregnancy and CHD and, 255 LVH. See Left ventricular hypertrophy (LVH)
Maternal risk, in CHD, 253–254 Mayne sign, 19 Mechanical circulatory support, 454 Mechanical prosthetic valve thrombosis, 216–218 Meckel, Johann Friedrich, 340 Mercury properties, 11 use in blood pressure measurement, 11
LVOTO. See Left ventricular outflow tract obstructive lesions (LVOTO)
Mercury sphygmomanometer, 12
M
Methemalbuminemia, 379
M-mode color flow propagation velocity, 176–177
Methemoglobinemia
Macaroni’s sign, 576, 576f Machinery murmur, 26 Macitentan, 631 Magnetic resonance imaging (MRI), 405. See also Cardiac magnetic resonance imaging (CMRI)
Messenger RNA (mRNA), 557 Metformin, 483 Methemoglobin, 379 acquired, 379 congenital, 379 methemalbuminemia, 379 methemoglobin, 379 pseudocyanosis, 379 sulfhemoglobinemia, 379
adults with repaired TOF, 400, 400f
Methotrexate, 582–583
in aortic diseases, 608
Methoxamine, 36
cardiac, 451
Microbiology, infective endocarditis, 206
in cardiac myxoma, 752–753 in chronic constrictive pericarditis, 527
Midaortic dysplastic syndrome, 608
CoA in adults, 362, 363f
MitraClip, 220–221, 221f
Minervini’s sign, 19
09-11-2018 14:51:13
Mitral annulus repair
indirect (pseudo) annuloplasty, 222–223, 222f–223f Mitral regurgitation (MR), 23, 64–66, 73, 128–129 assessment, by echocardiography, 137t assessment of, 148–150, 149f sources of variations during, 149–150, 150f asymptomatic severe, outcome of, 80–81, 80t, 81t causes, 135t clinical assessment of severity, 64–65, 65b clinical features, 182–183 diagnosis, 183 ischemic dynamic nature of, 182 quantitation of, 183–185 mitral valve prolapse, 65–66 moderate MR and PTMC, 98 natural history, 79–81 nonrheumatic. See Nonrheumatic mitral regurgitation percutaneous techniques annular modification techniques, 186 left ventricular remodeling, 186 surgical treatment, 186–187 valve leaflet procedures, 186
prognosis, 188
features of severe, 63–64, 64b
treatment, 186
general appearance, 61
without CAD, 188
heart sounds, 61–64
severity assessment methods, 150–156 color flow jet area in left atrium, 150–151, 151f proximal isovelocity surface area volumetric measurements, 153– 154, 153f pulsed-wave doppler velocity, 155–156, 156f regurgitant orifice area by real-time 3D echocardiography (RT3DE), 154–155, 155f vena contracta width, 151–152, 152f symptomatic severe, outcome of, 81 symptoms, 64 treatment medical management, 185 percutaneous/surgical management, 185–186 two-dimensional (2D) echocardiography, 183 Mitral stenosis (MS), 60–64, 73, 128, 129f, 130f, 724–725, 724f, 725f arterial pulses in, 61 assessment in LS, 341, 341f assessment of, 156–165 continuity equation for, 163
first heart sound (S1), 61–62 murmur, 62–64, 63t opening snap, 62, 62t, 63t history, 60–61 jugular venous pulse in, 61 juvenile MS, BMV in, 102 with left atrial thrombus (case study), 131 mitral valve morphology assessment in, by 2DTTE/ TEE, 134t natural history, in era prior to definitive therapy, 87–90 clinical course after relief of severe valvular obstruction, 89–90, 89t, 90t unselected MS in contemporary era, 88–89 severity assessment, 134t Mitral valve anatomy apparatus, 180, 181f Carpentier’s classification, 180 distortion in ischemic mitral regurgitation, 184 Mitral valve disease MR. See Mitral regurgitation (MR) MS. See Mitral stenosis (MS)
echocardiographic techniques, 156, 157f
Mitral valve prolapse (MVP), 65–66
etiology of, 180, 180t
hemodynamics, 156–159, 157f–158f
Mitral valve repair, 220–225
floppy mitral valve/mitral valve prolapse, 180–181
miscellaneous parameters, 164–165
mitral valve prolapse spectrum, 181, 182f
mitral valve area, 159, 160t
primary causes of, 187
pathophysiology, 181 quantitation of, 183–185 syndromic mitral valve prolapse, 181 treatment, 186
mitral valve area planimetry, 159–161 pressure half-time (PHT) method, 161–163 proximal isovelocity surface area method, 163–164
progression rate of, 79–80
calcific MS and PTMC, 98, 99f
secondary
cardiac examination, 61
causes, 188
precordium, 61
etiology of, 180, 180t
right ventricular impulse, 61
ischemic mitral regurgitation, 181 pathophysiology, 181–182
causes, 133, 133t diagnosis, by echocardiography, 133, 133t
Index
direct (true) annuloplasty, 223–225, 224f
valsalva maneuver, 33 combination of TC MV repair techniques, 225 edge-to-edge mitral leaflet repair MitraClip, 220–221, 221f PASCAL mitral valve repair system, 222, 222f mitral annulus repair direct (true) annuloplasty, 223– 225, 224f indirect (pseudo) annuloplasty, 222–223, 222f–223f subvalvular basal ventriculoplasty, 225 chordal implantation, 225, 225f Mitral valve replacement, 225–229 MV therapy, 228–229
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TMVR in mitral annular calcification, 226
mechanism, 25
N
in MS, 62–64, 63t
TMVR in native (non-calcified) annulus (dedicated TMVR), 226–228, 227f
overview, 25
N-terminal pro-brain natriuretic peptide (NT-pro-BNP)/BNP, 629 Nasopharyngitis, 631 Native coarctation of aorta, 360 balloon coarctoplasty for, 364 Natural history of AR, 81–83, 82t, 83t bicuspid aortic valve anomalies, 192–193 CCTGA, 259 Eisenmenger syndrome, 387–388, 388f of MR, 79–81 asymptomatic severe MR, outcome of, 80–81, 80t, 81t progression rate, 79–80 symptomatic severe MR, outcome of, 81 of MS in era prior to definitive therapy, 87–90 clinical course after relief of severe valvular obstruction, 89–90, 89t, 90t unselected MS in contemporary era, 88–89 subclinical RHD, 77 of VSD, 319–323 antenatal, 320 classification, 319 postnatal, 320–323 types of , location, 319, 319f VSD with AR, 327 Neck, examination, in AF, 22 Newborn, cyanosis in, 371–377 central cyanosis, causes of, 372 airway diseases, 372 cardiac diseases, 372 lung diseases, 372 chest radiograph, 374, 375f congenital heart disease and, 373– 374, 373t–374t echocardiography, 374–375 electrocardiography, 374 hyperoxia test, 373 initial evaluation, 372 initial management prostaglandin E1, role of, 375 supplemental oxygen, role of, 376f, 377
