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Heart Rhythm Disorders: History, Mechanisms, and Management Perspectives [1st ed.]
9783030450656, 9783030450663

Author / Uploaded
J. Anthony Gomes

Table of contents :
Front Matter ....Pages i-xxiv
Front Matter ....Pages 1-1
Discovery of the Circulatory System (J. Anthony Gomes)....Pages 3-9
The Road to Unearthing the Conducting System of the Heart (J. Anthony Gomes)....Pages 11-19
Birth of Clinical Cardiac Electrophysiology (J. Anthony Gomes)....Pages 21-39
Molecular Basis of Impulse Generation and Propagation (J. Anthony Gomes)....Pages 41-47
The Concept of Entrainment (J. Anthony Gomes)....Pages 49-63
Front Matter ....Pages 65-65
Atrioventricular Nodal Reentry (J. Anthony Gomes)....Pages 67-77
Wolff–Parkinson–White Syndrome (J. Anthony Gomes)....Pages 79-91
Ablative Therapy of Bypass Tracts, AV Junction, and AV Nodal Reentrant Tachycardia (J. Anthony Gomes)....Pages 93-106
Atrial Tachycardia (J. Anthony Gomes)....Pages 107-127
Atrial Flutter (J. Anthony Gomes)....Pages 129-139
Atrial Fibrillation (J. Anthony Gomes)....Pages 141-168
Front Matter ....Pages 169-169
The Ventricular Premature Complex (J. Anthony Gomes)....Pages 171-178
The Substrate of Ventricular Tachycardia (J. Anthony Gomes)....Pages 179-188
Catheter Ablation of Ventricular Tachycardia (J. Anthony Gomes)....Pages 189-220
Ventricular Tachycardia Associated with Left Ventricular Assist Device (J. Anthony Gomes)....Pages 221-228
The Evolution of Coronary Intervention and Its Impact on Cardiac Arrhythmias (J. Anthony Gomes)....Pages 229-237
Front Matter ....Pages 239-239
Sudden Cardiac Death (J. Anthony Gomes)....Pages 241-253
Sudden Cardiac Death in Athletes (J. Anthony Gomes)....Pages 255-265
The Channelopathies and Sudden Death (J. Anthony Gomes)....Pages 267-289
Hypothermia Post-Cardiac Arrest (J. Anthony Gomes)....Pages 291-296
Defibrillation: A Historical Overview (J. Anthony Gomes)....Pages 297-302
Front Matter ....Pages 303-303
Antiarrhythmic Medications (J. Anthony Gomes)....Pages 305-333
Programmed Electrical Stimulation-Guided Pharmacotherapy (J. Anthony Gomes)....Pages 335-342
Front Matter ....Pages 343-343
The Implantable Defibrillator: A Historical Overview and its Use in Secondary and Primary Prevention (J. Anthony Gomes)....Pages 345-357
Uses, Overuses, and Problems Associated with the Implantable Defibrillator (J. Anthony Gomes)....Pages 359-373
Front Matter ....Pages 375-375
Noninvasive Risk Stratification for Sudden Cardiac Death (J. Anthony Gomes)....Pages 377-391
The Signal-Averaged ECG: Clinical Applications (J. Anthony Gomes)....Pages 393-407
Front Matter ....Pages 409-409
The Sick Sinus Syndrome (J. Anthony Gomes)....Pages 411-421
Heart Blocks (J. Anthony Gomes)....Pages 423-438
Neurocardiogenic Syncope (J. Anthony Gomes)....Pages 439-445
Front Matter ....Pages 447-447
The Artificial Pacemaker: A Historical Overview (J. Anthony Gomes)....Pages 449-460
The Evolution of Resynchronization Therapy (J. Anthony Gomes)....Pages 461-469
Front Matter ....Pages 471-471
Obesity and Atrial Fibrillation (J. Anthony Gomes)....Pages 473-478
Novel Devices for Stroke Prevention (J. Anthony Gomes)....Pages 479-484
Remote Heart Rhythm Monitoring (J. Anthony Gomes)....Pages 485-489
Back Matter ....Pages 491-496

Citation preview

J. Anthony Gomes

Heart Rhythm Disorders History, Mechanisms, and Management Perspectives

123

Heart Rhythm Disorders

J. Anthony Gomes

Heart Rhythm Disorders History, Mechanisms, and Management Perspectives

J. Anthony Gomes Icahn School of Medicine Mount Sinai Hospital New York, NY USA

ISBN 978-3-030-45065-6 ISBN 978-3-030-45066-3 (eBook) https://doi.org/10.1007/978-3-030-45066-3 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To my wife, Margarita Suren; and to the memory of Dr. Anthony N. Damato.

Foreword

This is a remarkably well balanced and beautifully written book with evocative photography of pioneers and their important contributions figurately represented in electrocardiographic/ electrophysiologic tracings. It also has a collection of excellent chapters taking the reader through the history of diagnosing and treating cardiac arrhythmias from ancient times to the present. It is written by a single author, who clearly devoted several years to the project, narrating history eloquently of what transpired in the past and the progress we have made in the management of cardiac arrhythmias. The book describes how in the first half of the twentieth century several investigators, using cardiac anatomy, animal experiments, and deductive reasoning to the surface electrocardiogram (ECG), contributed to the knowledge of cardiac impulse generation and conduction, construing hypotheses on mechanisms of arrhythmogenesis and heart block. Thereafter, in the second half of the twentieth century, the introduction of advanced diagnostic extra- and intracardiac techniques resulted in rapid evolution of our understanding of the physiology and pathophysiology of cardiac arrhythmias that in turn resulted in the development of several new modalities of treatment. An important moment, as discussed in Chap. 3, was the birth of clinical cardiac electrophysiology as a new subspecialty in Cardiovascular Medicine. I had the good fortune to be present at the start of that new era. It happened in Amsterdam in 1966. By positioning catheters inside the intact human heart for intracardiac pacing, a new method was born to study rhythm disturbances. That initiative came after Professor Dr. Dirk Durrer showed during epicardial mapping in a patient with the Wolff-Parkinson-White (WPW) ECG who required surgical closure of an atrial septal defect that the patient had an extra atrioventricular connection. It started the discussion in our group: If there are two pathways between the atrium and ventricle in WPW syndrome, can we create unidirectional block in one AV pathway followed by retrograde conduction over the anterogradely blocked pathway inducing the supraventricular tachycardia which is often present in WPW patients? For that, we needed catheters to pace inside the heart with a safe, reliable stimulator. Our first patient was a young woman suffering from frequent palpitations and we could show that it was possible to initiate and terminate her tachycardia by appropriately timed intracardiac stimuli during pacing. This new approach was called programmed electrical stimulation of the heart (PES). Of interest, at about the same time, independent from the ongoing work in Amsterdam, Dr. Philippe Coumel and coworkers in Paris reported on the use of programmed stimulation in a patient with a narrow QRS tachycardia. In 1969, another major milestone occurred. Drs. Benjamin Scherlag, Anthony N. Damato, Sun H. Lau, and associates, at the United States Public Health Service Hospital in Staten Island, New York, reported on a catheter technique to reproducibly record a His bundle electrogram. This was another seminal achievement, since it made it possible to localize the site of a conduction disturbance and to separate supraventricular from ventricular rhythms. Initially, programmed electrical stimulation together with His bundle recordings was used to localize the site of block and the origin of different types of arrhythmias and/or the tachycardia pathways. Undoubtedly, these studies resulted in a much better interpretation of the

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Foreword

12-lead ECG by correlating the new information from intracardiac studies with ECG changes and ushered the specialty of clinical cardiac electrophysiology. Thereafter, as scholarly discussed in the book, programmed electrical stimulation of the heart moved from an investigational tool to development of new therapies. The ability to localize the arrhythmia, to differentiate supraventricular from ventricular arrhythmias by recording activity from the His bundle and other structures from the cardiac conducting system, and to obtain insights into the mechanism of arrhythmias opened the door to surgical excision of the arrhythmia substrate or interruption of a critical part of the tachycardia circuit. Programmed electrical stimulation was also used for selecting antiarrhythmic drug therapy in the past, before the era of the internal defibrillator. Its role became clear in supraventricular tachycardias, but less so in ventricular arrhythmias. This was related to the observation that surviving Purkinje-muscle fibers in ventricular scar could potentially result in different tachycardia circuits with variable responses to antiarrhythmic drug therapy. Cooperation between cardiac electrophysiologists and industry resulted in the introduction of novel catheter systems, 3-dimentional mapping systems, and sophisticated pacing devices for brady- and tachycardias. An important and revolutionary development was Dr. Michel Mirowski’s introduction of the implantable defibrillator, a device capable of converting life-threatening ventricular arrhythmias to sinus rhythm regardless of the underlying mechanism. The saga of Michel Mirowski, his trials and tribulations during the development of the internal defibrillator, is effectively and elegantly described by the author. It was followed by catheter ablation of cardiac arrhythmias ranging from supraventricular tachycardias and atrial fibrillation to ventricular tachycardias using advanced imaging techniques and accurate cardiac 3- dimensional activation-propagation mapping. Another more recent development was resynchronization of abnormal ventricular activation by cardiac pacing in patients with heart failure, and the introduction of leadless pacemakers, and left atrial appendage occlusion devices. In this book, each of the different types of heart rhythm disorders has received a separate chapter as to their history, diagnosis, mechanism and treatment. Other chapters review our currently used diagnostic and therapeutic techniques always with a critical analysis of their value and limitations. The author also discusses the future of cardiac arrhythmia management. Despite the enormous advances made during the last 50 years most of our interventions are still palliative. They make the patient live longer with a better quality of life, but few offer a real cure, except in catheter ablation of the accessory pathway in patients with the WPW syndrome, and in most supraventricular tachycardias. We still have a long way to go to reach a cure and prevention of cardiac arrhythmias and sudden cardiac death. What will be the contribution of genetic information coupled with artificial intelligence to improve risk stratification and management? I want to close by congratulating and thanking Dr. Gomes for his unique review of the past, present and future of heart rhythm disorders. This is an important and uniquely well written book. It deserves a wide audience among the health professionals taking care of patients with cardiac arrhythmias.

Hein J. J. Wellens, MD Emeritus Professor of Cardiology, Maastricht University Maastricht, The Netherlands

Preface

For while knowledge defines all we currently know and understand, imagination points to all we might yet discover and create. — Albert Einstein

In 1967 and 1969, two monumental studies would change the course of heart rhythm disorders, ushering a new field in cardiovascular medicine, that of clinical cardiac electrophysiology. This book is about the diagnosis, mechanisms, and treatment of Heart Rhythm Disorders that plague the old as well as the young affecting their quality of life and often resulting in premature death. I have been fortunate to have lived to see and partake in the astronomical advances in cardiovascular medicine over the last five decades and, moreover, to have been at the birth of my specialty, of clinical cardiac electrophysiology. The contributions to the field of cardiac electrophysiology have come over several decades from a host of individuals often working independently in different institutions mostly in Europe and the United States, and from device and drug companies here and abroad. While in the past, the advancement in medical science was often the domain of pioneering individuals (The ECG—Willem Einthoven; Angioplasty— Andreas Roland Grüntzig; Internal Defibrillator— Michel Mirowski etc.), more recently, the developments have often come from pharmaceutical, technological, and device companies with physician collaboration. Moreover, the field has kept on advancing at a rapid pace in the basics and genetics of cardiac arrhythmias as well as in the introduction of novel catheters and mapping systems. During my teaching rounds to the Cardiology as well as Electrophysiology Fellows, I came to recognize their lack of knowledge as well as an unmitigated hunger for the history of cardiovascular medicine, including heart rhythm disorders, specifically, how the field started, the evolution of the specialty, and the contributions of several pioneers who made the field what it is today. This observation and my own profound interest in history prompted me not only to give a perspective of the diagnosis, mechanisms, and current treatment of Heart Rhythm Disorders in this book but also to write about its history. For in the words of Isaac Asimov: “There is not a discovery in science, however revolutionary, however sparkling with insight, that does not arise out of what went before.” “If I have seen further than other men,” said Isaac Newton, “it is because I have stood on the shoulders of giants.” And so, in my historical musings, I have tried my very best to abide by the standards of Miguel de Cervantes: “Historians ought to be precise, faithful and unprejudiced; and neither interest nor fear, hatred nor affection, should make them swerve from the way of the truth.” However, I’m cognizant of the fact that I might have erred at times and at other instances left out the contributions of some individuals inadvertently, and others I could not reach. To them I extend my sincere apologies and a depth of gratitude. New York, NY, USA

J. Anthony Gomes, MD

ix

Acknowledgments

I have many people to offer my gratitude. To begin with, I would like to thank Richard Lansing, Editorial Director for Clinical Medicine at Springer, for accepting my book proposal after a mere 4 days, and to Michael Griffin of Springer Nature for his editorial assistance. To my wife, Margarita, for her patience and encouragement as I spent endless hours on the computer researching and writing. I would like to express my most sincere appreciation to a host of clinicians and clinicianscientists for their overt enthusiasm for this book and for providing their photographs and electrocardiographic/electrophysiological tracings, their time, and effort, some more than others, in communicating their own contributions to the field of cardiac electrophysiology and those of their colleagues. These physicians include: Dr. Andre d’ Avilla; the late Dr. Masood Akhtar; Drs. Pedro Brugada, Srinivas Dukkipati, John D. Fisher, and John J. Gallagher; the late Dr. Mark Josephson; and Drs. Warren Jackman, Frank Marchlinski, Rahul Mehra, Robert Myerburg, Eric Prystowski, Carlo Papone, Pratap Reddy, Vivek Y. Reddy, Jeremy Ruskin, Benjamin Scherlag, Melvin N. Scheinman, Peter Schwartz, Nabil L. Sherif, William G. Stevenson, Hein J.J. Wellens, Albert Waldo, Stephen Winters, and Douglas P. Zipes. I am indebted to my electrophysiology colleagues at The Mount Sinai Medical Center and The Leona M. and Harry B. Helmsley Charitable Trust Center for Cardiac Electrophysiology, specifically to Drs. Subharao Choudhry, Srinivas Dukkipati, Jacob Koruth, Marc Miller, Vivek Y. Reddy, and William Whang, for providing me with some of the illustrations of cases done in our EP laboratories, as well as providing their precious time in reading and commenting on some of the chapters. Among these colleagues, a very special thanks to Dr. Marc Miller for a range of technical assistance while penning this book, and to Dr. William Whang for promptly reviewing some of the chapters. A note of appreciation to Dr. Umesh Gidwani for his comments on the chapter on Hypothermia. I would also like to recognize my ex-associates Drs. Marie Noelle Langan and Davendra Mehta, and the CT surgeons Drs. Arisan Ergin and Jorge Cammunas. Finally, I want to express my gratitude to the fulltime cardiovascular faculty at Mount Sinai Medical Center, specifically to Drs. Valentin Fuster, Samin K. Sharma, Jonathan L. Halperin, Annapoorna S. Kini, and Martin E. Goldman, as well as to the voluntary faculty for their trust in administering to their patients and their consistent support and friendship over the last 36 years.

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Contents

Part I The Enlightenment Period in Cardiovascular Dynamics 1 Discovery of the Circulatory System�� 3 Introduction�� 3 Egyptian View of the Heart�� 3 The Asian View: The Pulse�� 5 The Ancient Greek View of Circulation�� 5 Galen’s View of the Circulatory System�� 5 The Islamic View �� 5 Ibn al-Nafis and the Discovery of Pulmonary Circulation�� 6 Leonardo da Vinci’s View of the Heart�� 6 Contribution of Michael Servetus and Realdo Colombo �� 7 William Harvey and the Ultimate Discovery of Circulation of Blood�� 8 References�� 9 2 The Road to Unearthing the Conducting System of the Heart�� 11 Introduction�� 11 Jan Evangelista Purkyně and the Discovery of Purkinje Fibers�� 12 Wilhelm His Jr. and the Discovery of the His Bundle �� 12 The Contribution of Walter Gaskell �� 12 Sunao Tawara and the Discovery of the AV Node �� 13 Arthur Keith and Martin Flack and the Discovery of the Sinus Node�� 13 Modern Concepts of Impulse Generation and Transmission�� 13 References�� 17 3 Birth of Clinical Cardiac Electrophysiology �� 21 Introduction�� 21 The Electrocardiogram�� 21 Programmed Electrical Stimulation of the Heart�� 22 Recording of Intracardiac Electrical Activity: Dr. Benjamin Scherlag, PhD�� 22 The Anthony N. Damato School of Cardiac Electrophysiology�� 24 The Dutch School of Cardiac Electrophysiology�� 27 The Mushrooming of EPS Laboratories�� 28 The Heart Rhythm Society�� 28 References�� 30 4 Molecular Basis of Impulse Generation and Propagation �� 41 Introduction�� 41 The Action Potential�� 41 Sodium Channels �� 43 Voltage-Gated Calcium Channels�� 43 Voltage-Gated Potassium Channels �� 44 The Funny Current of the Sinus Node �� 45 xiii

xiv

Contents

Gap Junction Channels�� 46 Conclusions�� 46 References�� 46 5 The Concept of Entrainment�� 49 Introduction�� 49 Historical Perspectives�� 49 Criteria for Reentry�� 50 Criteria for Transient Entrainment [7] �� 51 Entrainment of Different Tachycardias�� 51 Atrioventricular Reentrant Tachycardia (AVRT) �� 51 Atrioventricular-Nodal Reentrant Tachycardia (AVNRT) �� 52 Atrial Flutter and Macro-reentrant Atrial Tachycardias�� 53 Ventricular Tachycardia �� 56 Post-pacing Interval After Entrainment �� 58 Stimulus to QRS Interval �� 60 Limitations of Entrainment Mapping�� 61 Conclusions�� 62 References�� 62 Part II Supraventricular Tachycardias 6 Atrioventricular Nodal Reentry �� 67 Introduction�� 67 Historical Perspective�� 67 Clinical Presentation�� 68 Mechanism of AV Nodal Reentry�� 68 Typical and Variants of AVNRT�� 70 The Case for and Against Dual Pathway Physiology�� 70 Evidence for Anatomic Slow and Fast Pathways in AVNRT�� 72 Unifying Concept in AVNRT�� 74 Management of AVNRT�� 75 Conclusions�� 76 References�� 76 7 Wolff–Parkinson–White Syndrome�� 79 Introduction�� 79 Historical Overview �� 79 Prevalence of WPW Syndrome�� 80 The Mechanism of the WPW Syndrome: Historical Background�� 80 Anatomic Structure of Accessory Pathways�� 82 Diseases Associated with the WPW Syndrome �� 82 Tachycardias Associated with the WPW Syndrome�� 83 Multiple and Less Common Accessory Pathways �� 83 Natural History of WPW Syndrome in Children and Adults�� 87 Risk Stratification in WPW Syndrome�� 88 Conclusions�� 90 References�� 90 8 Ablative Therapy of Bypass Tracts, AV Junction, and AV Nodal Reentrant Tachycardia�� 93 Introduction�� 93 Surgical Ablation�� 93 Historical Case Study�� 94 Catheter Ablation with DC Current �� 95

Contents

xv

Catheter Ablation with Radiofrequency Current �� 97 Catheter Ablation of Bypass Tracts�� 98 Catheter Ablation for AVNRT�� 101 Conclusions�� 104 References�� 105 9 Atrial Tachycardia �� 107 Introduction�� 107 Classification of Atrial Tachycardia �� 107 Focal Atrial Tachycardias: Pathophysiology and Mechanisms�� 108 Relationship Between Heart Failure, Atrial Tachycardia, and Atrial Fibrillation�� 109 Clinical Manifestations of Atrial Tachycardia �� 109 Differentiation Between Focal AT and Other Forms of PSVT�� 110 Specific Atrial Tachycardias�� 110 Inappropriate Sinus Tachycardia�� 110 Sinus Node Reentrant Tachycardia�� 112 Differentiation Between SNRT and Other Tachycardias of Similar Morphology �� 112 Other Focal Atrial Tachycardias�� 113 Atrial Tachycardia Arising from the Superior Vena Cava and Right Atrial Appendage�� 113 Crista Terminalis�� 114 Pulmonary Vein Tachycardias�� 122 Multifocal Atrial Tachycardia�� 123 Conclusions�� 124 References�� 125 10 Atrial Flutter�� 129 Introduction�� 129 Historical Overview �� 129 Epidemiology�� 130 Clinical Presentation�� 130 ECG Classification of AFL�� 131 Electrophysiological Classification�� 131 Right Atrial Isthmus-Dependent AFL�� 131 Non-isthmus-Dependent AFL�� 134 Scar AFL�� 134 Left Atrial Flutters�� 135 Rare Variety of AFL �� 135 Treatment of AFL�� 135 Ablative Therapy�� 137 Conclusion �� 137 References�� 137 11 Atrial Fibrillation�� 141 Introduction�� 142 Epidemiology�� 142 Symptomatology�� 142 Types of Atrial Fibrillation�� 142 Vagally Mediated AF �� 143 Risk Factors �� 143 Mechanisms: Paroxysmal AF�� 143 Persistent and Chronic AF �� 145 The Role of Gap Junctions in Atrial Remodeling in Persistent AF �� 145 Hereditary Factors in AF�� 146 Secondary Atrial Fibrillation�� 146

xvi

Contents

Hyperthyroidism-Associated AF �� 146 Postoperative AF�� 146 AF Associated with Mitral Valve Disease�� 147 Treatment of AF Associated with Mitral Valve Disease�� 147 Clinical Evaluation of Patients with AF�� 148 Treatment of Atrial Fibrillation�� 148 Stroke Prevention �� 148 Prior to Cardioversion�� 148 Long-Term Anticoagulation�� 148 Historical Case Study�� 149 The New Anticoagulants�� 150 Rhythm Control �� 150 Rate Control �� 151 Ablation: Historical Perspectives�� 152 Focal and Circumferential Pulmonary Vein Isolation�� 152 Atrial Substrate Modification�� 153 Other AF Ablative Methods �� 154 Novel Methods of AF Ablation: Identification and Ablation of Rotors�� 154 Complications of AF Ablation �� 157 Ablation Versus Antiarrhythmic Drug Therapy for Rhythm Control in PAF�� 158 Ablation Versus Antiarrhythmic Drug Therapy for AF in CHF�� 160 Historical Case Study�� 160 Novel Catheter Ablative Technology for AF Ablation�� 161 Conclusions�� 163 References�� 164 Part III Ventricular Arrhythmias 12 The Ventricular Premature Complex�� 171 Introduction�� 171 Historical Perspectives�� 171 Prevalence and Clinical Presentation �� 172 VPC-Induced Cardiomyopathy�� 173 The Common Types and Origins of VPC’s�� 173 Outflow Tract PVCs �� 174 Fascicular PVCs�� 174 Purkinje VPC �� 174 Treatment of VPCs�� 174 Catheter Ablation �� 175 Case Study �� 176 Conclusions�� 177 References�� 177 13 The Substrate of Ventricular Tachycardia�� 179 Introduction�� 179 Deciphering Mechanisms: A Historical Overview�� 179 Bundle Branch Reentry�� 180 Subendocardial Reentry in Remote Infarcts�� 181 Animal Models of Ischemic VT�� 182 Abnormal Automaticity and Triggered Activity�� 182 Surgical Approach to VT: Historical Perspectives �� 184 The Substrate of VT in Remote MIs�� 186 Conclusions�� 187 References�� 188

Contents

xvii

14 Catheter Ablation of Ventricular Tachycardia�� 189 Introduction�� 190 Clinical Manifestations of VT�� 190 Catheter Ablation: A Historical Perspective�� 191 The Identification of the VT Substrate and Response to DC Shocks�� 191 The Introduction of Radiofrequency Current for VT Ablation�� 192 Substrate-Based Ablation: Historical Perspectives�� 192 The Endocardial Catheter Ablation Procedure: General Principals�� 195 Substrate Mapping and Ablation�� 197 Hemodynamic Support During VT Ablation �� 198 Ablation of Focal (Purkinje) VT�� 198 Complications of Catheter Ablation�� 198 Epicardial Mapping and Ablation�� 199 Complications of Epicardial Ablation�� 200 Catheter Ablation of Scar-Related VT �� 200 Prophylactic Catheter Ablation to Prevent ICD Shocks�� 202 Map-Guided VT Ablation Versus Substrate Modification �� 202 Outcome of Catheter Ablation in Scar-Related VT �� 202 Ablation of VT in Other Structural Entities�� 204 Hypertrophic Cardiomyopathy (HOCM)�� 204 Catheter Ablation in Structurally Normal Hearts�� 209 Idiopathic Monomorphic VT �� 209 RVOT Tachycardia�� 209 LV Outflow Tract VT �� 209 Fascicular VT �� 209 Epicardial VT �� 210 Mitral Annulus VT �� 211 Brugada Syndrome�� 211 Alternate Methods of Ablation�� 212 Intramural VTs �� 212 Stereotactic Radioablation �� 213 Autonomic Modulation�� 213 Conclusions�� 213 References�� 214 15 Ventricular Tachycardia Associated with Left Ventricular Assist Device�� 221 Introduction�� 221 Incidence of Ventricular Arrhythmias�� 221 Proposed Mechanisms of Ventricular Arrhythmias�� 222 Outcome of LVAD Patients with VT/VF �� 222 The Impact of ICD in LVAD Patients�� 222 ICD Programming in LVAD Patients�� 222 The Impact of CRT-D in LVAD Patients�� 223 Management of Ventricular Arrhythmias�� 223 Case Study �� 223 Role of Catheter Ablation�� 224 Procedural Issues Related to the Ablative Procedure�� 226 Conclusions�� 226 References�� 226 16 The Evolution of Coronary Intervention and Its Impact on Cardiac Arrhythmias�� 229 Introduction�� 229 Historical Perspective on Coronary Intervention�� 229 The Birth of Interventional Cardiology �� 230

xviii

Contents

Cardiac Arrhythmias in Acute Coronary Syndromes�� 231 Post-intervention Arrhythmias �� 232 Prognostic Significance of Early Versus Late Ventricular Arrhythmias Post PCI �� 232 Arrhythmic Events Post-MI in Patients with Depressed Left Ventricular Function �� 233 Impact of Time to Reperfusion on Late Ventricular Arrhythmias�� 233 Management of Cardiac Arrhythmias During/Post PCI�� 234 Conclusions�� 234 References�� 235 Part IV Sudden Cardiac Death and Its Associations 17 Sudden Cardiac Death�� 241 Introduction�� 241 Epidemiology�� 242 The Pathophysiologic Substrate of SCD�� 243 The Population Spectrum of SCD�� 246 The Mechanism of the Terminal Event�� 247 EPS in Survivors of SCD �� 248 Preventive Strategies for SCD�� 249 Acute Treatment of SCD�� 250 Trends in Survival Post-Cardiac Arrest�� 250 Current Approach to the Treatment of Survivors of SCD�� 250 Conclusions�� 251 References�� 251 18 Sudden Cardiac Death in Athletes�� 255 Introduction�� 255 ECG and Echocardiographic Changes in Athletes�� 255 The Epidemiology of SCD in the Athlete�� 256 Athletic Activity and the Triggering of Sudden Cardiac Death �� 256 Heart Disease in Athletes Dying Suddenly�� 256 Differences in American Versus European Athletes�� 257 Common Causes of SCD in Athletes �� 257 Hypertrophic Cardiomyopathy (HCM)�� 257 Arrhythmogenic Right Ventricular Dysplasia (ARVD) �� 258 Genetics of ARVD �� 258 Clinical Presentation and Pathophysiology�� 259 Commotio Cordis�� 259 Anomalous Origin of Coronary Arteries and SCD�� 260 The Pre-screening of Competitive Athletes �� 261 Conclusions�� 263 References�� 263 19 The Channelopathies and Sudden Death�� 267 Introduction�� 268 The Long QT Syndrome: A Historical Overview�� 268 The Genetics of LQTS �� 271 Potassium-Related Abnormalities�� 271 Sodium-Related Abnormalities�� 271 Calcium-Related Abnormalities�� 271 The Timothy Syndrome �� 271 CALM1-3 (LQT14–16): Calmodulinopathy �� 271

Contents

xix

Triadin Knockout Syndrome: 18 TRDN (LQT17)�� 272 Clinical Manifestations�� 272 Genetic Testing in LQTS �� 272 Treatment of LQTS�� 273 Beta-Adrenergic Blockers�� 273 Left Cardiac Sympathetic Denervation (LCSD)�� 273 Implantable Cardioverter-Defibrillator (ICD)�� 273 Historical Case Study�� 273 Short QT Syndrome (SQTS)�� 274 Treatment �� 275 Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)�� 275 Historical Overview �� 275 Clinical Manifestations�� 275 Diagnosis�� 275 Role of Genetic Testing in CPVT�� 275 Treatment �� 276 The Brugada Syndrome �� 277 Historical Overview �� 277 Electrocardiographic Features �� 277 Genetics of BrS�� 279 Clinical Manifestations�� 279 Risk Stratification: Invasive �� 280 Risk Stratification: Noninvasive�� 280 Treatment Options�� 281 The J Wave Syndrome�� 281 Etiology and Mechanism of the J Wave Syndrome �� 282 Treatment �� 282 Idiopathic Ventricular Fibrillation�� 282 Genetics of IVF�� 283 Clinical Features, Evaluation, and Natural History �� 283 Management�� 284 Historical Case Study�� 284 Discussion�� 284 Conclusions�� 285 References�� 285 20 Hypothermia Post-Cardiac Arrest �� 291 Introduction�� 291 Historical Perspective�� 291 The Use of Hypothermia Post-Cardiac Arrest �� 292 Mechanisms of Neuroprotection�� 294 Temporal Trends in the Use of Therapeutic Hypothermia in the USA�� 294 Survival in Non-shockable and Inhospital Cardiac Arrest�� 295 Outcome Assessment �� 295 Conclusions�� 295 References�� 296 21 Defibrillation: A Historical Overview�� 297 Introduction�� 297 Defibrillation in the Twentieth Century �� 298 Defibrillation in the Soviet Union�� 299 Defibrillation in the US and Europe and its Ultimate Universal Appeal �� 300 Conclusions�� 301 References�� 301

xx

Part V Drug Therapy 22 Antiarrhythmic Medications�� 305 Introduction�� 306 Historical Overview �� 306 Classification of Antiarrhythmic Drugs �� 307 Class I Antiarrhythmic Drugs�� 307 Quinidine�� 311 Historical Overview �� 311 Electrophysiologic Effects �� 312 Clinical Use�� 312 Procainamide�� 313 Historical Overview �� 313 Clinical Use�� 313 Disopyramide�� 313 Lidocaine and Its Analog Mexiletine �� 313 Historical Overview �� 313 Electrophysiologic Effects �� 313 Clinical Uses�� 313 Flecainide and Propafenone�� 314 Historical Overview �� 314 Electrophysiologic Effects �� 314 Clinical Uses and Side Effects �� 314 Class II: The Beta-Blockers �� 316 Historical Overview �� 316 Electrophysiologic Effects �� 316 Role of Beta-Blockers in the Treatment of Cardiac Arrhythmias�� 316 Side Effects�� 316 Class III Antiarrhythmic Drugs�� 317 Amiodarone�� 317 Historical Overview �� 317 Electrophysiological Properties �� 318 Clinical Uses�� 318 Ibutilide�� 318 Electrophysiologic Effects �� 318 Clinical Use�� 318 Side Effects�� 318 Sotalol�� 318 Historical Overview �� 318 Hemodynamic Effects�� 319 Role in Cardiac Arrhythmias �� 319 Dofetilide �� 320 Electrophysiologic Effects �� 320 Clinical Efficacy in Arrhythmias�� 320 Side Effects�� 320 Dronedarone�� 321 Dronedarone for Rate Control in Atrial Fibrillation�� 322 Dronedarone in Congestive Heart Failure�� 322 Where Do We Stand on the Use of Dronedarone Today?�� 322 Class IV: Calcium Channel Blockers�� 322 Historical Overview �� 322 Other Drugs�� 323 Adenosine�� 323 Atropine �� 323

Contents

Contents

xxi

Digitalis Glycosides �� 324 General Principles in the Use of AADs �� 327 Conclusions�� 327 References�� 328 23 Programmed Electrical Stimulation-Guided Pharmacotherapy�� 335 Introduction�� 335 Historical Perspective�� 335 Limitations and Criticism of PVS�� 338 Inducibility and Reproducibility of Ventricular Arrhythmias�� 339 Comparison of the Three Methods�� 339 References�� 341 Part VI The Implantable Defibrillator 24 The Implantable Defibrillator: A Historical Overview and its Use in Secondary and Primary Prevention�� 345 Introduction�� 345 Historical Background �� 345 Development of the Implantable Defibrillator �� 346 The Subcutaneous ICD (S-ICD)�� 348 Secondary Prevention Trials of the Implantable Defibrillator �� 350 Prognosis of Patients After ICD Implantation for Secondary Prevention�� 353 Primary Prevention Trials of the Implantable Defibrillator �� 353 ICD in Primary Prevention in Chronic Ischemic Heart Disease�� 353 ICD for Primary Prevention in Patients with Recent Myocardial Infarction�� 355 ICD for Primary Prevention in Idiopathic Dilated Cardiomyopathy �� 355 ICD for Primary Prevention in Heart Failure�� 355 Conclusions�� 356 References�� 356 25 Uses, Overuses, and Problems Associated with the Implantable Defibrillator�� 359 Introduction�� 359 Recommendations for Secondary and Primary Prevention �� 359 Secondary Prevention: Ischemic Heart Disease�� 359 Primary Prevention�� 360 Non-ischemic Cardiomyopathy �� 360 Secondary Prevention�� 360 Primary Prevention�� 361 Channelopathies�� 361 Structurally Normal Hearts�� 361 Survival of Primary Prevention ICD Patients in Clinical Practice Versus Clinical Trials �� 362 Overuses of ICDs �� 362 Complications Associated with ICD Use�� 364 Risk Factors for Device Infections�� 365 Complications Associated with Device Replacements�� 365 Lead Fractures/Recalls�� 365 Inappropriate Shocks �� 367 Reduction in IAS and Mortality by ICD Programming�� 368 Complications Associated with S-ICD�� 371 Conclusions�� 372 References�� 372

xxii

Part VII Risk Stratification 26 Noninvasive Risk Stratification for Sudden Cardiac Death�� 377 Introduction�� 377 Risk Assessment in the Asymptomatic Population�� 378 Risk Assessment in Structural Heart Disease�� 379 Historical Elements in Risk Stratification in Ischemic Heart Disease�� 379 Historical Case Study�� 380 Dynamic Changes in Risk Evolution �� 381 The Value of Test Combination in Risk Stratification�� 382 The Role of the Ejection Fraction�� 385 Biochemical Markers in Risk Stratification�� 385 Cardiac Magnetic Resonance Imaging (CMR) in Risk Stratification�� 385 Genetic-Based Risk Stratification�� 386 Artificial Intelligence in Risk Stratification �� 386 Conclusions�� 386 References�� 386 27 The Signal-Averaged ECG: Clinical Applications�� 393 Introduction�� 393 Signal-Averaged ECG Measurements �� 394 SAECG in Infiltrative Heart Disease �� 395 Sarcoidosis �� 395 Chagas Disease�� 395 Amyloidosis �� 396 Other Infiltrative Diseases�� 396 SAECG in Right Ventricular Dysplasia �� 397 SAECG in the Evaluation of Syncope �� 398 SAECG in Tetralogy of Fallot�� 399 SAECG in the Brugada Syndrome�� 399 SAECG Post-Ablation of Ventricular Tachycardia�� 401 SAECG in Atrial Fibrillation �� 403 Conclusions�� 404 References�� 405 Part VIII Abnormal Slow Rhythms 28 The Sick Sinus Syndrome�� 411 Introduction�� 411 Sick Sinus Syndrome: Historical Aspects�� 412 Clinical Manifestations�� 412 Etiology of SSS�� 413 Pathophysiology and Natural History�� 413 Evaluation of Suspected SSS �� 416 Sinus Node Recovery Time�� 416 Sinoatrial Conduction Time �� 416 Direct Recording of Sinus Node Potentials in Man�� 417 The Role of Electrophysiologic Testing of Sinus Node Function �� 417 Treatment �� 418 Biologic Pacing�� 419 Conclusions�� 419 References�� 420 29 Heart Blocks �� 423 Introduction�� 423

Contents

Contents

xxiii

First-Degree AV Block�� 424 Second-Degree AV Block�� 424 Historical Overview �� 424 Causes of AV Blocks�� 427 The Bifascicular and the Trifascicular Concept�� 429 Historical Perspective�� 429 Bifascicular Blocks and Their Significance �� 430 The HV Interval in Bifascicular Blocks�� 430 Longitudinal Dissociation within the His Bundle�� 431 Paroxysmal AV Block�� 431 Trans-aortic Valve Replacement-Related AV Block�� 433 Predictors and Risk Stratification of Post-TAVR PPM Implantation�� 433 Clinical Presentation of AV Blocks�� 433 Clinical Evaluation of Patients with AV Block�� 433 Treatment �� 434 Conclusions�� 434 References�� 435 30 Neurocardiogenic Syncope�� 439 Introduction�� 439 Definition �� 439 Situational Syncope (Vasovagal)�� 440 Non-situational (Neurocardiogenic Syncope)�� 440 Mechanism of Neurocardiogenic Syncope�� 440 Diagnostic Investigation�� 441 Postural Orthostatic Tachycardia �� 442 Treatment �� 442 Conservative Management�� 442 Drug Treatment�� 443 Pacemaker�� 443 Treatment of POTS�� 443 Conclusion �� 443 References�� 444 Part IX Technological Advancements in Bradycardia and Heart Failure Management 31 The Artificial Pacemaker: A Historical Overview�� 449 Introduction�� 449 The First Pacemakers �� 449 The Hymanotor�� 450 Intracardiac Stimulation�� 451 The Transcutaneous Pacemaker �� 451 The Wearable Pacemaker �� 453 The First Implanted Pacemaker �� 455 The Divine Revelation �� 456 The Atomic Pacemaker�� 457 The Future of the Implantable Pacemaker �� 457 The Leadless Pacemaker�� 457 Types and Techniques�� 458 Clinical Data on Performance and Complications�� 458 Potential Clinical Uses�� 459 Induction Technology�� 459 Conclusions�� 459 References�� 459

xxiv

32 The Evolution of Resynchronization Therapy�� 461 Introduction�� 461 Historical Overview of Dyssynchrony and Resynchronization Therapy�� 461 Clinical Trials and Outcomes�� 462 Other Methods of Resynchronization Therapy�� 464 His Bundle Pacing�� 464 Epicardial and Endocardial Pacing�� 464 Left Bundle Pacing�� 465 Ultrasound-Mediated Energy Transfer�� 465 Conclusions�� 467 References�� 467 Part X New Frontiers in Heart Rhythm Disorders 33 Obesity and Atrial Fibrillation �� 473 Introduction�� 473 Association Between Obesity and AF�� 473 Mechanisms of Obesity-Related AF�� 474 Diastolic Dysfunction�� 474 Cardiac Fat Deposition and AF�� 474 Atrial Remodeling and Inflammatory Response�� 474 Obstructive Sleep Apnea�� 475 Long-Term Benefit of Goal-Directed Weight Loss in Atrial Fibrillation�� 475 Conclusions�� 477 References�� 477 34 Novel Devices for Stroke Prevention�� 479 Introduction�� 479 Watchman Device�� 480 Amplatzer Cardiac Plug and Amulet �� 482 Lariat Device�� 482 Cost Effectiveness�� 483 Conclusions�� 483 References�� 483 35 Remote Heart Rhythm Monitoring�� 485 Introduction�� 485 Historical Overview �� 485 Remote Monitoring of Patients with Pacemakers and Implantable Cardioverter- Defibrillators�� 486 Remote Monitoring and Its Effect on Survival�� 486 ECG Apps, iPhone, and IWatch �� 487 Conclusions�� 488 References�� 488 Index�� 491

Contents

Part I The Enlightenment Period in Cardiovascular Dynamics

1

Discovery of the Circulatory System

Contents Introduction

3

Egyptian View of the Heart

3

The Asian View: The Pulse

5

The Ancient Greek View of Circulation

5

Galen’s View of the Circulatory System

5

The Islamic View

5

Ibn al-Nafis and the Discovery of Pulmonary Circulation

6

Leonardo da Vinci’s View of the Heart

6

Contribution of Michael Servetus and Realdo Colombo

7

William Harvey and the Ultimate Discovery of Circulation of Blood

8

References

9

Introduction Since ancient times, the heart has been equated to a household divinity, a light of consciousness, the cosmic axis, and the source of life and that of the immortal soul. Throughout the Middle Ages, poets, kings, lords, and subjects alike had all romantically characterized the heart as the emblem of human emotions. Andrés Laguna de Segovia (1499–1559), a Spanish physician to popes and kings, as well as a pharmacologist and botanist, had written in 1535: “If indeed from the heart alone rise anger or passion, fear, terror, and sadness; if from it alone spring shame, delight, and joy, why should I say more?” [1]. If we ask someone what he or she associates with emotions, the heart springs to mind. We see it in the phrase “give your New York,” and in the heart to,” on bumper stickers as “I heart symbol on Valentine’s Day. The heart is our center—a “heart’s desire” is an innermost yearning. It is kindness. We say a cruel person “doesn’t have a heart.” It is compassion, as in “have a heart” and “heart of gold.” Milan Kundera wrote in The Unbearable Lightness of Being: “when the heart speaks, the

mind finds it indecent to object” [2]. It is commitment, courage, and love all together. The heart is immediate. It feels alive. And it all began with the Ancient Egyptians.

Egyptian View of the Heart For ancient Egyptians, the heart had paramount importance in earthly life and in death. It was the only organ left in the body after mummification. Why leave the heart? Why bother with mummification at all? In Egyptian mythology, death was not the end—the dead person’s soul would begin an extraordinary and dangerous journey through the underworld at the very end of which it would enter the Hall of Two Truths and come before the god Anubis. He’d weigh the person’s heart to see if it had become heavy with sin during life. If the heart weighed less than or equal to the feather of Ma’at—an ostrich feather symbolizing the goddess of truth, balance, and morality (Fig. 1.1), the person’s soul would then rejoin the body—in the mummy,

© Springer Nature Switzerland AG 2020 J. A. Gomes, Heart Rhythm Disorders, https://doi.org/10.1007/978-3-030-45066-3_1

3

4

Fig. 1.1 The weighing of the heart against the feather of Ma’at. Legend: The god Anubis proceeds to the weighing of the dead person’s heart against the feather of Ma’at—symbol of truth, on a balance.