valve-in-ring procedures, 226 valve-in-valve procedures, 225–226 Mitralign, 223–224, 224f
systolic, 26 to-and-fro, 26, 26f, 26t in TR, 112 tricuspid valve disease
Mitraspan transapical segmental reduction annuloplasty (TASRA), 224–225
decreased murmur intensity, 112
MMF. See Mycophenolate mofetil (MMF)
increased murmur intensity, 112
diastolic murmur, 113, 113t murmur of MR, differentiating from, 112
Mode of delivery, pregnancy and CHD, 257
in TS, 112
Moderate MR, PTMC and, 98
types, 26, 26f
Modified World Health Organization (WHO) classification of maternal cardiovascular risk, 254
Muscle biopsy, 540 Muscle enzymes, 640 Muscular ventricular septal defects CHD echocardiography, 294, 294f
MOGE(S) classification, for cardiomyopathy, 464
MVP. See Mitral valve prolapse (MVP)
Molecular mimicry, 46, 47
Mycophenolate mofetil (MMF), 583
Morton and Mahon sign, 19
Mycotic aneurysm, 609, 610f
MR. See Mitral regurgitation (MR)
MYH7 gene, 421, 462
MR-angiography (MRA), 587
Myocardial damage, in acute rheumatic fever, 50
MRI. See Magnetic resonance imaging (MRI) MS. See Mitral stenosis (MS); mitral stenosis (MS) Müller maneuver, dynamic auscultation, 33–34 Muller sign, 19 Multi-detector cardiac computed tomography (MDCT), 309
Myocardial infarction (MI) diagnosis, computer-interpreted ECG in, 664–665, 666f inferior, 700, 701f isolated true posterior, 699, 699f Myocardial tuberculosis, 484 Myocarditis, 450–451, 492–497
Multimodality imaging, 517, 519f
antiviral therapy, 495, 497f
Multivalvular lesions, 72–73
causes of, 492, 493t
AS and AR, 73
classification of, 492
MS and AR, 73
clinical features, 492–493
MS and AS, 73 Multivalvular RHD, 75
immunosuppressive therapy, 495, 495b
Murmur(s)
investigations
in AS, 70–71
biomarkers, 494
in AR, 67–69, 68t
cardiovascular magnetic resonance imaging, 494, 494f
Austin flint murmur, 68–69, 68t diastolic murmur, 68 systolic murmur, 68 in ASOVs, 353, 354f combined systolic and diastolic, 26, 26f, 26t continuous. See Continuous murmur
780
KG-Index.indd 780
diastolic, 26
echocardiography, 493–494 electrocardiogram, 493 endomyocardial biopsy, 494 management of, 495 natural course of disease, 494, 495f Myosin-binding protein-C gene (MyBPC3), 450, 460
09-11-2018 14:51:14
interpretation, 737–741 image analysis, 738–739
overview, 371
noncardiac physiological and pathological findings, 739
pulse oximetry, role of, 374 NOACs. See Novel oral anticoagulants (NOACs) Noncardiac manifestations, acute rheumatic fever, 49
Noninvasive techniques
present-day methods, 12–13 Nonrheumatic mitral regurgitation, 180–188 etiology, 180, 180t overview, 180 Nonspecific aortoarteritis (NSAA), 581–585. See also Takayasus’s arteritis (TA) abatacept and, 584
severity, 202 therapeutic management, 202
dobutamine, 737 pharmacologic, 736–737 Nwosu, 19
Partial anomalous pulmonary venous connection (PAPVC), 428 PASCAL mitral valve repair system, 222, 222f Passive leg elevation (sudden lying down), dynamic auscultation, 34–35, 35f
O Obesity blood pressure measurement and, 15 Obstruction, 429
Pasteur- Rondot maneuver. See Hepatojugular reflux (HJR) Patent ductus arteriosus (PDA), 17, 25, 26–27, 27f, 429
Obstructive lesions, evaluation of, 722, 724–725
amplatzer vascular plugs, 347, 347f–348f
Obstructive sleep apnea, 485
devices selection, 344
Occult CAD, 482 Opening snap (OS) in MS, 62, 62t, 63t
activity and severity, 581–582
arterial or venous delivery, 344 feasibility test for device closure, 348–349, 349f, 350t
corticosteroids and, 582
Oscillometric methods, 12–13
morphologic classification, 344, 344f
disease modifying anti-rheumatic drugs and, 582, 583–584
Osler, William, 127
overview, 344
Ostium primum atrial septal defect, 332
with PAH, devices for, 347–348, 349f
Ostium secundumatrial septal defect, 332
use of devices, indications, 344–347
antirheumatic drugs and, 582–583
follow-up, 584–585 immunotherapy, 582, 583f immunotherapy during surgery and perioperative period, 584 Normal cardiopulmonary adaptation, at birth, 371–372
in tricuspid valve disease, 111
anatomy, 332, 333f Outlet foramen, 404 Overnight oxymetry, 628 Oxygen therapy Eisenmenger syndrome, 391
Normal-flow, low-gradient aortic stenosis definition and pathophysiology, 202–203 outcomes and risk stratification, 203 severity, 203 Novel oral anticoagulants (NOACs), 615 Nuclear cardiac imaging, 467 Nuclear factor erythroid 2–related factor 2 (Nrf2), 633 Nuclear imaging in Anderson-Fabry disease, 476 in cardiac amyloidosis, 474, 475f Nuclear scintigraphy adults with repaired TOF, 400 Nuclear stress test, 736–744 image acquisition protocol, 737 image display, 737, 738f
KG-Index.indd 781
outcomes and risk stratification, 202
radiotracers, 737
blood pressure measurement first sphygmomanometer, 11–12, 12f
definition and pathophysiology, 202
patient preparation, 736 stress protocols, 736
Noncompaction cardiomyopathy, 470–471, 471f
Paradoxical (preserved left ventricular ejection fraction) low-flow, low-gradient aortic stenosis
Index
normal cardiopulmonary adaptation at birth, 371–372
amplatzer duct occluder I (ADO I), 345, 345f amplatzer duct occluder II (ADO II), 345, 346f amplatzer duct occluder II additional size (ADO II AS), 345–347, 347f Patent foramen ovale (PFO), 429–430
P
Pathogen, rheumatic fever, 46
P wave, analysis of, ECG, 271, 271f left atrial enlargement, 271 right atrial enlargement, 271 P’ waves, 675 identification of, 687, 688f PA band, in CCTGA, 260, 262f Pacemaker rhythms, 666 PAH. See Pulmonary arterial hypertension (PAH) Palmar click, 19 Palpation, tricuspid valve disease, 111 Papillary fibroelastoma, 753–754 PAPVC. See Partial anomalous pulmonary venous connection (PAPVC)
Patient factors, blood pressure measurement arm position, 13 body posture, 13 other factors, 13 site of measurement, 13 Patient positioning 45 degrees inclination, 4–5, 5f jugular venous pressure, interpretation, 4–5, 5f Patient-related challenges, secondary prophylaxis, 44 PAU. See Penetrating aortic ulcer (PAU) PAVM. See Pulmonary arteriovenous malformation (PAVM)
781
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PDA. See Patent ductus arteriosus (PDA) PE. See Pulmonary embolism (PE) Penetrating aortic ulcer (PAU), 601, 604 Penicillin-related challenges, secondary prophylaxis, 44 Penny sign, 19 Pentoxyphylline, 642 Pentraxin 3 (PTX3), 581 Percussion, tricuspid valve disease, 111 Percutaneous intervention/surgery during pregnancy, CHD and, 257 Percutaneous pulmonary valve replacement/implantation adults with repaired TOF, 401–402 Percutaneous techniques, MR annular modification techniques, 186 left ventricular remodeling, 186 surgical treatment, 186–187 valve leaflet procedures, 186 Percutaneous therapies, for tricuspid valve, 229–231 Percutaneous transvenous mitral commissurotomy (PTMC), 92–104. See also Balloon mitral valvotomy (BMV) anatomy, 92 calcific MS and, 98, 99f contraindications, 92 dextrocardia and, 99 indications for BMV, 92 in kyphoscoliosis, 102, 103f in left atrium clot, 96–98, 97f Lutembacher’s-ASD/RHD severe MS with severe submitral disease, 99–104 Manjunath’s classification of LA clot, 97f, 98 moderate MR and, 98 overview, 92 pathophysiology, 92 post-mitral valve repair stenosis and, 101–102, 102f during pregnancy, 102, 103f severe submitral disease and, 98, 98f technique BMV, 93–96 echocardiography in BMV, 92–93
782
KG-Index.indd 782
pre-evaluation, 92
venous anomalies and, 100–101, 101f Percutaneous valve interventions beyond transcatheter aortic valve implantation, 219–231 mitral valve repair, 220–225 mitral valve replacement, 225–229 overview, 219–220, 219t percutaneous therapies for tricuspid valve, 229–231 Perfusion defects, location of, 739 Pericardial disease, JVP and, 9 Pericardiectomy, 525 for chronic constrictive pericarditis, 528–529 Pericarditis, ECG findings, 279f, 280 Periodic holter monitoring adults with repaired TOF, 399 Peripartum cardiomyopathy (PPCM), 455, 484 Peripheral arterial disease (PAD), 22 Peripheral cyanosis, 379, 439 in adults, 379 Peripheral pulmonary artery stenosis CHD echocardiography, 290–291, 290f, 291f Peripheral signs, in AR, 67, 67t Permanent junctional re-entrant tachycardia, 679–680, 681–682f Peroxisome proliferator-activated receptor (PPAR) agonists, 483 Persistent junctional reciprocating tachycardia (PJRT), 504 PERT. See Pulmonary embolism response team (PERT) PET. See Positron emission tomography (PET) PFO. See Patent foramen ovale (PFO) PFT. See Pulmonary function test (PFT) PH. See Pulmonary hypertension (PH) Pharmacological maneuvers, dynamic auscultation amyl nitrite, 36 methoxamine, 36 phenylephrine, 36 Pharmacomechanical thrombolysis (PMT), 616 Pharmacotherapy, for IPAH management, 630 Phenylephrine, 36 Phlebotomy, Eisenmenger syndrome, 390
Phosphodiasterase type 5 inhibitors Eisenmenger syndrome, 392 Physical examination atrial fibrillation, 21 blood pressure, 22 jugular venous pulse, 22 neck examination, 22 pulse, 21–22 Physiological maneuvers, dynamic auscultation clinical implications, 32–33, 34f isometric exercise, 35–36 Müller maneuver, 33–34 passive leg elevation or sudden lying down, 34–35, 35f rapid standing from squatting or lying posture, 33 sudden squatting, 35, 35f valsalva maneuver, 32, 33f, 33t Physiological repair (conventional repair), in CCTGA, 260 Pistol shot sound, 18 PJRT. See Persistent junctional reciprocating tachycardia (PJRT) Planned peripartum care, for CHD, 298–299, 299f Plastic bronchitis, 416 Platelet abnormalities, in Eisenmenger syndrome, 388 PLE. See Protein-losing enteropathy (PLE) PMT. See Pharmacomechanical thrombolysis (PMT) Poiseuille, 11 Polyarthralgia, diagnosis-related challenges, 42 Polyarthritis, 41 diagnosis-related challenges, 42 Polycythemia, 441 Polysomnography, 628 Pompe’s disease, ECG findings, 277, 278f Population-based survey studies epidemiological trends of burden of RHD in India, 54, 55t Positive Kussmaul’s sign, 6 Positron emission tomography (PET), 475–476, 482, 482f in cardiac myxoma, 753 FDG-PET scanning, 577 Post-mitral valve repair stenosis, PTMC and, 101–102, 102f
09-11-2018 14:51:14
care in puerperium, 257
Post-tricuspid shunts, 243
genetic counseling, 257
Postnatal natural history, of VSD, 320–323
high-risk anatomic lesions, 255
fetal risk, 254
aortic regurgitation, 321
high-risk pathophysiologic states, 254–255
infective endocarditis, 322–323
maternal risk, 253–254
premature death due to CHD, 320
mode of delivery, 257
pulmonary vascular obstructive disease, 321–322, 322f
overview, 252
right ventricular outflow tract obstruction development, 321 small VSD with LVVO, 323
percutaneous intervention/ surgery during, 257
Prostaglandin E1 cyanosis in newborn, 375 Prostanoids, Eisenmenger syndrome and, 392–393 Prosthetic valve thrombosis (PVT) left-sided
physiological changes during, 252–253, 254t
clinical presentation and diagnosis, 216–217
thrombolytic therapy, 256
incidence of, 216 management of, 217, 217f
spontaneous reduction in size or closure of defect, 320–321
and Ebstein’s anomaly treatment, 426
mechanical, 216–218
survival like general population, 323
Eisenmenger syndrome and, 391
pathogenesis, 216, 216f
unresolved issues about, 322
PTMC during, 102, 103f
recommendations for management, 217, 218
Potts shunt, 632
secondary prophylaxis during, 121
PPCM. See Peripartum cardiomyopathy (PPCM)
Premature death due to CHD, VSD and, 320
PR. See Pulmonary regurgitation (PR)
Premature ventricular contractions (PVCs), 718, 718f
PR segment, analysis of, ECG, 271–273, 272f short PR interval, causes, 272–273, 272f Practical points, in blood pressure measurement apparatus factors, 13 patient factors arm position, 13 body posture, 13 other factors, 13 site of measurement, 13 Pre-evaluation, in BMV, 92 Precordium