1 Discovery of the Circulatory System

(Book of the Dead, circa 1250 BCE). (From: https://www.educationforlifeacademy.com/unit-1-7-maat/)

Fig. 1.2 The Ebers Papyrus. Legend: The Ebers Papyrus, also known as Papyrus Ebers, is an Egyptian medical papyrus dating to circa 1550 BC. It was purchased at Luxor, (Thebes) by Georg Ebers and is currently kept at the library of the University of Leipzig, in Germany. The papyrus is thought to have been copied from earlier texts, perhaps dating as far back as 3400 BC. It is a 110-page scroll and about 20 meters long and is among the oldest preserved medical documents. The papyrus contains a “treatise on the heart.” It notes that the heart is the center of the blood supply, with vessels attached for every member of the body

which had preserved it—and would enter Aaru—the heavenly paradise [3, 4]. But without the heart, paradise would be lost for eternity.

In their worldview, the heart, or ib, was actually part of the soul—the source of intelligence, as it was for the Mesopotamians and Babylonians. The Ebers Papyrus (Fig. 1.2) purchased by the German Egyptologist George

The Islamic View

5

Ebers in 1872 was discovered 10 years earlier between a mummy’s legs in a tomb at Thebes. It dates back to around 1550 BC, over a thousand years before Hippocrates, and it is one of the most important writings in ancient medicine [5– 7]. It is a 68-foot scroll, replete with archaic phrases and magic chants, but it also has a “treatise on the heart,” mentioning that the heart is the center of blood supply, with vessels attached for every member of the body. The ancient Egyptians had also linked the heart to the pulse. As is written in the Ebers Papyrus: “In the Heart are the vessels to the whole of the body. As to these, every physician, every sexet- priest, every magician, will feel them when he lays his finger on the head, on the back of the head, on the hands, on the stomach region, on the arms, on the legs. Everywhere he feels his Heart because its vessels run to all his limbs” [6, 7].

of all blood vessels. Thus, he reinforced the cardio-centric view of the soul advanced by the Egyptians [3]. However, the ancient Greeks would perpetuate erroneous ideas about the circulation of blood [11]. While Praxagoras of Kos (340 BC) was the first to differentiate between arteries and veins, theorizing that arteries begin in the heart, but like Erasistratus, he wrongly assumed that arteries carry pneuma (air), while veins originate in the liver and carry blood (Fig. 1.3a) [11]. The Stoic philosophers Zeno of Citium (331–262 BCE) and Chrysippus of Soli (277–204 BCE) viewed the soul as the unity of thoughts, feelings, and desires all governed by a single principle, the hegomonikon, located in the heart [3]. Hegomonikon is the source of our word “hegemony,” meaning dominance.

The Asian View: The Pulse

From Galen to Harvey, the scientific road to the discovery of the circulatory system was long and tedious [11]. It began with the Greek physician Aelius Galenus or Claudius Galenus, better known as Galen of Pergamum (129–c. 200/216 CE; Fig. 1.4a). He was a brilliant man, the surgeon to gladiators in Pergamum, on the Aegean coast of modern Turkey. At the age of 33 years, he came to Rome and was appointed physician to Emperor Marcus Aurelius. He challenged the concept that the heart was the seat of the soul held by the ancient Egyptians, Aristotle, and the Stoic philosophers. He proposed that it was the brain that was the seat of the soul and not the heart. However, his views on the circulation of blood were complex and misled physicians for centuries. He inherited a rather flawed knowledge base from the ancient Greeks on which to build his views. He perceived blood as moving outward in two separate systems (Fig. 1.3b). In one system, the liver turned food into the darker, venous blood, which flowed out to organs. Some of this blood he believed seeped through pores in the ventricular septum, where it mixed with air from the lungs giving it the brighter reddish color. In this second system, the arteries provided heat and motion to the rest of the body and “psychic spirits” to the brain. Galen also believed in the presence of tiny blood vessels he called rete mirabile (wonderful net) at the base of the brain, where “vital spirits” changed to “animal spirits” before going throughout the body.

As far back as 600 BCE, the Chinese physician Pien Ts’Io asserted the importance of the pulse both for the diagnosis and prognosis of disease [8]. He viewed the human body as a string instrument with a wide array of pulses corresponding to the different strings and their tones. Much later, Wang Shuhe (c. 180–c. 270 CE) wrote a highly influential treatise called The Pulse Classic [8]. In it, Wang described 24 kinds of pulses and linked the type of pulse to specific organs, which suggests that the Chinese physicians tried to diagnose diseases of other organs such as the liver by taking the pulse. The ancient Indian Ayurveda physician Sage Kanád (c. 550 BCE) wrote an important book on the pulse called Science of Sphygmica, where he says: “Immediately after pressing the pulse just below the hand-joint, firstly there is the perception of the beating of bdyu (air); secondly . . . there is the perception of pitta (bile); thirdly or the last, the perception of the beating of slesmd or kaph (phlegm), is gained.” As the quote indicates, he theorized that each pulse had three phases, and abnormality in any of them reflects disease in one of the three main humors of the body: air, bile, and phlegm [9, 10]. Perhaps most intriguingly, Ayurveda physicians also counted the pulse rate. They calculated it per “pal,” with each pal equaling 24 seconds. Like the ancient Chinese, the ancient Indians entirely focused on the pulse as the surrogate for other organs.

The Ancient Greek View of Circulation Hippocrates and his contemporaries believed that animals and humans need nourishment distributed from the intestines to all parts of the body rejecting the role of divine causation. They maintained that disruption of the nutritive process plays a key role in the causation of disease. Aristotle (circa 384–383 BCE) believed that the heart is the center of all physiological mechanism, the seat of the soul, and the source

Galen’s View of the Circulatory System

The Islamic View In his Canon of Medicine [12, 13], the Persian philosopher Abu ‘Ali al-Husayn ibn Sina better known in Europe by the Latinized name “Avicenna” (980–1037) integrated Aristotle’s ideas into his largely Galenic physiology (Fig. 1.4b). He wrote: “The heart is the root of all faculties and gives the faculties of nutrition, life, apprehension, and movement to several other members” [1]. His ideas prevailed like those of Galen in Medieval Europe [14].

6

1 Discovery of the Circulatory System

Erasistratus’s open-ended vascular system (Air in arteries)

a

Galen’s open-ended vascular system (Air and blood in arteries; pores in heart)

b

c

Waste Air

Colombo’s open and closed vascular system (Pulmonary circuit)

Harvey’s closed circulatory system (Blood in arteries)

d

Waste Air

Fig. 1.3 The circulatory system from the ancient Greeks to Harvey. Legend: Schematic of the cardiovascular system over time. (a) According to Erasistratus, arteries and veins are separate. Veins contain blood (blue color), while arteries contain air (white color). Food is taken up in the intestines by the portal veins, delivered to the liver (black color), transformed into blood, and then transported to the vena cava by way of the hepatic vein. From the vena cava, venous blood is delivered to all parts of the body. Some of the blood is diverted to the right ventricle (blue-colored chamber in the heart), from where it enters the pulmonary artery to nourish the lungs. Air is taken up in the lungs by the pulmonary veins, transferred to the left ventricle, and distributed to the tissues via the arteries. Fuliginous vapors (waste) are excreted by retrograde flow through the mitral valve and pulmonary vein. (b) Galen demonstrated that arteries normally contain blood (red color) and air. Arterial blood is derived from the passage of venous blood through invisible pores in the interventricular septum (shown as interrupted sep-

tal wall). (c) Colombo described the pulmonary circuit, in which venous blood in the right ventricle passes through the lungs into the left ventricle and arteries. However, Colombo maintained the ancient Greek view that blood flow in veins is centrifugal (away from the liver and toward all tissues), with only a small amount entering the right heart. Thus, Colombo’s system is a hybrid between closed (pulmonary) and open (systemic). (d) Harvey discovered that blood circulates not only in the lung but also around the whole body. An important clue was the presence of valves in the veins (two of them are shown in white). The liver is no longer the source of veins. Rather, the system is driven by the mechanics of the heart (now shown in black). Transfer of blood from arteries to veins in the lung and periphery may occur through direct connections or anastomoses (as shown) or through porosities in the flesh (the latter mechanism being favored by Harvey). (Reproduced with permission from Aird [11])

I bn al-Nafis and the Discovery of Pulmonary Circulation

Muhyo Al-Deen el Tatawi came across the manuscript in the Prussian State Library in Berlin in the course of writing his doctoral thesis for the medical faculty of Albert Ludwig’s University of Freiburg in Breisgau, Germany [15, 16]. Max Meyerhof, an eminent medical orientalist in Cairo, was made aware of the discovery and wrote a short commentary on Dr. Tatawi’s thesis to save it from oblivion. Meyerhof subsequently published German, French, and English translations of the relevant parts of the Commentary of Ibn al-Nafis [15].

A couple of centuries later, it was the Arab physician Ibn al- Nafis (1210–1288; Fig. 1.4c) who first challenged Galen’s and Avicenna’s concept of circulation. In his Commentary on Anatomy in Avicenna’s Canon, written at a young age of 29, he was the first to describe pulmonary circulation [15]. He wrote that blood flowed from the right half of the heart to the lungs and subsequently down to the left half. In addition, he held that in the lungs, blood passed through minute channels from veins to arteries and turned from dark to bright. Al-Nafis also maintained that Galen’s invisible pores in the ventricular septum did not exist. Not surprisingly, his views were largely ignored, and his Commentary was only made known to the Western world around the late 1920s, when a young Egyptian physician

Leonardo da Vinci’s View of the Heart The revival of anatomy during the Renaissance period made it possible to clarify basic structures of the heart. Leonardo da Vinci (1452–1519), who painted the Mona

Contribution of Michael Servetus and Realdo Colombo

7

NAME

ORIGIN

A

Aelius Glaenus or Caludius Galenus (129c-200/216)

Brain and not the Heart as seat of the soul CIRCULATION OF BLOOD

GREECE

B

Ibn Sina or Avicenna (930-1037)

CANNON OF MEDICINE The Heart is the root of all faculties

PERSIA

C

Ibn-Al Nafis (1210-1288)

Commentary on the Anatomy of Avicenna’s Cannon PULMONARY CIRCULATION

SYRIA (Damascus)

D

Michael Servetus (1509-1553)

Manuscript of Paris (1546) Christianismi Restituto PULMONARY CIRCULATION

SPAIN (Aragon)

E

Realdo Colombo (1515-1559)

De Re Anatomica PULMONARY CIRCULATION

ITALY (Rome)

F

Willam Harvey (1578-1657)

Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus 1628 On the Motion of the Heart and Blood in Living Being

ENGLAND

Fig. 1.4 Main contributors to the circulation of blood. Legend: The columns depicts the photos, the names of the main contributors of the discovery of the circulatory system, and their origins

Lisa, the Last Supper, Salvator Mundi, and many other masterpieces, was also an architect, an engineer, and a scientist with keen interest in human anatomy. Somewhere between 1504 and 1508, he began taking interest in the human heart. At that time, he met a very old man in the hospital of Santa Maria Nuova in Florence, who told him he was 100 years old and did not feel, in Leonardo’s own words, “any bodily ailment other than weakness.” While Leonardo was at his bedside, the centenarian suddenly died. It is then that Leonardo did something unheard of for a man with no medical background: He did an autopsy on the old man “and found that it proceeded from weakness through the failure of blood and of the artery that feeds the heart and the other lower members, which I found to be very dry, shrunken and withered” [17]. It is believed that he was the first to describe atherosclerosis of the aorta. His drawings illustrate the typical Renaissance image of the heart with two basic chambers, the ventricles, divided by the septum. He showed that the heart is a muscle and that it does not warm the blood as previously thought. He also attributed the pulse to the contraction of the left ventricle. He wrote: “the heart is a vessel made of thick muscle, vivified and nourished by artery and vein as are other muscles” [8]. He was the first to identify the atria as heart chambers. However, like everyone else in his time, Leonardo was a Galenist in his views on circulation of blood.

ontribution of Michael Servetus and Realdo C Colombo Centuries later, the Aragonese Michael Servetus (1509– 1553; Fig. 1.4d) [17] also independently identified pulmonary circulation, but his discovery, first written in the Manuscript of Paris (1546), did not reach the public. It was later incorporated into the theological work Christianismi Restitutio (Restoration of Christianity, 1553) [18], in which he rejected the doctrine of the Trinity and the concept of predestination, both of which were fundamental to Christianity since the time of St. Augustine and reemphasized by John Calvin in his magnum opus, Institutio Christianae Religionis. It also contained his views on pulmonary circulation [19]. However, there is no evidence that Servetus actually carried out his own experiments. Whether Servetus was aware of the Commentary on Anatomy in Avicenna’s Canon of Ibn al- Nafis is much debated; however, many historians believe that he was unaware [18] and credit both for the discovery of pulmonary circulation. Unfortunately, Servetus met a tragic and violent end. His views were considered heretical by both Catholics and Calvinists, and as a result he was burned at the stake on the plateau of Champel at the gates of Geneva. The book was suppressed, but Servetus had been in communication with many other scholars in Europe, and some of them knew of his ideas. Only three copies of the book survive today located

8

at the National Library of France, the Library of the University of Edinburgh, and the National Library of Vienna [18]. Later, the same ideas on pulmonary circulation were expressed by Realdo Colombo (1510–1559), the celebrated Paduan anatomist, and the Belgian anatomist Andreas Vesalius (1514–1564) [11, 18]. In 1539, Vesalius first described the veins that drew blood from the side of the body and opened the way to the study of the venous valves. Subsequently, Fabricius, an anatomist from Padua, published his work On the Valves In Veins in 1603 [20]. It is noteworthy that neither Realdo Colombo nor Andreas Vesalius made any reference to the work of Ibn al-Nafis or Servetus and probably were unaware of their contributions. It is important to point out that neither Servetus nor Realdo Colombo (Fig. 1.3c) overthrew Galenic doctrine entirely. Both maintained that only a small amount of the venous blood was diverted to the right heart and consequently to the left ventricle. Most of the blood remained in the vena cava and was distributed centrifugally to the periphery. In their view the pulmonary circuit replaced the septal pores as a means of transferring blood from the right to left ventricles.

illiam Harvey and the Ultimate Discovery W of Circulation of Blood Although the Arab physician Ibn Al-Nafis and the Aragonese Michael Servetus showed the crucial role of the lungs in circulation, it was ultimately the English physician William Harvey (1578–1657; Fig. 1.4e) who, with the use of dissection, comparative anatomy, and scientific methodology, disposed of Galenic circulation of blood entirely after more than 1400 years (Fig. 1.3d). He was born in Folkestone, England, and after graduating from Cambridge, he studied medicine at the University of Padua, in Italy, the most prominent medical school of the times. The curriculum included the study of Galen’s circulatory physiology and anatomy and that of Aristotle. At the medical school in Padua, Harvey studied under Fabricius, and it is possible that he saw a demonstration of the venous valves before its publication in 1603 [11]. Whether Harvey’s experimental approach to the study of circulation was influenced by Galileo who occupied the chair of mathematics remains debatable. After completing his medical studies in 1602, at the age of 24, he returned to England and obtained his doctorate in medicine from Cambridge University. He soon began his research on the heart of small animals including the slow-beating hearts of cold-blooded animals, such as fish, and warm-blooded animals during the process of dying at which time their heart’s contractions became slower and slower. He found the heart’s movements rather bewildering; but eventually, through sheer patience and

1 Discovery of the Circulatory System

meticulous observation, he felt his way around to describe the motions and function of the heart and blood vessels (Fig. 1.3d). Harvey emphasized that the heart’s function was to pump blood and clearly differentiated the contractions of the auricles from those of the ventricles, noting that the auricles contracted before the ventricles. This last observation was truly novel and monumental. He elaborated his findings in the landmark 1628 work written in Latin, Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus, published in 1628 [21]. The English translation appeared two decades later, entitled On the Motion of the Heart and Blood in Living Beings. In it, he described systole and diastole and refuted the Galenic concept of blood passage through interventricular septal pores. “The heart’s one role,” Harvey wrote, “is the transmission of the blood and its propulsion, by means of the arteries, to the extremities everywhere.” Yet, in his descriptions, he edified the lofty position of the heart and did not entirely challenge its metaphysical significance. He wrote: “The heart, consequently, is the beginning of life; the sun of the microcosm, even as the sun in his turn might well be designated the heart of the world; for it is the heart by whose virtue and pulse the blood is moved, perfected, and made nutrient, and is preserved from corruption and coagulation; it is the household divinity which, discharging its function, nourishes, cherishes, quickens.” William Harvey would marry the daughter of Queen Elizabeth’s physician in 1604, and in 1618 he was appointed royal physician to King James I and, later, King Charles I. His ideas on blood circulation came under heavy fire at first, since Galen’s influence towered above all else for several centuries [22]. This is not entirely surprising since in Medieval Europe, mysticism and religious beliefs played a legitimate role in scientific rationale carried out by unstructured investigation and theory often expounded by philosophers. Harvey expected that his views on circulation of blood would be rejected by some expressing his fears in the following passage in his book, where he wrote: “…not only do I fear danger to myself from the malice of a few, but I dread lest I have all men as enemies, so much does habit or doctrine once absorbed, driving deeply its roots, become second nature, and so much does reverence for antiquity influence all men.” Among his many critics was James Primrose who wrote a dissent to Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus arguing that Harvey’s doctrine was a “novelty” and only served to “destroy” traditional medicine [22]. It was the French mathematician and philosopher René Descartes (1596–1650) who was one of the first to accept Harvey’s novel views on circulation. He mentioned his approval in Discourse on Method (1637); however, he rejected Harvey’s notion of forceful systole declaring that “natural heat implanted by God in the heart” caused blood to vaporize

References

and expand, resulting in diastole [23]. The vaporization propelled the blood forward, “…causing all the branches of the arterial vein [pulmonary artery] and the grand artery [aorta] to swell almost at the same time as the heart. Immediately after, the heart deflates as do these arteries, because the blood that has entered them has grown cold” [23]. He also concluded that blood is ejected at the peak of ventricular diastole. It is noteworthy that these assumptions were entirely theoretical and lacked experimental proof [23]. Descartes also noted that Harvey had not explained the heartbeat. “What made the heartbeat?” he asked. “We imagine some faculty which causes the movement, the nature of which is much more difficult to conceive than what it is invoked to explain,” he wrote [24]. He believed that the heart had an innate heat, which made it to beat, but the answer to this question would lie a century ahead. Harvey’s observations on the heart and circulation of blood would become universally accepted after his death, and medical schools would begin to accept the practice of anatomical investigation [25].

References 1. A History of the Heart. https://web.stanford.edu/class/history13/ earlysciencelab/body/heartpages/heart.html 2. Kundera M. The unbearable lightness of being. English translation 1984 by Harper & Row Publishers, Inc. 3. Merlo L. The anatomic location of the soul from the heart, through the brain, to the whole body, and beyond: a journey through Western history, science and philosophy. Neurosurgery. 2009;65(4):633–43. 4. Uncredited. Egyptian mummies: exploring ancient lives. Arts Review. 21 Dec 2016. http://artsreview.com.au/egyptian-mummiesexploring-ancient-lives. 5. Papyrus E, Bryan CP, trans., Geoffrey Bles, London, 1930, pp. 129. https://web.archive.org/web/20130921055114/http://oilib.uchicago.edu/books/bryan_the_papyrus_ebers_1930.pdf 6. Saba MM, Ventura HO, Saleh M, Mehra MR. Ancient Egyptian medicine and the concept of heart failure. J Card Fail. 2006;12(6):416–21. 7. Mark JJ. Ancient Egyptian medical text. https://www.ancient.eu/ article/1015/ancient-egyptian-medical-texts/. 8. Wang Z’g. In: Peng C, editor. History and development of traditional Chinese medicine. Beijing: Science Press; 1999. p. 99.