Pressure and heart rate response, valsalva maneuver, 32, 33f
Pseudoaneurysms, 609
Pretricuspid shunts, 243 Primary mitral regurgitation (MR) causes of, 187 etiology of, 180, 180t floppy mitral valve/mitral valve prolapse, 180–181 mitral valve prolapse spectrum, 181, 182f quantitation of, 183–185
in LS, 341
syndromic mitral valve prolapse, 181
BAV and, 196–197 blood pressure measurement and, 15
Proximal isovelocity surface area volumetric measurements, 153–154, 153f
Pressure half-time (PHT) method, 161–163
in AR, 67
adults with repaired TOF and, 401
Proximal isovelocity surface area method, 163–164
PS. See Pulmonary stenosis (PS)
pathophysiology, 181
Pregnancy
Protein-losing enteropathy (PLE), 416
Pressure-gradients, recording of, 722, 724–725
in AS, 70
in MS, 61
KG-Index.indd 783
Prospective Comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, 453
treatment, 186 Primordial prevention, RF/RHD, 119–120 PRKAR1A gene, 751
pseudo-TS, 107 Pseudocyanosis, 379 Pseudocynosis, 439 Pseudohypertension, 14 PTMC. See Percutaneous transvenous mitral commissurotomy (PTMC) Pulmonary arterial hypertension (PAH), 60, 282–283 Pulmonary Arterial Hypertension Soluble Guanylate Cyclase– Stimulator Trial 1 (PATENT-1), 630–631 Pulmonary arteriovenous fistula, 29, 30f Pulmonary arteriovenous malformation (PAVM), 435– 438
Proaggregant effect, 252
clinical features, 435–436, 435t
in CCTGA, 263
Progression rate, MR, 79–80
history of, 435
CHD and, 252–257
Prophylaxis, secondary
investigations, 436, 437f
anticoagulation management, recommendations, 255–256, 256f
health system-related challenges, 44
cardiovascular drugs in, 255, 255t
patient-related challenges, 44
measures to improve rates, 44 penicillin-related challenges, 44
Index
Post-pericardiectomy low cardiac output syndrome, 530–531
management of, 436–438, 437f neurological complications, 436, 436t Pulmonary artery angioplasty, 592, 595t, 596f
783
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Essentials of Postgraduate Cardiology
Pulmonary artery denervation, 632 Pulmonary artery hypertension (PAH), 27 assessment in LS, 342 JVP and, 9 PDA with, devices for, 347–348, 349f Pulmonary dysfunction, in Eisenmenger syndrome, 389 Pulmonary embolism (PE), 615–622 anticoagulation, 615, 615t catheter-based therapy. See Catheter-based therapy (CBT) systemic thrombolytic therapy, 616 Pulmonary embolism response team (PERT), 615 Pulmonary function test (PFT), 628 Pulmonary hypertension, 243–250 pregnancy and CHD, 254 Pulmonary hypertension (PH), 443, 624–629 algorithmic approach to, 624–628, 625f blood tests, 628–629 chest X-ray in, 626 clinical classification of, 624, 624t clinical symptoms and signs, 624–625 computed tomography in, 627–628 with congenital heart disease, 624, 625t definitive diagnosis of, 624 ECG in, 626 echocardiogram in, 626, 626f, 627t electrocardiogram in, 626 evaluation of patient with, 721 exercise testing, 628 overnight oxymetry, 628 polysomnography, 628 pulmonary function test, 628 right heart catheterization in, 626, 627, 628t, 629f 6-minute walk test, 628 ventilation/perfusion lung scan, 628
echocardiographic findings, 145– 146, 145t–146t Pulmonary vascular obstructive disease postnatal natural history of VSD and, 321–322, 322f Pulmonary vascular obstructive disease (PVOD), 243 Pulmonary vascular resistance (PVR), 540 Pulmonary vascularity assessment, chest X-ray in CHD, 282–283 decreased pulmonary blood flow (pulmonary oligemia), 282 increased pulmonary blood flow (pulmonary plethora), 282 pulmonary arterial hypertension, 282–283 pulmonary venous hypertension, 283 Pulmonary vein stenosis, CHD echocardiography, 292, 292f Pulmonary venous hypertension (PVH), 283 Pulse oximetry, role in cyanosis in newborn, 374 Pulsed-wave doppler velocity, 155–156, 156f PVCs. See Premature ventricular contractions (PVCs) PVH. See Pulmonary venous hypertension (PVH) PVR. See Pulmonary vascular resistance (PVR)
Q QRS complex, ECG, 272–274 bundle branch blocks, 273 left ventricular hypertrophy, 273– 274, 274f right ventricular hypertrophy, 273, 273f QuantumCor, 224 Quincke’s pulse, 18
Pulmonary oligemia, 282
R
Pulmonary plethora, 282
Radiation-induced cardiomyopathy, 478
Pulmonary regurgitation (PR), 72
KG-Index.indd 784
Ranolazine, 631–632 Rapid standing from squatting or lying posture, in dynamic auscultation, 33 RCM. See Restrictive cardiomyopathy (RCM) Real-time 3D echocardiography (RT3DE), regurgitant orifice area by, 154–155, 155f Recent multinational registry (REMEDY) report, 74 Recurrence, of rheumatic fever, 42 Recurrent coarctation of aorta, 360 balloon coarctoplasty for, 364 Regenerative therapy, 454 Renal angioplasty, 589–590 procedure, 590–591, 592f, 593t, 594f Renal function, in Eisenmenger syndrome, 389 Reoperations, in adults with repaired TOF, 401 Residual ventricular septal defects adults with repaired TOF and, 398 Respiratory variation interpretation of, JVP and, 5–6 Restrictive cardiomyopathy (RCM), 460, 461, 462, 471–472, 472f, 536–545 cardiac amyloidosis and, 540, 541, 542 chronic constrictive pericarditis vs., 540, 543t clinical presentation, 536, 537t constrictive pericarditis vs., 722, 723f diagnosis of, 536, 538–539f, 538t, 539t echocardiographic findings in, 536, 540f endomyocardial fibrosis. See Endomyocardial fibrosis (EMF) etiologies of, 536, 537t hemodynamic in, 539–540, 541f, 542f
adults with repaired TOF, 398
Radiography, CoA in adults, 361
hereditary hemochromatosis and, 544–545
echocardiographic findings, 145– 146, 145t–146t
Radiotracers, 737
sarcoidosis and, 543–544, 544f, 544t
RALES trial. See Randomized Aldactone Evaluation Study (RALES) trial
tissue biopsy for diagnostic evaluation, 540, 542f
Pulmonary stenosis (PS), 72
784
Randomized Aldactone Evaluation Study (RALES) trial, 453
ECG findings, 277
Revascularization, 590
09-11-2018 14:51:15
pathogen, 46
hospital admission data, 54, 54t
Revised Jones criteria 2015 update, 40t
social factors, 47
population-based survey studies, 54, 55t
RF. See Rheumatic fever (RF) Rhabdomyomas, 754 RHC. See Right heart catheterization (RHC) RHD. See Rheumatic heart disease (RHD) Rheumatic aortic stenosis with left ventricular dysfunction (case study), 131–132 Rheumatic fever (RF). See also Acute rheumatic fever (ARF); Rheumatic heart disease (RHD) causes, 39 data sources for estimation of burden of, 53–54 decline of, 53–57, 56f
prevention antistreptococcal vaccine, 120–121
estimated burden, 57
primary, 120–121, 120t, 121t
immunological mechanisms, 47–49, 48f
primordial prevention, 119–120 secondary, 121–122, 121t, 122t secondary prophylaxis during special situations, 121 secondary prophylaxis in anticoagulated patients, 122 prevention and control, challenges and opportunities, 57 recurrence of, 42 revised Jones criteria 2015 update, 40t
diagnosis, 39–40, 40t, 119, 120t
risk of, 53
hospital admission data, 54, 54t population-based survey studies, 54, 55t school-based surveys, 54–56, 55t epidemiology, 119 estimated burden, 57 incidence, 39 incidence of, 53 Jones criteria, 39 major criteria carditis, 40–41 polyarthritis, 41 subcutaneous nodules and erythema marginatum, 41 Sydenham’s chorea, 41 management, 42–44
Rheumatic heart disease (RHD), 23, 39, 42. See also Rheumatic fever (RF) AF in, 115–117
pathogenesis of, 46–51 environmental risk factors, 47 host susceptibility, 46–47
epitope spreading, 49 humoral immune response and endothelial injury, 47 molecular mimicry, 47 incidence of, 53 natural history of, 77 overview, 74 pathogenesis, controversies in, 49–50, 50–51 endothelial heterogeneity, 49 healing ability, 49 recent conflicting evidences in, 50
inflammation and structural remodeling, 115
valve involvement, 50 vicious inflammatory cycle, a, 49
management, 116
pathogenesis of, 46–51
overview, 115
prevention
pathophysiology, 115 pulmonary veins, electrical remodeling and stretch, 115–116
antistreptococcal vaccine, 120–121 pregnancy and breastfeeding, 121
rhythm control, 117
primary, 120–121, 120t, 121t
thromboembolism, 116
primordial prevention, 119–120
ventricular rate control, 116–117
secondary, 121–122, 121t, 122t
borderline RHD, 76 management of, 77 data sources for estimation of burden of, 53–54
diagnosis-related challenges, 41–42
collagen autoimmunity hypothesis, 49
correction of underlying disorder, 116
clinical. See Clinical RHD
clinical features not included in Jones Criteria, 41
cellular immune response in, 47–49
myocardial damage in, 50
challenges in, 43–44, 44t
minor manifestations
evolution into chronic, 50
anticoagulation, 116
bedrest, 42 of clinical manifestations, 42–43, 43t
epidemiology, 119
pregnancy and breastfeeding, 121
detection methods, 53 epidemiological trends of burden of, in India, 54
school-based surveys, 54–56, 55t
decline of, 53–57, 56f definite RHD, 75–76 management of, 77
secondary prophylaxis during special situations, 121 secondary prophylaxis in anticoagulated patients, 122 prevention and control, challenges and opportunities, 57 recognition of process, 74–75
detection methods, 53
risk of, 53
diagnosis, 119, 120t
subclinical. See Subclinical RHD
diagnostic criteria for latent, 75, 75b–76b
targets for screening, 77
epidemiological trends of burden of, in India, 54
Index
Reversible cardiomyopathies, 478
WHF criteria, limitations for, 76–77 Rheumatic multivalvular heart disease (case study), 132
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Rheumatic pneumonia, 41
incidence and prevalence, 559
Rhythm control
positron emission tomography in, 475–476
AF in RHD and, 117 Rhythm disorders, in utero therapy for, 299
presentations, 559–560, 560f, 561f
Right atrial pressure, calculation of, 5
and restrictive cardiomyopathy, 543–544, 544f, 544t
Right atrium, 283, 283f Right heart catheterization (RHC), 626, 627, 628t, 629f Right-to-left (cyanotic) shunt, chest X-ray in CHD, 285–288, 285t, 286f large aorta with decreased lung vascularity, 285–287 large pedicle with increased vascularity, 287 normal aorta with decreased lung vascularity, 287–288 small aorta with increased vascularity, 287 Right ventricle (RV), 3, 284 atrialized, 419 functional, 419, 421
prognosis, 560, 561
treatment of, 566–569, 568f, 569t School-based surveys epidemiological trends of burden of RHD in India, 54–56, 55t Screening RHD, targets for, 77 Second degree atrioventricular block (II-AVB), 694–696, 695f, 696f, 697f, 698t Second heart sound in AS, 70 in AR, 67 in tricuspid valve disease, 111 Secondary mitral regurgitation (MR) causes, 188
Right ventricular impulse, in MS, 61
etiology of, 180, 180t
Right ventricular outflow tract obstructions
pathophysiology, 181–182
in adults with repaired TOF, 398
ischemic mitral regurgitation, 181 prognosis, 188
Riociguat, 630–631
treatment, 186
Riva Rocci Cuff, 12, 12f
without CAD, 188
Rosenbach sign, 19
Secondary prophylaxis
Royal Academy of Medicine, 11
in anticoagulated patients, 122
RSOV. See Ruptured sinus of Valsalva aneurysm (RSOV)
health system-related challenges, 44
Rudimentary chamber, 403
measures to improve rates, 44
Ruptured ASOVs, 352
patient-related challenges, 44
Ruptured sinus of Valsalva aneurysm (RSOV), 17, 25, 27, 28t
penicillin-related challenges, 44
RV dysfunction management, in CCTGA, 262–263
during special situations, 121 pregnancy and breastfeeding, 121 Selenium (Se) deficiency, 485
S
Selexipag, 631
Sail sound, 111
Self-blood pressure monitoring, 14
Sailer’s sign (Gerhardt sign), 19
Senile systemic amyloidosis, 553
Sarcoidosis, 455–456, 474–475, 492, 559–569
Serologic testing, 555
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Serological testing, 629
cardiac magnetic resonance imaging in, 475