9 9. Ramachandra Rao SK. The conception of Nadi and its examination. Anc Sci Life. 1985;4(3):148–52, p. 150. https://www.ncbi. nlm.nih.gov/pmc/articles/PMC3331513/pdf/ASL-4-148.pdf. 10. Ghasemzadeh N, Zafari AM. A brief journey into the history of the arterial pulse. Cardiol Res Pract. 2011;2011. https://www.hindawi. com/journals/crp/2011/164832/. 11. Aird WC. Discovery of the cardiovascular system: from Galen to William Harvey. J Thromb Haemost. 2011;9(1):118–29. https:// www.ncbi.1lm.nih.gov/pubmed/21781247. 12. Avicenna’s Canon of Medicine - Internet Archive. https://archive. org/stream/.../9670940-Canon-of-Medicine_djvu.txt. 13. Mahdi M, Gutas D, Abed SB, et al. Avicenna. Encyclopedia Iranica. London: Routledge and Kegan Paul; 1987. Volume 3. [Google Scholar]. 14. Tibi S. Al-Razi and Islamic medicine in the 9th century. 2005. The James Lind Library. 15. West JB. Ibn al-Nafis, the pulmonary circulation, and the Islamic Golden Age. J Appl Physiol. 1985;105(6):1877–80. https://www. ncbi.nlm.nih.gov/pmc/articles/PMC2612469/7. 16. el Tatawi MD. Der Lungenkreislauf nach el Koraschi. Wortlich Iibersetzt nach seinem Kommen-tar zum Teschrih Avicenna (Medical dissertation). Freiburg: University of Freiburg, Germany, 1924. 17. Boon B. Leonardo da Vinci on atherosclerosis and the function of the sinuses of Valsalva. Neth Heart J. 2009;17(12):496–9. 18. Stefanadis C, Karamanou M, Androutsos G. Michael Servetus (1511–1553) and the discovery of pulmonary circulation. Hell J Cardiol. 2009;50:373–8. http://www.hellenicjcardiol.org/archive/ full_text/2009/5/2009_5_373.pdf. 19. Servetus M. Christianismi Restitutio and other writings classics of medicine library; special ed edition; 1989. 20. Khan IA, Daya SK, Gowda RM. Evolution of the theory of circulation. Int J Cardiol. 2005;98(3):519–21. https://doi.org/10.1016/j. ijcard.2003.11.012. 21. Harvey, William. EXERCITATIO ANATOMICA DE MOTU CORDIS ET SANGUINIS IN ANIMALIBUS. With an English Translation and Annotations by Chauncey D. Leake. Tercentennial Edition. Published by Charles C. Thomas, Springfield, 1928. 22. Lubitz s a. Early reactions to Harvey’s circulation theory: the impact on medicine. The Mount Sinai J Med. 2004;71(4):274–80. 23. Descartes R. Discourse on method, and other writings. Wollaston A, translator. Baltimore: Penguin Books Inc.; 1960. 24. Petrescu L. Descartes on the heartbeat: the Leuven affair. Perspect Sci. 2013;21(4):400. http://www.mitpressjournals. org/doi/pdf/10.1162/OSC_a_00110. A History of the Heart. https:// web.stanford.edu/class/history13/earlysciencelab/body/heartpages/ heart.html. 25. Frank R. The image of Harvey in commonwealth and restoration England. In: Bylebyl J, editor. William Harvey and his age. Baltimore: The Johns Hopkins University Press; 1979. p. 103–44.

2

The Road to Unearthing the Conducting System of the Heart

Contents Introduction

11

Jan Evangelista Purkyně and the Discovery of Purkinje Fibers

12

Wilhelm His Jr. and the Discovery of the His Bundle

12

The Contribution of Walter Gaskell

12

Sunao Tawara and the Discovery of the AV Node

13

Arthur Keith and Martin Flack and the Discovery of the Sinus Node

13

Modern Concepts of Impulse Generation and Transmission

13

References

17

Introduction As mentioned in the previous chapter, the essence of the heartbeat remained a mystery for centuries. And so, the question that Descartes’ posed [1] still remained unanswered. William Harvey, in his description of the circulation of blood, did not explain the origin of the heartbeat. It was postulated that a pulsiac faculty accounted for the beating of the heart. In Descartes’ account, the bedrock of the explanation moved from a pulsiac faculty of the cardiac muscle to the innate heat within the heart itself [1]. Galen, having observed that an excised heart continued beating for some time after its removal, wrote: “The heart, removed from the thorax, can be seen to move for a considerable time… a definite indication that it does not need the nerves to perform its function” [2]. Leonardo da Vinci, who drew anatomic details of the organs of the body with a unique draftsmanship for the times said of the heartbeat: Del core. Questo si muove da se`, e non si ferma, se non eternalmente (“As to the heart: it moves itself, and doth never stop, except it be for eternity.”) [3]. Sometimes in the 1770s, the physician Luigi Galvani (1737–1798) [4] became interested in nerves. While experimenting, he was flabbergasted to see a frog’s muscles twitch

when touched with scissors during a thunderstorm. In yet another experiment, he accidentally touched a dead frog’s leg with a scalpel that had gained an electrical charge. There was a spark, and the leg kicked as if alive. He was the first to show that electricity passed through nerves to muscles, making them contract. And such ancient believes about “animal spirits” gave way to electrophysiology. However, the origin of the heartbeat and road to the heart’s conducting system remained a mystery. In De Generatione Animalium (1651), William Harvey [5] stated that “the pulse has its origin in the blood…the cardiac auricle from which the pulsation starts, is excited by the blood.” Likewise, irritability of the heart muscle by intracardiac blood was postulated by the German experimental physiologist, Albrecht von Haller, at the University of Göttingen [6], whereas Cesar Legallois in France, on the basis of crushed spinal cord experiments he performed in 1812, believed that the heartbeat had nervous origins [6]. Thus, it was held for several centuries that the heartbeat was triggered by inherent excitation of the heart muscle itself (myogenic theory) or was due to an electrical stimulus from the nervous system (neurogenic theory) [6]. Ultimately, the debate on the origin of the heartbeat was deciphered by anatomists and physiologists who discovered the site of origin of the electrical impulse and it’s conducting pathways.

© Springer Nature Switzerland AG 2020 J. A. Gomes, Heart Rhythm Disorders, https://doi.org/10.1007/978-3-030-45066-3_2

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Name

Photo

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1839

Purkinje fibers

1893

His bundle

Walter Gaskell English Physiologist (C)

1900

Trigger for heart beat in the upper right atrium

Sunao Tawara Japanese Pathologist (D)

1906

A-V node

1907

Sinus node

Jan Evangelista Purkyne Czech experimental physiologist (A) Wilhelm His Sr. Swiss Anatomist (B)

Arthur keith Scottish Anatomist and Anthropologist (E)

Fig. 2.1 The discoverers of the cardiac conducting system. (Legend: The name, photos of the discoverers, the date of discovery, and the discovery are shown in different columns)

J an Evangelista Purkyně and the Discovery of Purkinje Fibers The first advance toward unearthing the electrical system of the heart came from the Czech experimental physiologist, Jan Evangelista Purkyně (Fig. 2.1a), commonly known as Johannes Purkinje (“per-KIN-jee,” 1787–1869). In 1839, he described a mesh of gray, gelatin-like fibers in the ventricular subendocardium of the sheep heart. The fibers were composed of numerous corns with nuclei gathered tightly in a polyhedral form. Initially, Purkinje believed that they were cartilaginous fibers whose function he was unaware of; however, years later, he decided that they were muscular fibers [6]. Nonetheless, they carry his name: Purkinje fibers [6, 7]. They innervate the ventricles and carry electrical current to the cardiac muscle.

ventricle; however, in subsequent years, His found that the bundle communicated a single rhythm of contraction to all parts of the heart [9–12]. Following experiments on rabbits, he observed that when the bundle was severed it caused “asynchronie in the beat of the auricle and ventricle” [11]. Thus, he concluded that it was an “embryonic muscle bundle which united the auricles with the ventricles which transmits the auricular beat to the ventricles and when disturbed or interrupted causes heart block” [11]. He coined the term “heart block,” identifying it as the cause of AdamsStokes syncope [9, 14]. The bundle that His described came to carry his name: the bundle of His. It is undoubtedly a most important landmark structure that distinguishes rhythm disorders that arise in the upper chambers of the heart from those in the lower.

ilhelm His Jr. and the Discovery of the His W Bundle

The Contribution of Walter Gaskell

In 1893, the Swiss anatomist Wilhelm His Jr. (1863–1934; Fig. 2.1b) discovered a bundle of tissue leading away from the base of the atrium down into the septal wall at the University of Leipzig [8–13]. He was unable to conclude that the bundle transmitted impulses from the auricle to the

By the late nineteenth century, the search for the origin of the heartbeat had intensified. The Englishman Walter Gaskell (1847–1914; Fig. 2.1c) showed that the trigger for the cardiac impulse had to lie somewhere in the upper right atrium [15]. He also demonstrated that the electrical cur-

Modern Concepts of Impulse Generation and Transmission

rent paused (slowed) between the atrium and the ventricle. Furthermore, by tying off sections between the atria and ventricles, he found that he could create conduction block of varying degrees. Indeed, he was the first to claim that a special connecting tract had to exist between the atria and ventricles [15].

Sunao Tawara and the Discovery of the AV Node The delaying mechanism between the atria and the ventricles described by Gaskell was finally discovered by the pioneering Japanese pathologist Sunao Tawara (1873–1953; Fig. 2.1d) in 1906, at the Phillips University of Marburg, Germany [16]. Dr. Tawara traced the bundle of His up to the base of the atrium, where he located the atrioventricular node, usually called the AV node. When he published his findings, he also stated that the bundle of His could be part of a fast pathway conducting electricity to the Purkinje fibers and enabling the heartbeat.

rthur Keith and Martin Flack A and the Discovery of the Sinus Node Finally, the most important structure that sets the heartbeat was discovered by the Scottish anatomist and anthropologist Dr. Arthur Keith (Fig. 2.1e) together with his assistant Martin Flack, a medical student at Oxford University [17]. While Martin Flack was dissecting a mole’s heart in a makeshift laboratory in Keith’s study, he came across a “wonderful structure in the right atrium of the mole, just where the superior vena cava enters that chamber.” Keith and Flack named it the sino-auricular node, abbreviated to sinus node. In 1907, they wrote that “the dominating rhythm of the heart is believed to normally arise” in it. They had found the origin of the heartbeat. That the function of the sinus node was to initiate the cardiac impulse was demonstrated by Lewis and coworkers in 1910 [6]. It is obvious that the elements of the cardiac conduction system were discovered in a reverse order of impulse transmission generated in the sinus node (discovered 1907) and transmitted to the AV node (1906), then to the bundle of His (1893), and finally to the Purkinje network (1839). However, when carefully scrutinized, the role of the left and right bundle branches was reported by Tawara in 1906, 13 years after the discovery of the His bundle, and although Purkyně was the first to describe the Purkinje fibers, the unifying concept of impulse transmission is attributed to Tawara. He established the link between the AV node and the His bundle, the role of the left and right bundle branches and the fascicular system, and identified the Pirkinje system as the terminal ramifications of the conducting system.

13

In his monograph, The Conduction System of the Mammalian Heart, published in 1906 [18], Tawara also theorized about the velocity of the excitatory process in the conduction system and the mode of ventricular contraction.

odern Concepts of Impulse Generation M and Transmission The sinus node—or sinoatrial node or SA node—is the dominant pacemaker of the heart. It is referred as the “maestro” of the conducting system and what a maestro it is! It has its own intrinsic rate but is under the influence of the autonomic nervous system. While the sympathetic nervous system speeds up the heart rate and the force of muscle contraction, the parasympathetic slows it down. As a result, the heart reacts rapidly to fear, sexual, and other forms of excitement, increasing the sinus rate in an instant. On the other hand, the sinus node can slow down its rate when a person is at rest and during sleep. Long distance athletes and marathon runners have rates less than 60 beats per minute during the day, and resting heart rates in the 30s. The intrinsic rate of the sinus node can be measured after autonomic blockade, and the predicted intrinsic heart rate (IHR) can be calculated by the formula of Jose and Collision where: IHR = 118.1 – (0.57 × age) [19, 20]. The sinus node has a tripartite cellular population composed of pacemaker cells and conductor-like ordinary working myocardial cells [21–37]. The pacemaker cells that fire spontaneously number in the thousands and are highly resistant to damage and destruction. Studies of the rabbit heart, by Felix Bonke and those of Schuessler and Boineau in the canine experimental model [32, 33], as well as those of Gomes et al. [37] using direct sinus node recordings in the intact human heart [38, 39], have shown that the sinus node possesses dominant and subsidiary pacemaker cells with shifts from dominant to subsidiary sites. The dominant pacemaker cells have a resting potential of – 56 microvolts, a slow upstroke due to activation of the slow inward current and a larger Ca+ influx that keeps the diastolic potential at a low negative level. The dominant pacemaker cells are located at the superior aspect of the sinus node. On the other hand, the subsidiary pacemaker cells have a resting potential of – 80 microvolts, with different electrophysiological properties (slow and fast) and are located at the tail end of the sinus node. The latter can take control when the dominant cells fail or are suppressed by drugs or parasympathetic stimulation. The ionic basis for shifts includes discharge of acetyl choline with depression of slow inward current and increased membrane permeability to K+ resulting in an increase in extracellular K+ and inhibition of influx of Ca+. Sympathetic stimulation can shift the leading pacemaker site superiorly within the SAN resulting in an increase in heart rate [31], while parasympathetic stimulation can shift the pacemaker

14

2 The Road to Unearthing the Conducting System of the Heart CSM 1 2 1 HRA

A

A

A

640

A

700

A

1400

A

1000

A

940

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920

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720

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Fig. 2.2 Shift in sinus pacemaker complex during carotid sinus massage. (Legend: From top to bottom: L1, L2, V1, bipolar atrial and His bundle (HBE) recording, sinus electrogram (SNE) obtained by apposition of the catheter in the region of the sinus node and filtering at 0–25 Hz. Note that during carotid sinus massage (CSM), there is a pause with shift in primary negativity (arrow downward versus upward before the pause, implying shift in pacemaker complex). This is associ-

ated with a change in P wave morphology. Note that shift in pacemaker complex lasts for four beats and returns to the original dominant pacemaker site in the fifth beat with reappearance of primary negativity. Note the slower rate of the subsidiary sinus pacemaker relative to the dominant sinus pacemaker. (From Gomes and Winters [67], with permission)

to subsidiary sites with slowing of the sinus rate [30, 34, 37]. A shift in pacemaker complex in man following carotid sinus massage is shown in Fig. 2.2. Although shifts in sinus pacemaker complex occur infrequently spontaneously, they occurred after rapid atrial pacing in 63% of patients, following premature atrial stimulation at close coupling intervals in 56% and during carotid massage in 75% of patients studied during electrophysiologic studies [37]. Shifts were noted for one to six beats and returned to the original site within two to seven beats. The subsidiary pacemaker complex has a slower rate than the dominant pacemaker in man and could serve as an escape pacemaker within the sinus node. Conceptualization of shifts from the head end of the sinus node to the tail end is demonstrated in Fig. 2.3. Boineau and coworkers [40, 41] by studying the onset of epicardial excitation and potential distribution maps suggested a multicentric origin of the sinus pacemaker complex in the canine experimental model with three widely separated locations at the superior vena cava right atrial junction, whereas our studies [37] in man with direct sinus node recordings suggested an unicentric origin with constant shifts in pacemaker complex (Fig. 2.3). Recent optical mapping studies [42] in four isolated coronary- perfused preparations of the human sinus node found that it was electrically insulated from the rest of the atrial myocardium by connective tissue, fat, and coronary arteries, except for specific pathways. The sinus impulse originated in the middle of the sinus node, and then spread slowly (1–18 cm/s) and anisotropically to activate the atrium. After 82 ± 17 msec. conduction delay, the atrial myocardium was excited via superior, middle, and/or inferior sinoatrial conduction pathways (Fig. 2.4). Atrial excitation was initiated 9.4 ± 4.2 mm from the leading pacemaker site. Similar

to our observations in the intact human heart [37], they also found that atrial overdrive pacing resulted in shifts in sinus pacemaker complex. After activation of the right atrial myocardium, there is almost simultaneous left atrium activation through a special pathway known as the Bachman’s bundle, discovered in 1916 by Dr. Jean George Bachmann (1877–1959) [43]. From the right atrium, the electrical impulse spreads through internodal tracts to the AV node, where conduction slows down (Fig. 2.5). The AV node, like the sinus node, is unique in form and function, and like the sinus node, it is calcium channel dependent. The AV node has often been considered as a structure with a blunt posterior end. However, as far back as 1906, Sunao Tawara described posterior extensions of the node [44]. These posterior extensions have been confirmed by Anderson and Becker and coworkers as far back as 1975 [45, 46] and more recently [47]. In a series of 21 randomly selected and basically normal hearts, 20 of the 21 AV nodes had a rightward posterior extension from the compact part of the AV node, 13 of which had an additional leftward extension. The remaining heart had a leftward posterior extension. The leftward extension eventually disappeared within the central fibrous body at the site of the mitral valve annulus, whereas the rightward extension gradually merged with the atrial myocardium. These posterior extensions have gained considerable importance in the ablative therapy of atrioventricular nodal reentrant tachycardia (AVNRT). However, one of the major limitations of the studies of Inoue and Becker is that they did not study hearts with documented AVNRT, and therefore it remains uncertain whether the “slow pathway” is indeed a posterior extension or an anatomic variant in patients with AVNRT. Although, in the classical variety of

Modern Concepts of Impulse Generation and Transmission

15

Sne

Sne

1

2

3

1

2

A

A

A

P

P

P

3

Fig. 2.3 Schematic representation of sinus pacemaker shifts from dominant to subsidiary sites. (Legend: Shows a schematic rendering of the sinus node, and the position of a quadripolar catheter with 5 mm interelectrode spacing used for recording a sinus node electrogram and an atrial electrogram. The dominant sinus pacemaker originates in the head end of the sinus node (position 1). A shift to the tail end of the sinus node (position 3 is suggested by a loss of primary negativity (i.e., rapid negative deflection due to atrial activity shown as positive deflec-

tion in sinus nodal electrogram (SNE)) occurring after the sinus node potential. The presence of a sinus node potential with loss of primary negativity and slight change in P wave morphology suggests a change to position 2. Since this position is closer to position 1, the sinus node potential is preserved during the shift. While a shift to position 3 is associated with a loss of sinus nodal potential and loss of primary negativity. Abbreviations: A = atrial electrogram; P = P wave; Sne = sinus node potential. (Modified from Gomes and Winters [67])

AVNRT, the slow pathway (see Chap. 6), is used as the antegrade limb, it remains unclear whether the posterior extensions [39] are normally used for antegrade conduction. This however does not seem so. During incremental atrial pacing the impulse penetrates the AV node anteriorly (antegrade fast pathway) rather than posteriorly except in most patients with AVNRT at a critical pacing rate and at critical premature coupling intervals. After activation of the AV node, current races down the bundle of His to the right and left bundles (Fig. 2.5) which ultimately ramify into the fascicular system and the mesh of Purkinje fibers, which spreads the current into the ventricular muscle (Fig. 2.6). The bundle of His measures approximately 20 mm in length and up to 4 mm in diameter [48] and is encased in the central fibrous body (Fig. 2.5). It lies toward the left of the septum in the majority of individuals dividing at the junction of the membranous septum into the left and right bundle branches (Fig. 2.5). The right bundle emerges at an obtuse angle as a continuation of a rightward His [49] in the majority. It runs superficially in the right ventricular endocardium in its upper third up to the septal papillary muscle of the tricuspid valve and then courses deeper in the interventricular

septum. In its distal third it courses within the ventricular trabeculations [50] to the right ventricular wall in the moderator band. Rarely, the right bundle is either intramyocardial in its first two-thirds or subendocardial throughout its extent [51]. The left bundle is a broad fan-like structure that emerges beneath the non-coronary cusp of the aortic valve [49, 50] and gives rise to a thin anterior fascicle, a broader posterior fascicle, and in approximately 60 % of individuals the left median fascicle [52, 53] (see Chap. 29). There are variations in the proximal left bundle as well as its fascicular connections [54]. The anterior fascicle crosses the outflow tract to the anterolateral wall to the region of the anterolateral papillary muscle, while the posterior fascicle extends infero- posteriorly and inserts near the base of the posterior papillary muscle and the free wall. The median fascicle runs in the interventricular septum. The activation of the left ventricles occurs simultaneously at three endocardial sites: the anterior paraseptal wall just below the mitral valve, centrally on the left surface of the interventricular septum, and posterior paraseptal region. Right ventricular activation occurs 5–10 msec. later near the insertion of its anterior papillary muscle. The flow of current is endo-epicardial [55].