Serum protein electrophoresis (SPEP), 555
diagnosis of, 561–563, 562t, 563t
Severe MS, features of, 63–64, 64t
differential diagnosis, 563, 564f echocardiography in, 475, 476f
Severe submitral disease, PTMC and, 98, 98f
electrocardiogram in, 475
Sgarbossa criteria, 703, 704f
imaging in, 563–566, 565f, 566f, 567f
Sherman sign, 19
Shock, 404 Simpson’s biplane, 465 Single photon emission computed tomography (SPECT), 736 gated parameters, 741–743 Single ventricle (SV), 403–408 classification of, 403 clinical features, 404 hemodynamics, 404 investigations, 404–405 management of, 405, 406, 407–408 morphology, 403–404 Single ventricle, ECG findings, 277 Sinus tachycardia, ECG analysis, 675, 676f Sinus venosus defect, 333 Site, of blood pressure measurement, 13 Situs identification, ECG findings, 275 6-minute walk distance (6MWD), 628, 631 6-minute walk test (6MWT), 628 SLE. See Systemic lupus erythematosus (SLE) Small interfering RNA (siRNA), 557 Smoking, and BP measurement, 13 Social factors rheumatic fever, pathogenesis, 47 Sodium-glucose cotransporter-2 (SGLT2) inhibitors, 483 Speckle-tracking echocardiography (STE), 465–466 SPECT. See Single photon emission computed tomography (SPECT) SPEP. See Serum protein electrophoresis (SPEP) Sphygmomanometer(s) digital, 13 first, 11–12, 12f mercury, 12 Spironolactone, 632 Square-wave response, valsalva maneuver, 32, 34f Sree Chitra Tirunal Institute of Medical Sciences and Technology (SCTIMST), 547, 550 ST segment, ECG, 274 ST segment elevation (STE), 699 ST segment elevation myocardial infarction (STEMI), 664, 665 equivalents, 699–705 in paced patients, 703, 705, 705f signs of, 703, 704f
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Starnes procedure, 424
Stem cell therapy, 632 STEMI. See ST segment elevation myocardial infarction (STEMI) Steno-occlusive lesions of aorta, 608, 608f, 609f Stent implantation in CoA, 364, 365f Sternal angle, locating, 5
Sudden cardiac death Ebstein’s anomaly and, 421 Sudden cardiac death (SCD), 70 Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), 453–454 Sudden lying down (passive leg elevation), dynamic auscultation, 34–35, 35f Sudden squatting, in dynamic auscultation, 35, 35f Sulfhemoglobinemia, 379
Steroids, 642
Superior cavopulmonary anastomosis, 406, 407
Strain imaging
Superior vena cava (SVC), 3, 4
fundamentals of, 709 global longitudinal strain, 709, 709f, 710f in acute heart failure, 712 in heart failure, 710, 711f, 712 in monitoring cardiotoxicity for chemotherapy, 713 normal values, 709
Supplemental oxygen role in cyanosis in newborn, 376f, 377 Supravalvar aortic stenosis, CHD echocardiography, 291
dobutamine, 737 pharmacologic, 736–737 adenosine, 736–737 dipyridamole, 736 Stroke, 442 Structural heart defects, fetal interventions for, 299–300 Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN), 631 Subclavian artery interventions, 589, 589t, 590f
T T wave, ECG, 274–275 TA. See Takayasus’s arteritis (TA) Tachyarrhythmias, 299 Tachycardia-induced cardiomyopathy, 21 Tachycardias atrial, 675, 676–677, 677f atrioventricular nodal re-entrant, 677, 678–679, 679f atrioventricular re-entrant, 679, 680f permanent junctional re-entrant, 679–680, 681–682f
ECG analysis
atrial tachycardia, 675, 676–677, 677f
Stress protocols, 736
in AR, 68
Supraventricular tachycardia (SVT), 21
in valvular heart disease, 713
Stress-induced cardiomyopathy, 456
Systolic murmur, 26
clinical classification of, 676f
atrial fibrillation, 677, 678f
Streptococcal pharyngitis, 120
Systolic dysfunction, and late gadolinium enhancement, 512
Supraventricular arrhythmias, 503–504
relationship to ejection fraction, 710, 710f longitudinal, in cardiac amyloidosis, 712–713, 712f
Systolic clicks, in tricuspid valve disease, 111
atrial flutter, 677, 678f
sinus, 675, 676f Tachycardiomyopathy (TCMP), 456, 485–486, 486f, 500–504 and arrhythmias, 503–504
atrioventricular nodal re-entrant tachycardia, 677, 678– 679, 679f
case study, 500–501, 500–501f, 502f, 503f
atrioventricular re-entrant tachycardia, 679, 680f
definition of, 501, 503
permanent junctional re-entrant tachycardia, 679–680, 681–682f
pathophysiology, 503
sinus tachycardia, 675, 676f steps in, 675 SV. See Single ventricle (SV) SVT. See Supraventricular tachycardia (SVT) Sydenham’s chorea, 40, 41 management, 43, 43t Symptomatic severe MR, outcome of, 81
clinical features, 503–504 epidemiology, 503 timeline of events in, 504 Tafamids, 557 TAI. See Traumatic aortic injury (TAI) Tailored Immosuppression in Inflammatory Cardiomyopathy (TIMIC) study trial, 453 Takayasus’s arteritis (TA), 575–580, 586–595. See also Nonspecific aortoarteritis (NSAA) acute stage, 586
Syndromic mitral valve prolapse, 181
aortography in, 576, 576f
Systemic examination, atrial fibrillation, 22–23
chest x-ray in, 575, 575f
overview, 74
Systemic lupus erythematosus (SLE), 485
prevalence, 74
classification criterion for, 577–580, 578–580t
Subclinical carditis, 40–41 Subclinical RHD natural history, 77
chronic stage, 586
Systemic thrombolytic therapy, 616
Subcutaneous nodules, 39, 41
clinical activity score, 581
Systolic area index, 521
Subvalvular mitral valve repair
computed tomography in, 576–577, 577f, 587f
basal ventriculoplasty, 225
Systolic arterial hypertension, medical management of, 365–366
chordal implantation, 225, 225f
Systolic BP, 13
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Index
STE. See Speckle-tracking echocardiography (STE); ST segment elevation (STE)
EULAR/PRINTO/PRES criteria, 578, 580, 580t
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imaging in, 575
long-term follow-up, 397
interventions in
long-term follow-up, issues on, 398–399
arch artery. See Arch artery interventions endovascular, 587–588, 588t, 589t imaging for, 586–587, 586f lesions of, 589
magnetic resonance imaging, 400, 400f nuclear scintigraphy, 400 optimal frequency of clinical follow-up, 398
magnetic resonance imaging in, 576–577, 577f, 587
other cardiac comorbidities, 398
pathophysiology, 586
percutaneous pulmonary valve replacement/ implantation, 401–402
ultrasonography in, 575–580 Takotsubo cardiomyopathy, 456, 487–488
overview, 397
periodic holter monitoring, 399
TAPVC. See Total anomalous pulmonary venous connection (TAPVC)
pregnancy and, 401
Target heart rate (THR), 736
residual ventricular septal defects, 398
Targeted therapy Eisenmenger syndrome, 391
pulmonary regurgitation, 398 reoperations in, 401
Thrombosis, 416, 441–442 in Eisenmenger syndrome, 388–389 Thyroid dysfunction, 485 Ticlopidine, 642 TID. See Transient ischemic dilation (TID) TIMIC study trial. See Tailored Immosuppression in Inflammatory Cardiomyopathy (TIMIC) study trial Tissue biopsy for diagnostic evaluation of restrictive cardiomyopathy, 540, 542f Tissue Doppler, 516 Tissue velocity imaging, 472 Titin (TTN) gene, 461–462 To-and-fro murmurs, 26, 26f, 26t Tocilizumab, 584, 633
combination therapy, 393
right ventricular outflow tract obstructions, 398
endothelin receptor antagonist, 391–392, 392f
serial estimation of brain natriuretic peptide, 401
phosphodiasterase type 5 inhibitors, 392
standardized clinical assessment and management plans, 401
and cardiac catheterization, 432, 433b
surgical repair of unoperated TOF, 397
classification of, 428–429, 429t
prostanoids, 392–393 TAVI. See Transcatheter aortic valve implantation (TAVI) TCMP. See Tachycardiomyopathy (TCMP)
ECG findings, 275, 275f–276f Thallium-201 (Tl-201), 737
Total anomalous pulmonary venous connection (TAPVC), 428–433 associated lesions, 429
chest X-ray, 430–431, 431f clinical features, 430 computed tomography angiogram for, 433
TCPC. See Total cavopulmonary connection (TCPC)
Thiamine, 485
Technetium (99mTc)-labeled compounds (99mTc-sestamibi, 99mTc-tetrofosmin), 737
Third degree atrioventricular block (III AVB), 698
electrocardiogram for, 431
Third heart sound
etiology, 428
TEE. See Transesophageal echocardiography (TEE) ‘Ten Commandments’ for successful Fontan circulation, 411, 412t Tetralogy of Fallot (TOF), 9, 440 adults with repaired aortic root enlargement after, 398 arrhythmias, 398 cardiac catheterization and angiography, 401 complications on follow-up, predictors of, 401 computed tomography, 399– 400, 400f ECG, 398, 399f echocardiography, 398–399, 399f
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electrophysiology study for risk stratification, 401
Thiazide diuretics, discovery of, 11
echocardiography, 431–432, 431t, 432f embryology, 428
in AS, 70
history, 428
in AR, 67
infracardiac, 429, 431–432
in tricuspid valve disease, 111
magnetic resonance imaging for, 433
Thoracoabdominal aortic aneurysm, 600
morphology, 428–429
THR. See Target heart rate (THR)
natural history, 430
Three-dimensional transesophageal images
pathophysiology, 429–430
of ASD, 336, 337f intracardiac echocardiography, 336–339, 338f, 339t 3D echocardiography, 422–423, 424f, 466 Thromboembolic phenomena, 21 Thromboembolism, 416 AF in RHD and, 116 Thrombolytic therapyn in pregnancy, CHD and, 256
prenatal diagnosis of, 432 prevalence, 428 supracardiac, 429 surgery for, 433 Total cavopulmonary connection (TCPC), 407–408, 410, 412 lateral tunnel variant, 414, 414f TPG. See Transpulmonary gradient (TPG) TR. See Tricuspid regurgitation (TR) Trace elements, 484
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landmarks for, 93, 94f technique for, 93–94 Transcatheter aortic valve implantation
subxiphoid frontal (4-chamber) view, 333–334, 334f
percussion, 111
subxiphoid sagittal TTE view, 334, 334f
symptoms, 110
Traube’s double tone, 18
mitral valve repair, 220–225
Treat-repair-treat strategy
Traumatic aortic injury (TAI), 604, 604t Eisenmenger syndrome (ES) and, 393
overview, 219–220, 219t
Treprostinil, 631
percutaneous therapies for tricuspid valve, 229–231
Tricuspid atresia, ECG findings, 275
Transcatheter aortic valve implantation (TAVI) percutaneous valve interventions beyond, 219–231
Tricuspid regurgitation (TR), 71–72, 107–110 echocardiographic findings, 141– 145, 143t–144t etiologies, 107–109
mitral valve repair, 220–225
jugular venous pulse in, 110–111
mitral valve replacement, 225–229
murmurs in, 112
overview, 219–220, 219t
respiratory variation, 109–110
percutaneous therapies for tricuspid valve, 229–231 Transcatheter mitral valve replacement (TMVR)
jugular venous pulse in, 110–111 primary, 107
mid-esophageal aortic valve short-axis view, 335– 336, 335f mid-esophageal bicaval view, 336 Transient ischemic dilation (TID), 738–739 Transplantation, heart. See Heart transplantation Transpulmonary gradient (TPG), 721, 721f Transthoracic echocardiography (TTE), 607 of ASD, 333–335, 334f apical 4-chamber and modified apical 4-chamber TTE view, 334–335, 334f parasternal short-axis TTE view, 334f, 335
in CCTGA, 260, 262 Troponin I (TNNI3), 461, 462 Truncus arteriosus with pulmonary stenosis, 25 Trypanosoma cruzi, 484 TS. See Tricuspid stenosis (TS) TSD-5 mitral valve repair device (Harpoon), 225 TTE. See Transthoracic echocardiography (TTE) TTN gene, 450 Tubercular pericarditis clinical features, 523 diagnosis, 523–524, 523f differential diagnosis, 525 epidemiology, 523
echocardiographic findings, 141– 145, 143t–144t
in native (non-calcified) annulus (dedicated TMVR), 226– 228, 227f
mid-esophageal 4-chamber view, 335, 335f
Tricuspid valve repair/replacement
Tricuspid stenosis (TS), 71, 107
murmurs in, 112
of ASD, 335–336, 335f, 337f
tricuspid stenosis, 107
pathophysiology, 109
in mitral annular calcification, 226
Transesophageal echocardiography (TEE), 21, 607
tricuspid regurgitation, 107–110
Transthyretin-related amyloidosis, 557
percutaneous valve interventions beyond, 219–231 mitral valve replacement, 225–229
physical signs, 110–112
pseudo-TS, 107 secondary, 107