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2 The Road to Unearthing the Conducting System of the Heart

Fig. 2.4 Optical mapping of the perfused human sinus done showing origin of sinus pacemaker complex and activation of the right atrium. (Legend: Anatomic perspective of the human sinus node (SAN) preparation including anatomical location and atrial activation. The pink outline shows the sinus node; arteries are represented by blue lines; leading SAN pacemaker site is represented by a purple dot; and breakthrough sites represented by magenta dots. For further explanation, see text. (Modified from Fedorov et al. [42]))

The bundle branches progressively divide to form the mesh-like Purkinje network (Fig. 2.6), with a predilection for the papillary muscles and rather sparse distribution over the base of the ventricles [48]. Purkinje fibers innervate the subendocardium for approximately a third of the myocardial thickness [56–58]. Four to eight Purkinje cells constitute each of the muscular trabeculations that form a network within the left ventricular cavity and the Purkinje endocardial networks (Fig. 2.6) [58]. The His–Purkinje system is characterized by rapid conduction of 2.3 m/s, while conduction in the ventricular muscle is slower at 0.75 m/s. The rapid His–Purkinje conduction results in rapid activation of the myocardium resulting in synchronous contraction of the ventricles. Animal studies have identified Purkinje–ventricular myocyte junctions consisting of specialized transitional cells responsible for transmission of electrical signals to the ventricular myocardium [59]. In humans, however, there seems to be a direct connection between Purkinje tissue and ventricular cardiomyocytes (Fig. 2.6, bottom panel) [58]. The Purkinje-muscle junction has been proposed as the site of origin of triggered activity that leads to Purkinje-based ventricular arrhythmias [60–62]. It is important to recognize that the specialized conducting system of the human heart has the propensity (via a host of mechanisms such as reentry or automaticity) to fire spontaneously and to produce abnormal cardiac rhythms. In addi-

Panel A Memb.septum

Aorta

Panel B

LBB Vent. septum

LBB

Insulating sheath

RBB

PB RBB AVN CS

AVN

Fig. 2.5 Anatomic location of the AV node, the bundle of His, and bundle branches. Legend: (Panel A) Diagrammatic depiction of the atrioventricular junction in anatomical orientation, demonstrating the relationship of the penetrating bundle of His (PB) to the atrioventricular node (AVN), and its bifurcation into the left and right bundle branches (LBB and RBB, respectively) at the junction of the membranous and muscular ventricular septum. (Reprinted with permission from Ho and Ernst [69]) (Panel B) Illustration demonstrating the fibrous tissue (pur-

PB

ple) that invests the specialized conduction tissue (orange) as it emerges from the atrioventricular node (AVN). Note the thickness of the insulating sheath that surrounds the penetrating bundle of His (PB) and proximal bundle branches (LBB and RBB) as they emerge from the central fibrous body. From Tawara, Sunao. Provided courtesy of Mayo Clinic Libraries History of Medicine Collection. (Modified from [68]. Reprinted with permission))

References Fig. 2.6 The Purkinje network in the human heart. (Legend: Panel A: Scanning electron microscopic (SEM) images showing the luminal surface of the left ventricle of the human heart. T stands for muscular trabeculae; P for Purkinje element and M for muscle. Panel B shows light micrographs of the ventricular endocardial region impregnated with silver. Each Purkinje cell in the human is surrounded by a sheath. Bottom panel shows Purkinje network (P) and muscular trabeculae (T). Purkinje cells running in parallel within the trabeculae are continuous with a delicate network of polygonal or stellate cells ×120. (Modified from [58]))

17 Panel A

a

Panel B

c

c

tion to the normal conducting system that is insulated from the rest of the heart muscle, additional muscle bands and connections can exist and provide an alternate and additional pathway for conduction (see Chap. 7). These accessory pathways were originally described by the British physiologist, Stanley Kent, in 1913 [63, 64] and the French physician, Mahaim I, in 1938 [65]. Whether the accessory nodes described by Kent are reflective of the accessory pathways seen in the genesis of supraventricular tachycardia has been the source of much debate [66]; nonetheless, the presence of functional accessory pathways, as will be discussed later, is responsible for a host of tachyarrhythmias.

References 1. In Lucian Petrescu. Descartes on the heartbeat: the Leuven affair. Perspect Sci. 2013;21(4):400. http://www.mitpressjournals.org/doi/ pdf/10.1162/POSC_a_00110 2. Siegel RE. Galen’s system of physiology and medicine. New York: S. Karger; 1968. p. 45. 3. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol. 1993: (IF: 11.12). 4. Mary Bellis. Biography of Luigi Galvani. Developed theory of animal electricity. In Humanities history and culture. Jan 24 2018. 5. Aird WC. Discovery of the cardiovascular system: from Galen to William Harvey. J Thromb Haemost. 2011;9(1):118–29.

6. Silverman ME, Grove D, Upshaw CB Jr. Why does the heartbeat? The discovery of the electrical system of the heart. Circulation. 2006. 13;113(23):2775–81. 7. Mazura M, Kusa J, Purkinje JE. A passion for discovery. Tex Heart Inst J. 2018;45(1):23–6. 8. Roguin A. Wilhelm His Jr. (1863-1934)--the man behind the bundle. Heart Rhythm. 2006;3(4):480–3. 9. Bast TH, Gardner WD. Wilhelm His, Jr. and the bundle of His. J Hist Med Allied Sci. 1949;4:170–87. 10. His W Jr. The story of the atrioventricular bundle with remarks concerning embryonic heart activity. Klin Wschr. 1933;12:569–74; Bast TH, Gardner WD trans.: J Hist Med Allied Sci 1949; 4:319-333 11. His Jr. W. Die Tätigkeit des embryonalen herzens und deren bedeutung für die Lehre von der Hezebewegung beim Menschen. Arbeiten aus der medidizinischen Klinik zu Leipzig, 1893:14–49. Bast TH, Gardner WD trans. J Hist Med Allied Sci. 1949;4:289. 12. Fye WB. Disorders of the heartbeat: a historical overview from antiquity to the mid-20th century. Am J Cardiol. 1993;72:1055–70. 13. Wilhelm His Jr. (1863–1934). JAMA. 1964;187:453–54. 14. Hardewig A. Wilhelm His Jr., 1863–1934. Action of the embryonal heart. A case of Adams-Stokes disease with asynchronous beats of heart atrium and ventricle (heart block). Internist (Berl). 1969;10:87–91. 15. Silverman ME, Upshaw CB. Walter Gaskell and the understanding of atrioventricular conduction and block. J Am Coll Cardiol. 2002;39(10):1574–80. 16. Akiyama T, Tawara S. Discoverer of the atrioventricular conduction system of the heart. Cardiol J. 2010;17(4):428–33. 17. Silverman ME, Hollman A. Discovery of the sinus node by Keith and Flack: on the centennial of their 1907 publication. Heart. 2007;93:1184–7, p. 1185

18 18. Das TS. Reizleitungssystem des Säugetierherzens. Jena: Gustav Fischer; 1906. Google Scholar. 19. Jose AD. Effect of combined sympathetic and parasympathetic blockade on heart rate and cardiac function in man. Am J Cardiol. 1966;18:476. 20. Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res. 1970;4:160. 21. West TC. Ultramicroelectrode recordings from the cardiac pacemaker. J Pharmacol ExpTher. 1955;115:283–90. 22. Trautwein W, Uchizono K. Electronrnicroscopic and electrophysiologic study of the pacemaker in the sino-atrial node of the rabbit heart. Z Zellforsch Berlin. 1963;61:96–109. 23. Sarto T, Yamagishi S. Spread of excitation from the sinus node. Circ Res. 1965;16:423–30. 24. James TN, Sherf L, Fine G, Morales AR. Comparative ultrastructure of the sinus node in man and dog. Circulation. 1966;34:139–63. 25. Mason-Pevet M, Blecker WK, Mackaay AJC, Gross D, Bouman LN. Ultrastructural and functional aspects of the rabbit sinus node. In: FIM B, editor. The sinus node: structure. Function and clinical relevance. The Hague: Martinus Nijhoff Medical Division; 1978. p. 195–211. 26. Lewis T, Oppenheimer BS, Oppenheimer A. The site of origin of the mammalian heartbeat; the pacemaker in the dog. Heart. 1910;2:147–69. 27. Meek WJ, Eyster JAC. Experiments on the origin and propagation of the impulse of the heart. IV. The effect of vagal stimulation and cooling on the location of the pacemaker within the sino-auricular node. Am J Phys. 1914;3:368–83. 28. Lu HH, Lange G, Brooks MC. Factors controlling pacemaker action in cells of the sino-atrial node. Circ Res. 1965;17:460–71. 29. Lu HH. Shifts in pacemaker dominance within the sino-atrial region of the cat and rabbit heart resulting from increase in extracellular potassium. Circ Res. 1970;26:339–46. 30. Bowman LN, Gerlings ED, Biersteker PA, Bonke FIM. Pacemaker shift in the sino-atrial node during vagal stimulation. Pfluegers Arch. I968;302:255–67. 31. Toda N, Shemamoto K. The influence of sympathetic stimulation on transmembrane potentials in the S-A node. J Pharmacol Exp Ther. 1968;159:298–305. 32. Bonke FIM, Bouman LN, Van Rijn HE. Change of cardiac rhythm in the rabbit after an atrial premature beat. Circ Res. 1969;24:533–44. 33. Schuessler RB, Boineau JP, Bromberg BI. Origin of the sinus impulse. J Cardiovasc Electrophysiol. 1996;7:263–74. 34. Bouman LN. Mackaay AJC. Blecker WK. Becker AN. Pacemaker shifts in the sinus node: effects of vagal stimulation. temperature and reduction of extracellular calcium. In Ref. 5. In: Bonke FIM. ed. The Sinus Node: Structure. Function and Clinical Relevance The Hague: Martinus Nijhoff Medical Division; 1978. pp. 195–211. 35. Hariman RJ, Hoffman BF, Naylor RE. Electrical activity from the sinus node region in conscious dogs. Circ Res. 1978;47:775–91. 36. Hariman RJ, Hoffman SF. Effects of ouabain and vagal stimulation on sinus nodal function in conscious dogs. Circ Res. 1982;5:760–8. 37. Anthony Gomes J, Winters SL. The origins of the sinus pacemaker complex in man: demonstration of dominant and subsidiary foci. J Am Coll Cardiol. 1987;9:45–52. 38. Hariman RJ, Krongrad E, Boxer RA, Weiss HB, Steeg CN, Hoffman BF. Method for recording electrical activity of the sino-atrial node and automatic foci during cardiac catheterization. Am J Cardiol. 1980;45:755–x I. 39. Gomes JAC, Kang PS, El-Sherif N. The sinus node electrogram in patients with and without sick sinus syndrome: techniques and correlation between directly measured and indirectly estimated sinoatrial conduction time. Circulation. 1984;66:864–73. 40. Boineau JP, Schuessler RB, Mooney CR, et al. Multicentric origin of the atrial depolarization waves: the pacemaker complex. Relation

2 The Road to Unearthing the Conducting System of the Heart to dynamics of atrial conduction. P wave changes and heart rate control. Circulation. 1978;58:1036–4X. 41. Boineau JP, Miller CB, Schuessler RB, et al. Activation sequence and potential distribution maps demonstrating multicentric atrial impulse origin in dogs. Circ Res. 1984;54:332–47. 42. Fedorov VV, Glukhov AV, Chang R, et al. Optical mapping of the isolated coronary-perfused human sinus node. J Am Coll Cardiol. 2010;56:1386–94. 43. Hurst JW, Bachman JG. Profiles in cardiology. Clin Cardiol. 1987;10:135–6. 44. Tawara S. Das Reitzleitungssystem des Saugetierherzens: Eine anatomisch-histologische Studie u¨ber das Atrioventrikularbu¨ndel und die Purkinjeschen Fa¨den. Jena: Gustav Fischer; 1906. p. 135–6. 45. Anderson RH, Becker AE, Brechenmacher C, Davies MJ, Rossi L. The human atrioventricular junctional area: a morphological study of the A-V node and bundle. Eur J Cardiol. 1975;3:11–25. 46. Becker AE, Anderson RH. Morphology of the human atrioventricular junctional area. In: Wellens HJJ, Lie KI, Janse MJ, editors. The conduction system of the heart: structure, function, and clinical implications. Leiden: HE Stenfert Kroese BV; 1976. p. 263–86. 47. Inoue S, Becker AE. Posterior extensions of the human compact atrioventricular node a neglected anatomic feature of potential clinical significance. Circulation. 1998;97:188–93. 48. Waller BF, Gering LE, Branyas NA, et al. Anatomy, histology and pathology of the cardiac conducting system. Clin Cardiol. 1993;16(4):347–52. 49. Massing GK, James TN. Anatomic configuration of the his bundle and bundle branches in the human heart circulation. Circulation. 1976;53(4):609–21. 50. James TN, Sherf L, Urthaler F. Fine ultrastructure of the bundle- branches. Br Heart J. 1974;36(1):1–18. 51. Widran J, Lev M. The dissection of the atrioventricular node, bundle and bundle branches in the human heart. Circulation. 1951;4(6):863–7. 52. Demoulin JC, Kulbertus HE. Left hemiblocks revisited from the histological viewpoint. Am Heart J. 1973;86(5):712–3. 53. Kulbertus HE. Concept of left Hemiblocks revisited. A histological and experimental study. Adv Cardiol. 1975;14:126–35. 54. Demoulin JC, Kulbertus HE. Histopathological examination of concept of left hemiblock. Brtish Heart J. 1972;34(8):807–14. 55. Durrer D, van Dam RT, Freud GE, et al. Total excitation of the isolated human heart. Circulation. 1970;41(6):899–912. 56. Tawara S. Das reizleitungssystem des säugetierherzens Eine anatomisch-histologishe studie über das atrioventikularbündel and die purinkeschen fäden. Gustav Fischer: Jena; 1906. 57. Canale E, Fujiwara T, Campbell GR. The demonstration of close nerve-Purkinje fibre contacts in false tendons of sheep heart. Cell Tissue Res. 1983;230(1):105–11. 58. Ono N, Yamaguchu T, Ishikawa H, et al. Morphological varieties of the Purkinje fiber network in mammalian hearts as revealed by light and electron microscopy. Arch Histol Cytol. 2009;72(3):139–49. 59. Joyner RW, Ramza BM, Tan RC, et al. Effects of stimulation frequency on Purkinje-ventricular conduction. Ann N Y Acad Sci. 1990;591:38–50. 60. Berenfeld O, Jalife J. Purkinje-muscle reentry as a mechanism of polymorphic ventricular arrhythmias in a 3-dimentional model of the ventricles. Circ Res. 1998;82(10):1063–77. 61. Gilmour RF Jr, Evans JJ, Zipes DP. Purkinje-muscle coupling and endocardial response to hyperkalemia, hypoxia, and acidosis. Am J Phys. 1984;247(2 Pt 2):H303–11. 62. Li ZY, Wang YH, Maldonado C, Kupersmith J. Role of junctional zone cells between Purkinje fibers and ventricular muscle in arrhythmogenesis. Cardiovasc Res. 1994;28(8):1277–84. 63. Kent AF. Researches on the structure and function of the mammalian heart. J Physiol. 1893;14:i2–254.

References 64. Kent A. Observations on the auriculo-ventricular junction of the mammalian heart. Quart J Exp Physiol. 1913;7:193–5. 65. Mahaim I, Winston MR. Recherches d’anatomie compareé et de pathologie expérimentale sur les connexions hautes du faisceau de His-Tawara. Cardiologia. 1941;5:189–260. 66. Robert H, Anderson SYH, Gillette PC, Becker AE. Mahaim, Kent and abnormal atrioventricular conduction. Cardiovasc Res. 1996;31:480–91.

19 67. Gomes JAC, Winters S. The origins of the sinus node pacemaker complex in man: Demonstration of dominant and subsidiary foci. J Am Coll Cardiol. 1987;9:45–52. 68. Faisal F, Syed JJH, Lachman N, et al. J Interv Card Electrophysiol. 2014;39(1):45–56. 69. Ho SY, Ernst S. Anatomy for cardiac electrophysiologists: a practical handbook. Minneapolis: Cardiotext Publishing; 2012.

3

Birth of Clinical Cardiac Electrophysiology

Contents Introduction

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The Electrocardiogram

21

Programmed Electrical Stimulation of the Heart

22

Recording of Intracardiac Electrical Activity: Dr. Benjamin Scherlag, PhD

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The Anthony N. Damato School of Cardiac Electrophysiology

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The Dutch School of Cardiac Electrophysiology

27

The Mushrooming of EPS Laboratories

28

The Heart Rhythm Society

28

References

30

Introduction For most of human history, the heart was the essence of life—a divinity of the body, mind, and spirit, a light of consciousness that purloined man’s physical and spiritual existence. And yet, it would take centuries before an attempt would be made to record its electrical signals.

The Electrocardiogram The first recording of the cardiac electrical activity of the human heart was likely performed by Alexander Muirhead in 1869 [1]. He used a Thomson siphon recorder that had been designed to record transatlantic signals and was available at St. Bartholomew’s Hospital in London. But it was in 1887, that the British physiologist Augustus D. Waller (1856–1922) became interested in a novel device called a capillary electrometer to record the electrical activity of the heart. He was able to detect both depolarization and repolarization [2, 3]. His instrument was, arguably, the first electrocardiograph, but it was hard to use and yielded little detail. It is of interest that he himself was unimpressed by his achievement and in 1911 stated: “I do not imagine that electrocardiography is likely to find any extensive

use in the hospital. It can at most be of rare and occasional use to afford a record of some rare anomaly of cardiac action” [3]. In 1915, reminiscing the past, Waller stated that he had explored the very possibility of recording the electrical potential of the heart beat with a capillary electrometer: “… so, I dipped my right hand and left foot into a couple of basins of salt solution, which were connected with two poles of the electrometer and at once had the pleasure of seeing the mercury column pulsate with the pulsations of the heart” [4]. This demonstration was made at St. Mary’s laboratory in May of 1887 and witnessed by many physiologists—among them was Professor Einthoven of Leiden. According to some historians [5], however, the Dutch physician Willem Einthoven (1860–1927, Fig. 3.1) attended the First International Congress of Physiology in Basel, Switzerland, in 1889, and there, he saw Waller record electrical waves from the heart. The possibility of improving on recording cardiac electrical activity intrigued Einthoven. In the 1890s, he worked to improve the capillary electrometer but eventually gave up on it. He switched to the string galvanometer (Fig. 3.1b), and in 1901 he described a far more sensitive electrocardiogram (ECG) and ultimately labeled the ECG waves PQRST and later the U wave [5–7]. His electrocardiograph weighed 600 pounds. By 1906, by using the ECG, he described cardiac hypertrophy, heart

© Springer Nature Switzerland AG 2020 J. A. Gomes, Heart Rhythm Disorders, https://doi.org/10.1007/978-3-030-45066-3_3

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Fig. 3.1 Willem Einthoven and the string galvanometer. Legend: Panel A, Willem Einthoven. (Reprinted from Rivera-Ruiz et al. [5]). Panel B: Einthoven’s String Galvanometer. The string galvanometer was comprised of a thin, silver-coated quartz filament that passed between two electromagnets. An electric current passing through the filament produced a movement that projected a shadow, which was magnified and registered. It provided readings of higher quality than its precursor, the

capillary electrometer due to the thinness and minimal mass of the string and the ability to adjust tension to regulate sensitivity and response time. (Reprinted from Public Domain). Panel C: An early commercial ECG machine, built in 1911 by the Cambridge Scientific Instrument Company showing the manner in which the electrodes are attached to the patient. In this case, the hands and one foot are immersed in jars containing salt solution. (Reprinted from Public Domain)

block, atrial flutter, and premature beats. He was awarded the Nobel Prize in Medicine in 1924 [8]. Waller and Einthoven should stand side by side in the historical annals of electrocardiography and, if Waller was alive, perhaps share the Nobel Prize. Howard Burchell on a centennial note on Waller pointed out that although the two men were alike in their manifold contributions to cardiovascular medicine, they were quite different in many ways. “Waller a physiologist, a dedicated teacher and popular lecturer, with his laboratory in a hospital-based school, was apparently not greatly interested in his application of his discovery to the sick, whereas Einthoven, although a physician, more of a physicist, with a university-based laboratory over a mile from a hospital was intensively interested. Waller in his lectures was informal, fond of metaphors and folksy, and in his records apparently content with technical mediocrity. In contrast Einthoven, in his lectures was formal and methodical; in his records demanding of technical perfection” [4]. An early commercial ECG machine, built in 1911 by the Cambridge Scientific Instrument Company, is shown in Fig. 3.1c. The first ECG machine in the USA—the Edelman String Electrocardiograph was introduced in 1909 by Dr. Alfred Cohn, at the Mount Sinai Hospital in New York City [9]. The first portable ECG machine was developed by the Japanese physician Taro Takemi (1904–1983) in 1937 [10].

Sones in 1958 [11] at the Cleveland Clinic through a stroke of serendipity, no such development had occurred in recording intracardiac electrical activity of the intact human heart. Undoubtedly, the ECG had revolutionized cardiology, and it remained a vital tool; yet, it couldn’t record information from discrete sections of the conducting system, and by the 1960s, physicians often considered ideas based on its data to be conjecture or hypothesis. Nonetheless, by deductive analysis of the ECG, brilliant minds—that of Drs. Pick, Langendorf, and Katz and Scherf and Schott [12–14]—theorized on the origins and possible mechanisms of heart rhythm abnormalities. Finally, after almost 60 years following the invention of the ECG, a major breakthrough occurred in 1967. Two European groups, one in Holland led by Drs. Dirk Durrer and his associates, Leo Schoo, Reinier Schuilenburg, and Hein J.J. Wellens [15] and the other in France led by Drs. Phillipe Coumel, Christian Cabrol, Alexandre Fabiato, and their associates [16], reported almost simultaneously and independently that they had started and stopped cardiac rhythm disorders in patients by introducing premature beats through a catheter in the right atrium. For the first time, they could induce and terminate the rather elusive, sporadic rhythm abnormalities in the laboratory. This was a key undertaking that would enable assessment of the mechanism of tachycardias and the effects of medications and other treatment modalities.

rogrammed Electrical Stimulation P of the Heart While diagnostic cardiac catheterization was introduced by André Cournand and Dickinson Richards in the early 1940s, and selective coronary angiography was performed by Mason

ecording of Intracardiac Electrical Activity: R Dr. Benjamin Scherlag, PhD In questions of science, the authority of a thousand is not worth the humble reasoning of a single individual. — Galileo Galilei

Recording of Intracardiac Electrical Activity: Dr. Benjamin Scherlag, PhD

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Fig. 3.2 Dr. Benjamin Scherlag and His bundle recording in man. Legend: Panel A, photograph of Dr. Benjamin Scherlag. (Courtesy of Dr. Benjamin Scherlag); Panel B, chest X-Ray showing an anteroposterior view of a multipolar catheter across the tricuspid valve for His

bundle recording. Panel C shows an ECG lead and bipolar recordings from the various poles of the catheter. The lower two show a His spike (H) sandwiched between a P wave from the atria and a QRS wave from the ventricles. (Modified with permission from [23])

In 1965, Dr. Benjamin Scherlag (Fig. 3.2) was working in the laboratory of Dr. Brian Hoffman (1925–2013) in the Department of Pharmacology of Columbia University. He was assigned to create heart block in the anesthetized dog. He focused on the His bundle, a rather challenging target. The bundle is about 1.5 mm across or 1/17 of an inch. Recording its electrical activity at the time seemed an insurmountable task. However, in 1960, Giraud, Peuch, and Latour [17] in France had accidentally recorded activity from the His bundle during cardiac catheterization of a patient with an atrial septal defect. After many trials and errors, Scherlag finally developed a procedure for injecting formaldehyde through the atrial wall into the His bundle in the dog. Using this method, he achieved AV block. After finishing his postdoctoral training, Scherlag joined Dr. Anthony N. Damato at the Staten Island Public Health Service Hospital (part of the US Public Health Service, or USPHS, system). Dr. Damato set up an experimental laboratory in a short time, complete with a catheterization table, an X-ray fluoroscopic unit, a recorder, and a stimulator. It was here that Scherlag improved his technique using two Teflon-coated steel wires 0.007 inches in diameter to impale the His bundle with a needle and obtain its electrical signal. “With some time and practice,” he wrote, “the technique soon became a relatively easy procedure.” He and his associates published these studies in 1967 [18]. In 1968, Drs. Bernard Kosowski, Benjamin Scherlag, and Anthony N. Damato demonstrated that the hemodynamic and coronary flow response to His bundle pacing were significantly more efficacious than pacing from the right ventricular apex [19]. A few years later, I used this very technique in the same dog lab to study the effects of digitalis on the dog’s His–Purkinje system, which had not been determined previously and which was impossible to determine without His pacing and His extrastimulation in view of digitalis prolongation of AV nodal conduction and refractoriness [20]. It is of interest that it took more than three decades for His bundle pacing to reach the clinic [21].

In the meantime, Scherlag continued his experimental work in the canine using an 8-pole, 12 Fr. electrode catheter left by Dr. John Lister who had by then moved to Miami, Florida. Because of the stiffness of the catheter it could only be deployed from the jugular vein to be anchored in the right ventricular apex. Thus, the limited movement did not provide consistent recording from specialized tissues, i.e., the His bundle and right bundle. Instead, Scherlag used a 2–3 Fr. electrode catheter with one or two bi-poles that could be bent into a J-shape and introduced via the femoral vein and placed across the tricuspid valve to consistently record His bundle activity in the dog heart [22]. Subsequently, Scherlag’s clinician scientist coworkers at the USPHS Cardiopulmonary Laboratory, were anxious to move on to human studies. Drs. Scherlag and Sun H. Lau, an associate of Dr. Anthony N. Damato, were the first to attempt His bundle recording in a patient with the Wolff-Parkinson-White (WPW) Syndrome. They introduced the catheter through the antecubital vein in the upper arm but failed. However, recording a His bundle deflection in a patient with WPW syndrome could have been a difficult task since depending upon the degree of pre-excitation, the His bundle activation could have occurred within the ventricular electrogram and consequently invisible. They subsequently used the femoral vein in the groin and succeeded, since this approach allowed better positioning of the catheter in the His bundle region, just across the tricuspid valve. In 1969, Dr. Scherlag, together with Drs. Lau, Helfant, Berkowitz, Stein, and Damato, submitted the manuscript of the novel technique (Fig. 3.2, panels B and C) to Circulation. The reviewers were harsh, criticizing the paucity of patients studied and frankly expressing disbelief in the accomplishment. Dr. Howard Burchell, the then chief editor of Circulation, apologized for such remarks and said he would publish the paper. He added that it would become a “standard reference,” and it did for years to come [23]. Undoubtedly, the recording of electrical activity of the bundle of His was a seminal achievement in cardiovascular medicine, since for the first time it was possible to systemati-

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Fig. 3.3 Dr. Anthony and Damato and recordings from the human conducting system. Legend: Panel A, Photo of Dr. Anthony N. Damato. (Courtesy of the Heart Rhythm Society). Panel B: From top to bottom, ECG lead and recording of the specialized conducting system from three sites labeled as HBE with the simultaneous recordings of AV

nodal (N), His bundle (H), and right bundle-branch (RB) potentials recorded in a patient with Left Bundle Branch Block using a tripolar electrode catheter. A = atrial electrogram, V = ventricular electrogram. ECG-lead 2 of standard electrocardiogram. (Modified with permission from [187])

cally explore the conducting system of the human heart from inside its chambers without surgery. Soon thereafter, Damato AN (Fig. 3.3a) and associates reported on the recording of specialized conducting fibers, namely, the AV node, His bundle, and right bundle branch in man [24] (Fig. 3.3b). Intracardiac recording of electrical activity of the human conducting system was akin to the discovery of cardiac catheterization and coronary angiography. As soon as the Staten Island group discovered the ease of recording His bundle activity, several studies were launched to determine the conduction characteristics of the AV node and His–Purkinje–myocardial system [25]. Soon after, Dr. Scherlag moved to Miami to join Dr. Philip Samet’s group, where Dr. Onkar Narula was already performing His bundle studies and with Dr. Scherlag as coworker, published several seminal studies including the first report of His bundle pacing in man [26]. Subsequently, Dr. Anthony Damato and Dr. Sun Lau spearheaded all research activities in the Electrophysiology Lab at the USPHS hospital.

system and heart rhythm disorders that ultimately translated into the creation of a new specialty for the benefit of patient care. Dr. Melvin Scheinman, described him as “a brilliant mind and a wonderful mentor,” an assessment most of my colleagues and I wholeheartedly shared. He joins the ranks of basic and clinical electrophysiology luminaries of those times that include Drs. Dirk Durrer (Fig. 3.4) [27–73] of the Netherlands; Dr. Phillipe Coumel of France, (Fig. 3.5) who made substantial contributions to clinical cardiac electrophysiology [74–90] and the basic scientists Drs. Brian F. Hoffman (Fig. 3.6) [91–132] of Columbia University, New York; and Gordon K. Moe (Fig. 3.7) [133–160] of The Masonic Medical Research Laboratory, Uttica, New York. Some of their important contributions in clinical and basic electrophysiology are depicted in corresponding illustrations. These extraordinary individuals not only trained a whole generation of young Fellows in basic and clinical electrophysiology but also inculcated a sense of excitement to expand the frontier they had opened up. In addition to Scherlag, Lister, Helfant, Berkowitz, and Stein, there were more than 40 others that trained and worked at the USPHS Electrophysiology Laboratories for a variable period of time from the 1960s to 1970s. These include Drs. Akhtar M, Batsford W, Bobb G, Cohen S, Cannom D, Caracta A, Calon AH, Carambas C, Chen CM, Ellizari M, Foster J, Gallagher J, Goldrayer B, Gomes JA, Haft JI, Hariman R, Josephson M, Kosowsky B, Lisi K, Kline L, Mirowski M, Matthews L, Nau G, Przybyla A, Pauley K, Patton R, Patton E, Russo G, Ricciutti MA, Rosen K, Reddy P, Ruskin J, Rubenson D, Steiner C,

he Anthony N. Damato School of Cardiac T Electrophysiology The delicate balance of mentoring someone is not creating them in your own image but giving them the opportunity to create themselves. — Steven Spielberg

Dr. Anthony N. Damato, (Fig. 3.3a) together with Dr. Sun H. Lau, created a continuum of excellence in research of the physiology and pathophysiology of the human conducting

The Anthony N. Damato School of Cardiac Electrophysiology

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5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100

Fig. 3.4 Dr. Dirk Durrer and total excitation of the intact human heart. Legend: Panel A, Dr. Dirk Durrer. (Courtesy of Dr. Hein J.J. Wellens). Panel B: three-dimensional isochronal activation map of the human

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Fig. 3.5 Philippe Coumel and catecholaminergic polymorphic VT. Legend: Panel A, photo of Dr. Philippe Coumel. (Reprinted with permission from [359]). Panel B: ECG monitoring during a stress test (continuous strips). After acceleration of the sinus rate, monomorphic ventricular premature beats appear in bigeminal pattern. Supraventricular tachycardia (atrial fibrillation and junctional tachycardia) with narrow QRS complexes are then recorded interfering with multiform ventricular premature beats and bidirectional ven-

heart. Inset shows section levels. Color scheme shows activation pattern from endocardium to epicardium. (Reprinted with permission from [41])

c

tricular tachycardia. At the end of the exercise, the arrhythmia disappears in the reverse order. Panel C: Holter recording during syncope showing a polymorphic ventricular tachycardia, ventricular fibrillation-like, with a spontaneous conversion with transient sinoatrial block with post-pause repolarization changes and then a sinus tachycardia, polymorphic ventricular premature beats, and another episode of polymorphic ventricular tachycardia (30 seconds). (Reprinted with permission from [85])

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Fig. 3.6 Dr. Brian f. Hoffman and the genesis of cardiac arrhythmias. Legend: Panel A, Dr. Brian Hoffman. (Reprinted from https://www. downstate.edu/sesquicentennial/biographies_table.html.). Panel B: Triggered activity in preparations of infarct zone Purkinje fibers. Voltage calibrations are at the left of each panel; time calibration below

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each panel at right. Top and middle panels show onset of sustained rhythmic activity. Bottom panel shows termination of rhythm with single early diastolic extrastimulus (arrow). (Reprinted with permission from [125])

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Fig. 3.7 Dr. Gordon Moe and computer modeling of atrial fibrillation. Legend: Panel A, Dr. Gordon K. Moe. (Reprinted from: https://www. google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=2a hUKEwjIq-m4qoDmAhXMs1kKHRw5BdUQFjAAegQIAhAB&url=

https%3A%2F%2Fcardiaceps.org%2Fgordon-kmoe&usg=AOvVaw2XHCHtiD-uEmINgSv4kET4). Panel B: Bottom panel, computer model of atrial fibrillation showing different wavefronts. (Reproduced with permission from [140])

Schnitzler R, Seides S, Scheinman M, Ticzon A, Varghese J, Vargas G, Vivona V, Weiss M, Westura EE, Wit A, and Weisfogal G. Some of these electrophysiologists opened laboratories and arrhythmia units in the major university medical centers, passing their expertise on to the future trainees in cardiac electrophysiology. Prominent among these first generation cardiac electrophysiologists were Dr. Mark Josephson at the University of Pennsylvania, Dr. Jeremy Ruskin at the Massachusetts General Hospital, Dr. John J. Gallagher at

Duke University, Dr. Melvin Scheinman at Moffitt Hospital, and Dr. Masood Akhtar at The Mount Sinai Hospital in Milwaukie, Wisconsin. These physicians, all master teachers trained over the course of their brilliant careers several hundred Fellows not only from the USA but also from several other countries around the world. These clinicians would carry the torch to future generations both in academia and clinical practice. It was in the electrophysiology laboratory at the USPHS hospital under the tutelage of Dr. Anthony

The Dutch School of Cardiac Electrophysiology

N. Damato and Sun H. Lau that studies of the normal electrophysiology of the cardiac conducting system, the genesis of abnormal and rapid heart rhythms and the effects of drugs on the human conducting system and electrophysiologic-hemodynamic correlations were initiated. Several of these studies [19–25, 161–245] were done in the basic and the clinical electrophysiology laboratories. Briefly, custom designed catheters with electrical poles at the tip were introduced under fluoroscopic guidance into the right atrium, His bundle region, and right ventricular apex and were connected to a recording system, also custom-designed, and a custom designed stimulator (Bloom Inc.) for pacing and premature stimulation. The tracings of the electrical signals were recorded on rolls of photographic paper that needed development. Subsequently, days, evenings, and many late nights were spent in reading reams and reams of photographic paper—the Torah’s of cardiac electrical activity. Overall, the young Fellows in training were on an exciting adventure, unveiling ageold mysteries of heart rhythm. At the time, nobody fantasized that cardiac electrophysiology would assume importance as a clinical specialty. And all that is history! Over the last three decades, new commercial ventures would spring forth and market standard catheters and sophisticated recording systems, as well as a host of complex mapping and energy delivering catheters that included cool-tipped, pressure-sensitive, spiral, and basket-shaped catheters with multiple electrodes and catheters to deliver radiofrequency current, cryo or freezing capability, and laser energy into the cardiac muscle mass. Another major advance would occur in the late 1990s. Professor Shlomo Ben Haim of Israel and his company Biosense Webster [246] would develop a 3-dimentional electro-anatomic cardiac mapping system based on electromagnetic technology that enabled more accurate mapping of rhythm disorders. This sophisticated instantaneous digital recording systems and computer displayed 3-D color-coded activation and propagation mapping system would be used worldwide and further facilitate ablative therapy of cardiac arrhythmias. Ultimately, the combination of His bundle recording and the ability to start and stop cardiac arrhythmias with programmed premature stimulation was a revolutionary undertaking—it ushered the modern era of clinical cardiac electrophysiology.

27

Dr. Hein J.J. Wellens, described him as “a genius, a great scientist, and a wonderful teacher.” Dr. Durrer had a separate floor for basic electrophysiology research with animal facilities. There, together with his coworkers, he studied activation of the heart using specially developed electrodes that detected electrical activity from the endocardium, the epicardium, and transmurally. His major opus was the study on total excitation of isolated, healthy human hearts taken from people who had died of cerebral conditions [41] (Fig. 3.4, panel B). It was in this institution under the directorship of Durrer that a cardiac stimulator (Fig. 3.8) was designed and developed by Dr. Reinier Schuilenburg and Leo Schoo, a technician from the Department of Medical Physics. This device was capable of introducing a driving stimulus to create a regular basic rhythm and two testing stimuli to elicit premature beats—either separately or combined.

he Dutch School of Cardiac T Electrophysiology In the 1960s, Dr. Dirk Durrer (1918–1984) headed the Department of Cardiology at the Wilhelmina Gasthuis University Hospital in Amsterdam. His star pupil at the time,

Fig. 3.8 The original Dutch stimulator. Legend: The original Dutch Cardiac Stimulator. For further information, see text. (Courtesy of Dr. Hein J.J. Wellens)

28

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3 Birth of Clinical Cardiac Electrophysiology

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Fig. 3.9 Dr. Hein JJ. Wellens and induction and termination of ventricular tachycardia. (Legend: Panel A: Photo of Dr. Hein J.J. Wellens. Panel B: Shows induction of ventricular tachycardia (VT) with a single extrastimulus at 500 msec. Following a basic drive of 700 msec. Panel

C: shows a single extrastimulus introduced during VT at a coupling interval of 300 msec. Results in termination of VT. (Courtesy of Dr. Hein J.J Wellens)

“We were able to initiate and terminate tachycardia by appropriately timed stimuli,” wrote Hein Wellens, in our correspondence. “This was the birth of programmed stimulation of the heart, now more than 50 years ago, and we danced in the catheterization lab!” (Personal communication Dr. Hein J.J. Wellens). Dr. Hein Wellens (Fig. 3.9) who would ultimately take over the mantle of clinical cardiac electrophysiology in the Netherlands established an electrophysiology division at the University of Limburg in Maastricht in 1977, with his associate Dr. Jeronimo Farre. His major contribution was in the initiation and termination of ventricular tachycardia (Fig. 3.9b, c) that would ultimately lead to the understanding and treatment of this malignant arrhythmia. He would not only perform groundbreaking research [247–329], but train nearly 130 Fellows from all over the world. Together with Dr. Mark Josephson, he would establish a course for young trainees in the field of cardiac electrophysiology in Europe and the USA that started about 30 years ago and continued until recently.

the medical and cardiovascular community realized that clinical cardiac electrophysiologists could cure an arrhythmia with ablative therapy and instantly terminate ventricular fibrillation with an implantable defibrillator, the specialty shot up in prominence like a spectacular stock offering. Over the last two decades, great strides have occurred in heart rhythm disorders, not only in understanding the mechanisms but also in technology to map and treat cardiac arrhythmias with ablation, in the development and use of specialized pacemakers and defibrillators and in the genetics of heart rhythm disorders. A host of pioneering individuals and their groups laid the foundation stones in these important endeavors. Table 3.1 shows the progress in heart rhythm disorders spanning over four decades.

The Mushrooming of EPS Laboratories In the beginning, clinical cardiac electrophysiology and its associated electrophysiological studies or EPS were considered “too cerebral” and poorly grasped by cardiologists in academia and in clinical practice. However, when

The Heart Rhythm Society The trajectory of the Heart Rhythm Society [329] mirrored this rise. It came into being in 1979, created not by electrophysiologists but pacemaker implant surgeons. These physicians included Drs. Warren Harthorne of the Massachusetts General Hospital, Boston; Victor Parsonnet, a cardiac surgeon at Beth Israel Medical Center in New Jersey; Dryden Morse, a cardiac surgeon in New Jersey; and Seymour Furman, a surgeon at the Montefiore Medical Center, Bronx, New York (Fig. 3.10). They initially met in Newark in Dr. Parsonnet’s office, at first

The Heart Rhythm Society

29

Table 3.1 Progress in heart rhythm disorders spanning over four decades 1970s Study of the Cardiac conducting system

Mechanism of SVT

The sick sinus syndrome

1980s Study of ventricular tachycardia (VT): induction and mechanism Drug therapy for VT and SVT Prevention of sudden cardiac death with antiarrhythmic drugs The Cardiac Arrhythmia Suppression Trial (CAST) study Open heart surgery for Wolff-Parkinson-White syndrome and SVT Catheter ablation of AVJ Open heart surgery for VT Development of the implantable defibrillator (ICD) Risk stratification for SCD post-MI

1990s Catheter ablative therapy using radiofrequency current for WolffParkinson-White syndrome, SVT, and VT Multicenter Implantable defibrillator trials Atrial fibrillation trials (anticoagulation; rhythm vs. rate control) Genetics of arrhythmias

2000–2015 Implantable defibrillator therapy for secondary and primary prevention of sudden cardiac death Resynchronization therapy for heart failure Atrial fibrillation ablation Devices for stroke prevention Genetics of (LQT, HOCM, Brugada, ARVD, CVPT, short QTc, J-wave syndromes)

Introduction of novel color-coded 3-D Subcutaneous implantable defibrillator mapping techniques Leadless pacemaker

Abbreviations: SVT supraventricular tachycardia, VT ventricular tachycardia, LQT long QT syndrome, HOCM hypertrophic obstructive cardiomyopathy, ARVD arrhythmogenic right ventricular dysplasia, CVPT catecholaminergic polymorphic ventricular tachycardia Fig. 3.10 The founders of the Heart Rhythm Society. Legend: From left to right: Drs. Victor Parsonnet, J. Warren Harthorne, Seymour Furman, and Dryden Morse. For further explanation, see text. (Courtesy of the Heart Rhythm Society)

intending to form a pacemaker club in New York. But when they ultimately founded the society in 1979, they recognized the need to emphasize electrophysiology as well as cardiac pacing, both of which other cardiology organizations had poorly addressed [330]. The society was originally named The North American Society of Pacing and Electrophysiology (NASPE). It had its own journal, Pacing and Clinical Electrophysiology (PACE), with Dr. Seymour Furman as Founder and Editor-in-Chief

(1978–2004) followed by Dr. John D. Fisher (2004–2018) and Dr. Brad Knight subsequently. Dr. J. Warren Harthorne was the society’s first acting President from 1979 to 1981, followed by Dr. Seymour Furman, who later on was instrumental in tracing the history of clinical cardiac electrophysiology on behalf of the society, with whom I had substantial interaction in tracing the history of the USPHS electrophysiology lab in Staten Island, NY.

30

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Fig. 3.11 Dr. Douglas p. Zipes and accessory pathways and Brugada syndrome. Legend: Panel A, Dr. Douglas P. Zipes (Courtesy of Dr. Douglas P. Zipes). Panel B: One of the first demonstration of a con-

cealed pathway (Reprinted with permission from [360]). Panel C: First localization and ablation of VT in an experimental model of Brugada syndrome. (Reprinted with permission from [361])

In 2004, NASPE moved its headquarters from Boston to Washington, DC, and changed its name to the Heart Rhythm Society (HRS). Its periodical was also renamed to Heart Rhythm Journal, with a new Founding Chief Editor, Dr. Douglas P. Zipes (Fig. 3.11), from the Krannert Institute of Cardiology, Indiana University School of Medicine. A prolific investigator [331–357] and an educator who trained a cadre of prominent electrophysiologists, he steered the publication forward. Overall, as he stated, the Heart Rhythm Society has gone from representing two neglected subfields to being among “the most important medical societies in the US” [358]. The HRS now represents over 7000 physicians in 74 countries, all allied health and science professionals who specialize in heart rhythm disorders.