pathogenesis, 523 treatment, 525 Tuberculosis, 523 Tuberculous-constrictive pericarditis, 533–534 Tuberculous pericardial effusion, 532–533
Tricuspid valve (TV)
treatment of, 533
clinical anatomy, 106
Tuberculous pericarditis, 532
overview, 106
TV. See Tricuspid valve (TV)
percutaneous therapies for, 229–231
2D echocardiography, 422, 423f, 465, 471, 472f
physiology, 106
Index
Trans-septal puncture (TSP), in BMV, 93
Tricuspid valve disease, 106–113, 131 arterial pulse, 110
in chronic constrictive pericarditis, 527
auscultation, 111–112
mitral regurgitation (MR), 183
chest X-ray, 113 electrocardiogram, 113
U
etiology, 107
Uhl’s anomaly, 421
general appearance, 110
Ultrasonography
inspection, 111
in Takayasus’s arteritis, 575–580
jugular venous pulse, 110–111
Unguarded tricuspid valve, 421
maneuvers, effect of, 112–113
Univentricular palliation, in CCTGA, 260
decreased murmur intensity, 112 diastolic murmur, 113, 113t
Unnatural history, of VSD, 323
increased murmur intensity, 112
Unoperated TOF, surgical repair of, in adults, 397
murmur of MR, differentiating from, 112
Unresolved issues, related to VSD, 323, 323t
palpation, 111
Unruptured ASOVs, 352
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Unselected MS, in contemporary era, 88–89 UPEP. See Urine protein electrophoresis (UPEP) Uremic cardiomyopathy, 488
rheumatic multivalvular heart disease, 132 combined valvular and multivalvular heart diseases, 131
Uric acid clearance, in Eisenmenger syndrome, 389
evaluation, 127–128
Urine protein electrophoresis (UPEP), 555
incidences, 127
V ‘v’ waves, 7f, 9 VA. See Vereckei algorithm (VA) VADs. See Ventricular assist devices (VADs) Valsalva maneuver, 718–719, 719f Valsalva maneuver, dynamic auscultation, 32, 33f, 33t clinical implications, 32–33 method, 32 physiological changes, 32, 34f pressure and heart rate response, 32, 33f response in specific diseases, 33, 34f hypertrophic obstructive cardiomyopathy, 33, 34f mitral valve prolapse, 33 square-wave response, 32, 34f stages of, 33f, 33t Valvar quantifications, CHD echocardiography, 295, 295f Valve-in-ring procedures, 226 Valve-in-valve procedures, 225–226 Valve leaflet procedures, MR, 186 Valvular heart disease, 483 Valvular heart disease (VHD). See also specific entries; specific types acute aortic regurgitation, 69, 69t AF and, 131 aortic regurgitation, 66–69 aortic regurgitation assessment, 172–177 aortic stenosis, 69–71, 71t aortic valve assessment, 165–172 aortic valve disease AS, 129–130 AR, 130–131 case scenarios mitral stenosis with left atrial thrombus, 131 rheumatic aortic stenosis with left ventricular dysfunction, 131–132
future perspectives, 132 Indian perspective, 127 mitral regurgitation, 64–66 mitral regurgitation, assessment, 148–150, 149f mitral stenosis, 60–64 mitral stenosis, assessment, 156– 165 mitral valve disease MR, 128–129 MS, 128, 129f, 130f multivalvular lesions, 72–73 AS and AR, 73 MS and AR, 73 MS and AS, 73 MS and MR, 73 overview, 60, 127, 148 pitfalls in assessment, 148–177 pulmonary regurgitation, 72 pulmonary stenosis, 72 rheumatic mitral regurgitation severity assessment methods, 150–156 tricuspid regurgitation, 71–72 tricuspid stenosis, 71 tricuspid valve disease, 131 Vascular endothelial growth factor (VEGF), 443 Venous anomalies, PTMC and, 100– 101, 101f Venous hum, 29 Venous return (VR), 3 Venous thromboembolism (VTE), 615 Ventilation/perfusion lung scan (V/Q scan), 628 VenTouch system, 223 Ventricular arrhythmias, 504
Ventricular rate control AF in RHD and, 116–117 Ventricular septal defect (VSD), 353 ECG findings, 277, 278f natural history of, 319–323 antenatal, 320 classification, 319 postnatal, 320–323 types of , location, 319, 319f unnatural history, 323 unresolved issues-related to, 323, 323t Ventricular septal defect (VSD), with AR, 326–330 clinical presentation, 327–328 cardiac catheterization, 328 chest X-ray, 328 ECG, 328 echocardiogram, 328, 328f, 329f epidemiology, 326 history, 326 morphology, 327 natural history, 327 pathogenesis, 326–327 physiological effects, 327 treatment, 328–330, 330f Ventricular tachycardia (VT), 684–685f, 685 Ventriculoarterial (VA) connection, 403 Vereckei algorithm (VA), 690–691, 691f Veterans Affairs Cooperative trial, 11 VHD. See Valvular heart disease (VHD) Vicious inflammatory cycle, 49 Vierordt, Lord, 11 Vierordt’s sphygmograph, 12f Viral cardiomyopathy, 484 Viral myocarditis, 492 VSD. See Ventricular septal defect (VSD) VT. See Ventricular tachycardia (VT) VTE. See Venous thromboembolism (VTE)
W
Ventricular assist devices (VADs), 454
Watson pulse, 19
Ventricular dysfunction, 444
Waveforms, interpretation of
curable forms of, 481–488, 481t Ventricular functional errors, CHD echocardiography, 294–295 Ventricular pressure waveform, 729– 730
JVP and, 6, 6f, 7t Waves, JVP identification, 4–5, 5f correlation with clinical findings, 7
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regularity, assessment of, 685, 686– 687, 686f, 687f
X-ray. See Chest X-ray cyanotic heart disease with cardiomegaly, 381
types of, 684
cyanotic heart disease with relatively normal sized heart, 381
Wolff-Parkinson-White syndrome (preexcitation), 272–273, 272f Woods, Paul, 243
Index
tips for board examination, 6–7 Wellens’ syndrome, 700, 702–703f Wenckebach atrioventricular block, 700, 702f WHF criteria RHD diagnosis, 75b limitations of, 76–77 Wide pulse pressure, 18 Wide QRS tachycardia (WQT) definition of, 684 ECG assessment ventricular tachycardia, 684– 685f, 685 evaluation of, 687 morphologic analysis of, 688–691
World Heart Federation (WHF), 50, 74 WQT. See Wide QRS tachycardia (WQT)
Y ‘y’ descent, 7f, 9
X
rapid or sharp descent, 9 slow descent, 7f, 9
‘x’ descent, 7f, 8–9 ‘x’ descent wave, 7f, 8–9 attenuated/absent, 7f, 8–9
Z
increased depth of, 8–9
ZAHARA, 253–254
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