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31 46. Wellens HJ, Vermeulen A, Durrer D. Ventricular fibrillation occurring on arousal from sleep by auditory stimuli. Circulation. 1972;46(4):661–5. 47. Wellens HJ, Schuilenburg RM, Durrer D. Electrical stimulation of the heart in patients with ventricular tachycardia. Circulation. 1972;46(2):216–26. 48. Schuilenburg RM, Durrer D. Conduction disturbances located within the his bundle. Circulation. 1972;45(3):612–28. 49. van Dam RT, Roos JP, Durrer D. Electrical activation of ventricles and interventricular septum in hypertrophic obstructive cardiomyopathy. Br Heart J. 1972;34(1):100–12. 50. Schuilenburg RM, Durrer D. Rate-dependency of functional block in the human his bundle and bundle branch-Purkinje system. Circulation. 1973;48(3):526–40. 51. Meijne NG, Mellink HM, van Dam RT, Durrer D. Surgical treatment of ventricular preexcitation. A report of two cases. J Cardiovasc Surg. 1973;14(2):232–7. 52. Wellens HJ, Lie KI, Durrer D. Further observations on ventricular tachycardia as studied by electrical stimulation of the heart. Chronic recurrent ventricular tachycardia and ventricular tachycardia during acute myocardial infarction. Circulation. 1974;49(4):647–53. 53. Wellens HJ, Durrer D. Patterns of ventriculo-atrial conduction in the Wolff-Parkinson-white syndrome. Circulation. 1974;49(1):22–31. 54. Lie KI, Wellens HJ, van Capelle FJ, Durrer D. Lidocaine in the prevention of primary ventricular fibrillation. A double-blind, randomized study of 212 consecutive patients. N Engl J Med. 1974;291(25):1324–6. 55. Wellens HJ, Durrer D. Wolff-Parkinson-white syndrome and atrial fibrillation. Relation between refractory period of accessory pathway and ventricular rate during atrial fibrillation. Am J Cardiol. 1974;34(7):777–82. 56. Lie KI, Wellens HJ, Downar E, Durrer D. Observations on patients with primary ventricular fibrillation complicating acute myocardial infarction. Circulation. 1975;52(5):755–9. 57. Wackers FJ, Schoot JB, Sokole EB, et al. Noninvasive visualization of acute myocardial infarction in man with thallium-201. Br Heart J. 1975;37(7):741–4. 58. Billette J, Janse MJ, van Capelle FJ, Anderson RH, Touboul P, Durrer D. Cycle-length-dependent properties of AV nodal activation in rabbit hearts. Am J Phys. 1976;231(4):1129–39. 59. Wellens HJ, Lie KI, Bär FW, Wesdorp JC, Dohmen HJ, Düren DR, Durrer D. Effect of amiodarone in the Wolff-Parkinson-white syndrome. Am J Cardiol. 1976;38(2):189–94. 60. Becker AE, Anderson RH, Wellens JH, Durrer D. Proceedings: anatomy of ventricular pre-excitation. Br Heart J. 1976;38(8):879. 61. Liem KL, Lie KI, Durrer D, Wellens HJ. Clinical setting and prognostic significance of atrial fibrillation complicating acute myocardial infarction. Eur J Cardiol. 1976;4(1):59–62. 62. Lie KI, Liem KL, Schuilenburg RM, David GK, Durrer D. Early identification of patients developing late in-hospital ventricular fibrillation after discharge from the coronary care unit. A 5 1/2 year retrospective and prospective study of 1,897 patients. Am J Cardiol. 1978;41(4):674–7. 63. Downar E, Janse MJ, Durrer D. The effect of acute coronary artery occlusion on subepicardial transmembrane potentials in the intact porcine heart. Circulation. 1977;56(2):217–24. 64. Lie KI, Liem KL, Louridtz WJ, Janse MJ, Willebrands AF, Durrer D. Efficacy of lidocaine in preventing primary ventricular fibrillation within 1 hour after a 300 mg intramuscular injection. A double-blind, randomized study of 300 hospitalized patients with acute myocardial infarction. Am J Cardiol. 1978;42(3):486–8. 65. Janse MJ, Cinca J, Moréna H, et al. The "border zone" in myocardial ischemia. An electrophysiological, metabolic, and histochemical correlation in the pig heart. Circ Res. 1979;44(4):576–88.

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38 and reperfusion during thrombolytic therapy in acute myocardial infarction. Am J Cardiol. 1988;61(4):231–5. 308. Trappe HJ, Brugada P, Lezaun R, Wellens HJ. The significance of ventricular tachycardia morphology for prognosis and follow-up. Z Kardiol. 1989;78(10):633–9. German 309. Lemery R, Brugada P, Della Bella P, et al. Predictors of long-term success during closed-chest catheter ablation of the atrioventricular junction. Eur Heart J. 1989;10(9):826–32. 310. Vos MA, Gorgels AP, Leunissen-Beekman JD, Brugada P, Wellens HJ. The effect of an entrainment protocol on ouabain- induced ventricular tachycardia. Pacing Clin Electrophysiol. 1989;12(9):1485–93. 311. Trappe HJ, Brugada P, Talajic M, Lezaun R, Wellens HJ. Prognosis and follow-up of patients with ventricular tachycardias or ventricular fibrillation without coronary heart disease. Z Kardiol. 1989;78(8):500–9. 312. Brugada P, Talajic M, Smeets J, Mulleneers R, Wellens HJ. The value of the clinical history to assess prognosis of patients with ventricular tachycardia or ventricular fibrillation after myocardial infarction. Eur Heart J. 1989;10(8):747–52. 313. Lemery R, Brugada P, Wellens HJ. Manifest and concealed accessory pathways: behavior after catheter ablation of the atrioventricular conducting system. Am Heart J. 1989;118(1):188–91. 314. Lemery R, Brugada P, Janssen J, et al. Nonischemic sustained ventricular tachycardia: clinical outcome in 12 patients with arrhythmogenic right ventricular dysplasia. J Am Coll Cardiol. 1989;14(1):96–105. 315. Lemery R, Brugada P, Bella PD, et al. Nonischemic ventricular tachycardia. Clinical course and long-term follow-up in patients without clinically overt heart disease. Circulation. 1989;79(5):990–9. 316. Lemery R, Brugada P, Della Bella P, Dugernier T, Wellens HJ. Ventricular fibrillation in six adults without overt heart disease. J Am Coll Cardiol. 1989;13(4):911–6. 317. Brugada P, de Swart H, Smeets JL, Wellens HJ. Transcoronary chemical ablation of ventricular tachycardia. Circulation. 1989;79(3):475–82. 318. Trappe HJ, Brugada P, Talajic M, Lezaun R, Wellens HJ. Value of induction of pleomorphic ventricular tachycardia during programmed stimulation. Eur Heart J. 1989;10(2):133–41. 319. Stevenson WG, Linssen GC, Havenith MG, Brugada P, Wellens HJ. The spectrum of death after myocardial infarction: a necropsy study. Am Heart J. 1989;118(6):1182–8. 320. Vos MA, Gorgels AP, Leunissen JD, Wellens HJ. The in vivo response of ouabain-induced arrhythmias to pacing: acceleration instead of termination. Am Heart J. 1990;120(3):604–11. 321. Wellens HJ, Atié J, Smeets JL, et al. The electrocardiogram in patients with multiple accessory atrioventricular pathways. J Am Coll Cardiol. 1990;16(3):745–51. 322. Cruz FE, Cheriex EC, Smeets JL, et al. Reversibility of tachycardia- induced cardiomyopathy after cure of incessant supraventricular tachycardia. J Am Coll Cardiol. 1990;16(3):739–44. 323. Wellens HJ. The approach to nonsustained ventricular tachycardia after a myocardial infarction. Circulation. 1990;82(2):633–5. 324. Vos MA, Gorgels AP, de Wit B, Drenth JP, van Deursen RT, Leunissen JD, Wellens HJ. Premature escape beats. A model for triggered activity in the intact heart? Circulation. 1990;82(1):213–24. 325. Brugada J, Boersma L, Kirchhof C, et al. Double-wave reentry as a mechanism of acceleration of ventricular tachycardia. Circulation. 1990;81(5):1633–43. 326. Brugada P, de Swart H, Smeets J, Wellens HJ. Transcoronary chemical ablation of atrioventricular conduction. Circulation. 1990;81(3):757–61. 327. Wellens HJ. Electrocardiography. Past, present, and future. Ann N Y Acad Sci. 1990;601:305–11.

3 Birth of Clinical Cardiac Electrophysiology 328. Cruz FE, Havenith M, Brugada P, et al. Pathologic findings after sudden death in arrhythmogenic right ventricular dysplasia. Am J Cardiovasc Pathol. 1990;3(4):329–32. 329. Dassen WR, Mulleneers R, Smeets J, et al. Self-learning neural networks in electrocardiography. J Electrocardiol. 1990;23(Suppl):200–2. 330. Heart Rhythm Society History and Timeline. hrsonline.org. 331. Zipes DP, Orgain ES. Refractory paroxysmal ventricular tachycardia. Ann Intern Med. 1967;67(6):1251–7. 332. Zipes DP, Festoff B, Schaal SF, Cox C, Sealy WC, Wallace AG. Treatment of ventricular arrhythmia by permanent atrial pacemaker and cardiac sympathectomy. Ann Intern Med. 1968;68(3):591–7. 333. Zipes DP. Cardiac sympathectomy for arrhythmias. N Engl J Med. 1970;282(6):340–1. 334. Zipes DP, Fisch C. Initiation of ventricular tachycardia. Arch Intern Med. 1971;128(6):988–90. 335. Zipes DP, Fisch C. Accelerated ventricular rhythm. Arch Intern Med. 1972;129(4):650–2. 336. Zipes DP, Fisch C. Series of studies on heart rhythm disorders. 5. Potassium and rhythm disorders. Coeur Med Interne. 1972;11(2):277–91. 337. Zipes DP, Dejoseph RL. Dissimilar atrial rhythms in man and dog. Am J Cardiol. 1973;32(5):618–28. 338. Zipes DP, Arbel E, Knope RF, Moe GK. Accelerated cardiac escape rhythms caused by ouabain intoxication. Am J Cardiol. 1974;33(2):248–53. 339. Zipes DP, Fischer JC. Effects of agents which inhibit the slow channel on sinus node automaticity and atrioventricular conduction in the dog. Circ Res. 1974;34(2):184–92. 340. Zipes DP, Mihalick MJ, Robbins GT. Effects of selective vagal and stellate ganglion stimulation of atrial refractoriness. Cardiovasc Res. 1974;8(5):647–55. 341. Zipes DP, Fischer J, King RM, Nicoll A, De B, Jolly WW. Termination of ventricular fibrillation in dogs by depolarizing a critical amount of myocardium. Am J Cardiol. 1975;36(1):37–44. 342. Zipes DP, Besch HR Jr, Watanabe AM. Role of the slow current in cardiac electrophysiology. Circulation. 1975;51(5):761–6. 343. Elharrar V, Zipes DP. Cardiac electrophysiologic altera tions during myocardial ischemia. Am J Phys. 1977;233(3): H329–45. 344. Elharrar V, Gaum WE, Zipes DP. Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs. Am J Cardiol. 1977;39(4):544–9. 345. Zipes DP, Foster PR, Troup PJ, Pedersen DH. Atrial induction of ventricular tachycardia: reentry versus triggered automaticity. Am J Cardiol. 1979;44(1):1–8. 346. Martins JB, Zipes DP. Epicardial phenol interrupts refractory period responses to sympathetic but not vagal stimulation in canine left ventricular epicardium and endocardium. Circ Res. 1980;47(1):33–40. 347. Martins JB, Zipes DP. Effects of sympathetic and vagal nerves on recovery properties of the endocardium and epicardium of the canine left ventricle. Circ Res. 1980;46(1):100–10. 348. Gilmour RF Jr, Ruffy R, Lovelace DE, Mueller TM, Zipes DP. Effect of ethanol on electrogram changes and regional myocardial blood flow during acute myocardial ischaemia. Cardiovasc Res. 1981;15(1):47–58. 349. Prystowsky EN, Jackman WM, Rinkenberger RL, Heger JJ, Zipes DP. Effect of autonomic blockade on ventricular refractoriness and atrioventricular nodal conduction in humans. Evidence supporting a direct cholinergic action on ventricular muscle refractoriness. Circ Res. 1981;49(2):511–8. 350. Jackman WM, Zipes DP. Low-energy synchronous cardioversion of ventricular tachycardia using a catheter electrode in a

References canine model of subacute myocardial infarction. Circulation. 1982;66(1):187–95. 351. Roberts WC, Siegel RJ, Zipes DP. Origin of the right coronary artery from the left sinus of valsalva and its functional consequences: analysis of 10 necropsy patients. Am J Cardiol. 1982;49(4):863–8. 352. Minardo JD, Tuli MM, Mock BH, Weiner RE, Pride HP, Wellman HN, Zipes DP. Scintigraphic and electrophysiological evidence of canine myocardial sympathetic denervation and reinnervation produced by myocardial infarction or phenol application. Circulation. 1988;78(4):1008–19. 353. Inoue H, Zipes DP. Cocaine-induced supersensitivity and arrhythmogenesis. J Am Coll Cardiol. 1988;11(4):867–74. 354. Markel ML, Miles WM, Zipes DP, Prystowsky EN. Parasympa thetic and sympathetic alterations of Mobitz type II heart block. J Am Coll Cardiol. 1988;11(2):271–5. 355. Morita H, Zipes DP, Fukushima-Kusano K, et al. Repolarization heterogeneity in the right ventricular outflow tract: correlation

39 with ventricular arrhythmias in Brugada patients and in an in vitro canine Brugada model. Heart Rhythm. 2008;5(5):725–33. 356. Das MK, Zipes DP. Fragmented QRS: a predictor of mortality and sudden cardiac death. Heart Rhythm. 2009;6(3):S8–14. 357. Morita H, Zipes DP, Morita ST, Wu J. Genotype-phenotype correlation in tissue models of Brugada syndrome simulating patients with sodium and calcium channelopathies. Heart Rhythm. 2010;7(6):820–7. 358. Unknown, “Douglas P. Zipes, MD, FHRS,” 2009. http://www. hrsonline.org/Membership/Member-Spotlight/Douglas-P.-Zipes. 359. Leenhardt A, Beaufils P, Slama R. Obituary to Philippe Coumel, MD, 1935–2004. Heart Rhythm. 2004;4:527. 360. Zipes DP, Joseph RL, Rothbaum DA. Unusual Properties of Accessory pathways. Circ. 1974;49:1200–11. 361. Morita H, Douglas P, Zipes, et al. Epicardial ablation eliminates ventricular arrhythmias in an experimental model of Brugada syndrome. Heart Rhythm. 2009;6:665–71.

4

Molecular Basis of Impulse Generation and Propagation

Contents Introduction

41

The Action Potential

41

Sodium Channels

43

Voltage-Gated Calcium Channels

43

Voltage-Gated Potassium Channels

44

The Funny Current of the Sinus Node

45

Gap Junction Channels

46

Conclusions

46

References

46

Introduction In 1952, Hodgkin and Huxley [1] reported their findings on the channel theory and the gating system in the squid axon, by demonstrating how channels open and close and how ions pass through open channels. Their pioneering work won them a share of the 1963 Nobel Prize in Physiology of Medicine. At the cellular level, electrical activation is accomplished by a special gating system that is composed of opening and closing of gates (activation and inactivation) with cellular inflow and outflow of ionic channels [2].

The Action Potential Membrane currents generate the normal action potential (AP), shown in Fig. 4.1, with their respective inward and outward flow of sodium (Na+), potassium (K+), calcium (Ca+), and chloride (CL−) ions. The phases of the action potential are labeled 0–4 and account for depolarization (phase 0), the plateau phase [1, 2], repolarization (phase 3), and resting membrane potential (phase 4) with their respective ionic

movements. During phase 3, the T wave of the surface ECG is inscribed reflecting repolarization. The end of the T wave or phase 4 of the single cell reflects the resting potential. It is noteworthy that unequal distribution of ions produces electrochemical gradients across the cell membrane. The large differences in sodium and potassium concentration are made possible by the energy-dependent Na/K pump that requires adenosine triphosphate (ATP) for energy. Action potentials vary greatly in different regions of the heart due to variation in gene expression and regulation. Figure 4.2 demonstrates the marked variability in rate of rise and duration of action potentials in different cardiomyocytes in the atria and ventricles. The currents involved in depolarization and repolarization in the atrium and ventricle are depicted in Fig. 4.3. It is noteworthy that the AP upstroke in atria and ventricles is rapid due to their dependency on voltage-gated Na+ channels, while in the sinus and AV node, the upstroke is slow due to their dependency on the inward currents generated by voltage-gated Ca+ channels. The major ion channels involved in the action potential have been cloned and sequenced. Table 4.1 enumerates the description of each channel, the AP phase, the activation mechanism, as well as the clone and gene for each current [3].

© Springer Nature Switzerland AG 2020 J. A. Gomes, Heart Rhythm Disorders, https://doi.org/10.1007/978-3-030-45066-3_4

41

42 Fig. 4.1 Cardiac action potential. Legend: The phases of the action potential are labeled 0–4 and account for depolarization (phase 0), the plateau phase (1, 2), repolarization (phase 3), and resting membrane potential (phase 4) with their respective ion movements. I: stands for inward movement. Out: stands for outward movement

Fig. 4.2 Action potentials of different cardiac structures. Legend: Shows the action potential of different cardiac tissue. (Modified from Oudit and Backx [2])

4 Molecular Basis of Impulse Generation and Propagation

Voltage-Gated Calcium Channels

43

Fig. 4.3 Action potentials of atrium and ventricle with their corresponding currents. Legend: The top panel is from atrial (left) and ventricular (right) myocytes. The five phases of the action potential (AP) are labeled: 0, upstroke of the AP represents depolarization of the membrane; 1, initial repolarization; 2, plateau phase; 3, late repolarization phase; and 4, the resting (diastolic) phase. The rate of change of the AP is directly proportional to the sum of the underlying transmembrane ion currents (lower panels). Inward currents (red) depolarize the membrane, while outward currents (yellow) contribute to repolarization. Compared to an atrial AP, the ventricular AP typically has a longer duration, higher plateau potential (phase 2), and a more negative resting membrane potential (phase 4). The presence of an ultrarapid delayed rectifier K+ current (IKur) in atrial myocytes contributes to the lower plateau phase in the atrial AP. Greater inward rectifier K+ current (IK1) in ventricular cells provides a faster phase 3 repolarization and a more negative resting membrane potential (phase 4). (Modified from Oudit and Backx [2])

Sodium Channels The voltage-gated sodium channel [1, 4] is responsible for phase 0, characterized by rapid depolarization of cells throughout the myocardium. By rapid transmission of depolarizing current, they determine the opening of Na+ channels responsible for the QRS complex on the surface ECG. Due to the larger mass of the entire heart, as compared to the single cell, the ECG-QRS complex is much wider than the upstroke (i.e., phase 0) of the single cell. Na+ channels are highly concentrated in axons and muscle cells. In mammalian heart cells, more than 100,000 Na+ channels are expressed, while Purkinje fiber cells express more than one million per cell and account for rapid Purkinje conduction [5]. The mammalian genome is known to contain at least nine voltage-dependent Na+ channel genes, and the human cardiac Na+ channel has been mapped to the short arm of chromosome 3 (3p21-24). The genomic orga-

nization of the SCN5A gene has been described and has assumed importance in the genesis of the Brugada [6, 7] and the long QT3 syndromes [8, 9]. The importance of the Na+ channels cannot be overstated since in clinical practice they are the target of several antiarrhythmic drugs classified as Type I according to the Singh–Vaughan William classification [10]. Additionally, genetic defects (gain and loss of function) in Na+ channels result in various heritable forms of the long QT syndrome, the Brugada syndrome, and conduction defects.

Voltage-Gated Calcium Channels Calcium is essential for excitation–contraction coupling (E–C coupling), the plateau phase of the action potential, automaticity in sinus nodal cells, and gene expression. Six classes of voltage-gated Ca2+ have been described: T-, L-, N-,

44

4 Molecular Basis of Impulse Generation and Propagation

Table 4.1 Currents and their mechanisms, cloning, and genes Current Description α-subunit of action potential inward current channels /Na Sodium current Calcium current, L-type /Ca,L Calcium current, T-type /Ca,T α-subunit of action potential outward (K+) current channels It0,f Transient outward current, fast It0,s Transient outward current, slow

AP phase

Activation mechanism Clone

Gene

Phase 0 Phase 2 Phase 2

Voltage, depolarization Nav 1.5 Voltage, depolarization Cav 1.2 Voltage, depolarization Cav 3.1/3.2

SCN5A CACNA1C CACNA1G

Phase 1

Voltage, depolarization KV 4.2/4.3

KCND2/3

Phase 1

Voltage, depolarization KV 1.4/1.7/3.4 KCNA4

Delayed rectifier, ultrarapid

Phase 1

Voltage, depolarization KV 1.5/3.1

KCNA7 KCNC4 KCNA5

Delayed rectifier, fast Delayed rectifier, slow Inward rectifier ADP activated K+ current

Phase 3 Phase 3 Phase 3&4 Phase 1 & 2

Voltage, depolarization Voltage, depolarization Voltage, depolarization [ADP]/[ATP] ↑

KCNC1 KCNH2 KCNQ1 KCNJ2/12 KCNJ11

Phase 4

Acetylcholine

/KP

Muscarinic-gated K+ current Background current

All phases

Metabolism, stretch

/F

Pacemaker current

Phase 4

Voltage, hyperpolarization

/Kur

/Kr /Ks /KATP /KAch

HERG KVLQT1 Kir 2.1/2.2 Kir 6.2 (SURA) Kir 3.1/3.4 TWK-1/2 TASK-1 TRAAK HCN2/4

KCNJ3/5 KCNK1/6 KCNK3 KCNK4 HCN2/4

Modified from Grant et al. [3] Table showing current abbreviation, description, the action potential phase (AP), the activation mechanism, the clone, and gene of each current

P-, Q-, and R-type. Of these only the long-lasting (L)-type and transient (T)-type Ca2+ are expressed in cardiac cells [11, 12]. The latter contribute to automaticity and are expressed in the sinus node, AV node, and Purkinje fibers. The L-type calcium channels trigger the ryanodine receptor 2 (RyR2) gene to release calcium from sarcoplasmic reticulum into cytoplasm where Ca+ binding with troponin C enables actin– myosin interaction and cellular contraction [13]. Experimental studies in calcium (Cav. 1.2) knockout mice are lethal embryonically within 14 days [14]; similarly, mice lacking Cav. 1.3 reveal sinus bradycardia [14] and AV nodal dysfunction [15]. On the other hand, an increase in calcium influx via L-type Ca channels can lead to prolongation of action potential duration resulting in recovery of L-type Ca channel inactivation in the plateau phase of the action potential. This can result in cardiac arrhythmias due to early afterdepolarizations (EADs) [16]. An increase in L-type Ca current can also result in delayed afterdepolarizations (DADs) and cardiac arrhythmias. Mutations in L-type Ca2+ channels have been associated with inherited syndromes such as Timothy syndrome characterized by prolonged QT intervals and syndactyly and several variably penetrant phenotypes for autism spectrum disorders, craniofacial abnormalities, and hypoglycemia [17]. The mechanism related to the cardiac manifestations of Timothy syndrome is the fail-

ure of L-type Ca2+ channels to close during the plateau phase of the action potential [16]. Loss-of-function mutants (pore- forming α1C-, β2b-, and α2δ1-subunits) have been implicated in the Brugada syndrome, early repolarization, and short QT syndromes [18–20].

Voltage-Gated Potassium Channels Unlike voltage-gated Na+ and Ca+ channels that are responsible for inward currents, outward currents are provided by different types of K+ channels. They can be divided into three main classes depending whether the genes encoding the alpha-subunit have two, four, or six transmembrane segments. Those with two transmembrane segments are inward rectifier (KIR) channels, while those with four transmembrane segments are background K+ (K2P) channels. Cardiac K+ channels with six transmembrane segments are either voltage-gated (Kv) or Ca2+ -activated potassium (KCa) channels [2]. Variation in expression and regulation of K+ channels is responsible for the variation in shape of AP in different cardiac regions. Downregulation of K+ channels and reduction in Ito and KIR can result in prolongation of AP and predispose to EADs and DADs resulting in cardiac arrhythmias [21, 22]. On the other hand, mutations in K+ channels are

The Funny Current of the Sinus Node

45 Cycle length

2 Na+ Membrane potential

0 200 ms HCN

3 20 mV

MDP DD

4 ICa2T Membrane clock

ICa2L

IK

DD

ICa2T If

IK

ICa2L

If

INCX Calcium clock

LCRs

Wholecell AP-induced Ca2+ transient

K+

SERCA Ca2+ pumping

Fig. 4.4 Components of the sinus node pacemaker action potential. Legend: Left-hand panel shows the phases of the sinus node action potential including phase 4 (DD), the key to automaticity. Below are shown the “membrane clock” and the “calcium clock.” Right-hand panel depicts the HCN channel and Na/K exchange. Abbreviations: MDP = maximum diastolic potential; DD = diastolic depolarization; ICa2T = T-type voltage-dependent Ca2+ current; ICa2L = L-type

voltage-dependent Ca2+ current; INCX = sodium-calcium exchange current; IK2 = delayed rectifier potassium current; If = funny current; SERCA = sarco-endoplasmic reticulum ATPase; LCRs = local Ca2+ releases. (Reprinted with permission from Monfredi et al. Physiology 28;74–92, 2013; Reproduced with permission from The American Physiological Society. From Choudhury et al. [39])

responsible for the long QT syndrome, short QT syndrome, the J wave syndrome, and familial AF. Type III antiarrhythmic drugs exert their influence by blocking K+ channels. Block in the gating system with drugs or genetic abnormalities, inherited or mutated, can result in heart rhythm abnormalities.

channels, referred to as the “membrane clock,” and intracellular Ca2+ handling mechanisms, referred to as the “Ca2+ clock,” which leads to “automatic diastolic depolarization” and sinus node automaticity (Fig. 4.4). Multiple currents (If, Ik, ICal, ICaT INa/Ca) contribute to the sinus node action potential [26–30]. A small inward rectifier K+ current keeps the membrane potential of sinus nodal cells at a more depolarized state than that of other cardiac myocytes resulting in an inward Ca2+ current that accounts for the slow upstroke of sinus nodal cells. As sinus nodal cells repolarize, their hyperpolarization results in the opening of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that confers automaticity [26–28]. HCN channels have six transmembrane domains and are found in the heart and elsewhere in the body. Isoforms 1 and 4 are found in the sinoatrial node, whereas isoform 2 is found in the conducting system and myocardium. The critical aspects of the HCN channels that confer the property of automaticity are their activation on hyperpolarization and their modulation by autonomic nervous system. Both the sympathetic and parasympathetic nervous systems are the principal modulators via β-adrenergic or muscarinic receptor-G protein-linked pathways to increase (β-adrenergic) or decrease (muscarinic) cyclic AMP synthesis. Whereas all the currents mentioned above contribute to phase 4 depolarization and to pacemaker rate, the If current is the initiator of the

The Funny Current of the Sinus Node It took more than five decades after the discovery of the sinus node to solve the mystery of its automaticity [23–25]. The Milanese physiologist Dr. Dario DiFrancesco [26, 27] had been working on the rabbit sinus node as far back as 1976, first in Cambridge and subsequently at Oxford, UK. His experiments revealed that something very odd was happening. “When we discovered this thing (the channels involved in sinus node firing), we were very, very puzzled,” he recalled, “because it didn’t have any properties from the known channels at that time.” And so, he called it the “funny current (If).” The sinus cells fire spontaneously during hyperpolarization of the cells. These cells have no resting potential unlike other non-pacemaker cells, but instead generate spontaneous activity by inward movement of calcium currents instead of fast sodium currents. However, sinus nodal automaticity is dependent on an interplay of membrane ion

46

process. However, all pacemaker activity cannot be solely attributed to the If current since administration of If blocking drugs in experimental models and in man has resulted in slowing of sinus rate, but did not result in cessation of sinus rhythm [31, 32]. This obviously highlights the large reserve capacity of sinus nodal cells. The genes encoding If channels have been cloned and sequenced. Isolated reports of mutations in the HCN4 gene caused idiopathic sinus bradycardia and chronotropic incompetence [33]. Severe bradycardia, QT prolongation, and torsade de pointes have been described in another family. It is well-known that If expression is upregulated in cardiac hypertrophy and congestive heart failure and may be the underlying cause of atrial and ventricular arrhythmias in these conditions.

Gap Junction Channels Cell to cell rapid conduction in cardiac tissues is essential in the genesis of excitation–contraction coupling, and consequently, low resistance connections between cells are absolutely essential [34]. The velocity of propagation in a uniform cable is inversely related to the resistance. Thus, low resistance favors rapid conduction and vice versa. Furthermore, there is marked variation in horizontal versus transverse conduction, the former being faster than the latter. In cardiac cells, gap junction channels provide the low resistance necessary for conduction [35]. These are formed by two connexon hemichannels, each composed of six connexin molecules. The main connexins of the myocardium include Cx43, Cx40, and Cx45. While Cx43 is the dominant connexin in ventricular muscle, Cx40 is dominant in the His–Purkinje conduction system, and Cx45 is dominant in the AV and sinus nodes as well as in atrial and ventricular myocardium in lower amounts. The genetic code of connexins, their amino acid sequence, and their molecular function have been identified. It has been demonstrated that the electrical behavior of gap junction channels is dependent on the electrical field across the channel as well as on alterations in the intercellular milieu of Ca2+, Mg2+, ATP, and pH [36]. The latter may be an important factor in slowing conduction in acute ischemia predisposing to reentrant ventricular tachycardia and fibrillation. Heterogeneous expression of connexins, resulting in anisotropic propagation, has been implicated as an important factor in the genesis of atrial fibrillation and ventricular arrhythmias [37]. Furthermore, it has been shown that the ratio of Cx40:Cx43 expression is an important determinant of propagation velocity in human atria. While Cx40 dominance decreases local velocity, Cx43 dominance increases it [38]. Age-related changes in the density of gap junctions favor connective tissue deposition and cell separation resulting in conduction slowing and block. This may be the cause of age-related bundle branch blocks, sinoatrial conduction disease, and atrial fibrillation.

4 Molecular Basis of Impulse Generation and Propagation

Conclusions Major advances in basic electrophysiology of the conducting system including cloning and sequencing of the genes responsible for ion channels have enabled the understanding of several channelopathies such as the long QT syndrome, the Brugada syndrome, etc. These advances hold the futuristic promise of genetic manipulation in the treatment not only of hereditary arrhythmias but also acquired cardiac arrhythmias such as sinus node dysfunction, atrial fibrillation, and ventricular tachyarrhythmias.

References 1. Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952;117:500–44. 2. Oudit GY, Becks PH. Voltage-gated potassium channels. In: Zipes DP, Jalife J, Stevenson WG, editors. Cardiac electrophysiology: from cell to bedside. Philadelphia, PA 19103-2899: Elsevier Health Sciences; 2018 Edition. 3. Grant AO. Cardiac ion channels. Circ Arrhythm Electrophysiol. 2009;2:185–94. 4. Hille B. Ionic channels of excitable membranes. 3rd ed. Sunderland: Sinauer Associates Inc.; 2001. 5. Li RA, Tomaselli G, Malban E. Sodium channels. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology: from cell to bedside. Philadelphia, PA 19103-2899: Elsevier Health Sciences; 2004. 6. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. 1992;20:1992–391. 7. Brugada J, Brugada P, Brugada R. The syndrome of right bundle branch block ST segment elevation in V1 to V3 and sudden death— the Brugada syndrome. Europace. 1999;1:156–66. 8. Chiang C-E, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol. 2000;36:1–12. 9. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome gene-specific triggers for life- threatening arrhythmias. Circulation. 2001;103:89–95. 10. Vaughan Williams EM. A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Cardiovasc Pharmacol. 1984;24:129–47. 11. Bers DM. Excitation-contraction coupling and cardiac contractile force. 2nd ed. Dordrecht: Kluwer Academic Publishers; 2001. 12. Beran BP. Classes of calcium channels in vertebrate cells. Annu Rev Physiol. 1989;51:367–84. 13. Bers DM. Cardiac excitation-contraction coupling. Nature. 2002;415:198–205. 14. Platzer J, Engel J, Schrott-Fischer A, et al. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell. 2000;102:89–97. 15. Marger L, Mesirca P, Alig J, et al. Functional roles of Ca(v)1.3, Ca(v)3.1 and HCN channels in automaticity of mouse atrioventricular cells: insights into the atrioventricular pacemaker mechanism. Channels (Austin). 2011;5:251–61. 16. Splawski I, Timothy KW, Decher N, et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A. 2005;102:8089–96; discussion 8086–8088. 17. Betzenhauser MJ, Pitt GS, Antzelevitch C. Calcium channel mutations in cardiac arrhythmia syndromes. Curr Mol Pharmacol. 2015;8:133–42.

References 18. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007;115:442–9. 19. Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm. 2010;7:1872–82. 20. Cordeiro JM, Marieb M, Pfeiffer R, Calloe K, Burashnikov E, Antzelevitch C. Accelerated inactivation of the L-type calcium current due to a mutation in CACNB2b underlies Brugada syndrome. J Mol Cell Cardiol. 2009;46:695–703. 21. Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell. 2001;104:569–80. 22. Pogwizd SM, Bers DM. Na/Ca exchange in heart failure: contractile dysfunction and arrhythmogenesis. Ann N Y Acad Sci. 2002;976:454–65. 23. Fye WB. The origin of the heart beat: a tale of frogs, jellyfish, and turtles. Circulation. 1987;76:493–500. 24. Geison G. The Royal institution lectures of 1869. In: Michael Foster and the Cambridge School of Physiology, vol. 1978. Princeton: Princeton University Press. p. 200. 25. Mommersteeg MT, Hoogaars WM, Prall OW, et al. Molecular pathway for the localized formation of the sinoatrial node. Circ Res. 2007;100:354–62. 26. DiFrancesco D. A study of the ionic nature of the pacemaker current in calf Purkinje fibres. J Physiol. 1981;314:377–93. 27. DiFrancesco D. Block and activation of the pacemaker channel in calf Purkinje fibres effects of potassium, caesium and rubidium. J Physiol. 1982;222:329–47. 28. Biel M, Schneider A, Wahl C. Cardiac HCN channels structure, function, and modulation. Trends Cardiovasc Med. 2002;12:202–16.

47 29. Lakatta EG, Maltsev VA, Vinogradova TM. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart’s pacemaker. Circ Res. 2010;106:659–73. 30. Lakatta EG, DiFrancesco D. What keeps us ticking: a funny current, a calcium clock, or both? J Mol Cell Cardiol. 2009;47:157–70. 31. Thollon C, Bedut S, Villeneuve N, et al. Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity. Br J Pharmacol. 2007;150:37–46. 32. Borer JS, Fox K, Jaillon P, et al. for the ivabradine Investigators Group. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina. A randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107: 817–23. 33. Herrmann S, Stieber J, Ludwig A. Pathophysiology of HCN channels. Pflugers Arch. 2007;454:517. 34. Rohr S. Role of gap junctions in the propagation of the cardiac action potential. Cardiovasc Res. 2004;62:3019–322. 35. Spach M. Anisotropy of cardiac tissue: a major determinant of conduction? J Cardiovasc Electrophysiol. 1999;10:887–90. 36. Spray DC, White RL, Mazet F, Bennett MV. Regulation of gap junctional conductance. Am J Phys. 1985;248:H753–64. 37. Severs NJ, Bruce AF, Dupont E, Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res. 2008;80:9–19. 38. Kanagaratnam P, Rothery S, Patel P, Severs NJ, Peters NS. Relative expression of immunolocalized connexins 40 and 43 correlates with human atrial conduction properties. J Am Coll Cardiol. 2002;39:116–23. 39. Choudhury M, Boyett MR, Morris GM. Biology of the sinus node and its disease. Arrhythmia Electrophysiol Rev. 2015;4(1): 28–34.

5

The Concept of Entrainment

Contents Introduction

49

Historical Perspectives

49

Criteria for Reentry

50

Criteria for Transient Entrainment

51

Entrainment of Different Tachycardias Atrioventricular Reentrant Tachycardia (AVRT) Atrioventricular-Nodal Reentrant Tachycardia (AVNRT) Atrial Flutter and Macro-reentrant Atrial Tachycardias Ventricular Tachycardia Post-pacing Interval After Entrainment

51 51 52 53 56 58

Stimulus to QRS Interval

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Limitations of Entrainment Mapping

61

Conclusions

62

References

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Introduction

Historical Perspectives

The word entrainment was derived from entrain, “to draw along,” coined in the 1560s, from the French entrainer [1]. It was first applied to cardiac electrophysiology by Dr. Albert Waldo in 1977 [2] (Fig. 5.1). It is one of the most important concepts in cardiac electrophysiology, a concept that remained an intellectual curiosity for many years until catheter ablation entered the clinical arena for the treatment of supraventricular and ventricular tachycardia (VT). Since George Ralph Mines description of reentry as far back as 1913 [3], electrophysiological studies have decidedly established reentry as the underlying mechanism of most cardiac arrhythmias. As will be pointed out, entrainment of a tachycardia not only establishes “reentry” in contrast to other mechanisms such as abnormal and triggered automaticity, but it can also point to the critical site in the reentrant circuit (site of slow conduction or “isthmus”) where ablation will usually be successful.

I asked Dr. Waldo how the idea and concept of entrainment of tachycardias came about. “Entrainment began with atrial flutter,” he said. “When we started our studies, it was not because we knew there was something called entrainment. In the early 1970s, atrial flutter was certainly a well-recognized arrhythmia, but its mechanism was not very well understood. There were two schools of thought: one held that it was due to a single focus firing rapidly and the other that it was due to reentry. At that time, there appeared a series of articles in which investigators reported attempts to interrupt atrial flutter using rapid atrial pacing techniques, introduction of premature atrial beats, or both. None of these studies were systematic, and the results were quite variable. Some reported some success, and some reported failure. In fact, it was questioned whether one could reliably treat atrial flutter with cardiac pacing at all. We started our studies at the University of Alabama at the Birmingham Medical Center in 1972.

© Springer Nature Switzerland AG 2020 J. A. Gomes, Heart Rhythm Disorders, https://doi.org/10.1007/978-3-030-45066-3_5

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5 The Concept of Entrainment

A S

A II

I sec

II

1 sec

B II

B

S

S *

II

C II D

S

S

II

* = Same beat

C *

Fig. 5.1 Dr. Albert Waldo and entrainment of atrial flutter. Legend: Left-hand panel—ECG lead II recorded from a patient with atrial flutter (atrial cycle length = 264 msec.) (Line A). Lines B, C, and D show the end of rapid atrial pacing from a high right atrial site at cycle lengths of 254, 242, and 264 msec.). The atrial flutter was transiently entrained at each pacing cycle length, but without interruption of the atrial flutter. Right-hand panel: A: ECG lead II recorded from the same patient as

Fig. 5.1 during high right atrial pacing from the same site at a cycle length of 224 msec. With the seventh beat in this tracing, and after 22 seconds of atrial pacing at a constant rate, the atrial complexes suddenly became positive. B: ECG lead II recorded from the same patient. With abrupt termination of pacing, sinus rhythm occurred. C: Continued sinus rhythm. (Courtesy of Dr. Albert Waldo)

Because our surgeons left a pair of temporary epicardial wire electrodes on the right atrium of all patients undergoing open heart surgery, and atrial flutter was common following surgery, we had a unique opportunity to systematically study pace termination of atrial flutter. We soon found that to interrupt atrial flutter, pacing had to be performed at a critical rapid rate and for a critical duration. But we did not understand why [2]. The critical insight into entrainment that led to its understanding finally resulted from analysis of a single case of entrainment and interruption of VT [4]. And what we finally figured out to have occurred during transient entrainment and interruption of reentrant VT turned out to be true for every single reentrant tachycardia.”

nodal reentry (AVNRT) or reentry utilizing a bypass tract (AVRT) results in a sustained tachycardia. In other tachycardias such as in scar flutter and VT, the activation wavefront circulates around an area of anatomic or functional block. For reentry to manifest itself, the prerequisites include the following [3, 5, 6]:

Criteria for Reentry Reentry is the propagation of electrical activity which begins at one point and returns to its site of origin [3, 5]. Circular continuous activation through this pathway that consist of an antegrade and a retrograde limb such as in AV

• Pathways with differences in conduction and refractoriness that are joined proximally and distally so that conduction blocks in one pathway proximally (unidirectional block due to longer refractoriness) are available for retrograde conduction at its distal end (e.g., AVRT) • A central area of block around which the wavefront circulates (examples include VT and scar flutters) • An area of slow conduction that allows excitable tissue to maintain conduction ahead of the propagating wavefront and recovers in time for the next wavefront, referred to as an “excitable gap” (Fig. 5.2) • An initiating trigger usually a premature atrial or ventricular depolarization

Entrainment of Different Tachycardias

a

b

51

2. During tachycardia, while pacing at two or more constant rates that are faster than the rate of the spontaneous tachycardia, the demonstration of different degrees of constant fusion on the ECG at each rate (progressive fusion—Fig. 5.3) 3. During tachycardia, while pacing at a constant rate faster than the rate of the spontaneous tachycardia that interrupts the tachycardia, the demonstration of localized conduction block to a site(s) for 1 beat followed by activation of that site (s) by the next paced beat from a different direction and with a shorter conduction time 4. During tachycardia, when pacing at two constant rates that are faster than the rate of the spontaneous tachycardia but that fail to interrupt the tachycardia, the demonstration of a change in conduction time to and electrogram morphology at an electrogram recording site In simple terms, entrainment is the continual or repeated resetting of a reentrant tachycardia by each of a series of consecutive beats of a pacing train slightly faster than the rate of tachycardia.

Entrainment of Different Tachycardias Atrioventricular Reentrant Tachycardia (AVRT) Fig. 5.2 Schematic demonstration of an excitable gap and antidromic/ orthodromic collision during pacing. Legend: Features of a reentrant VT circuit. (a) VT circuit with a circulating wavefront (black arrows) around a central obstacle (gray area) and the presence of an excitable gap. (b) A premature extrastimulus depolarizes tissue during the excitable gap, producing a stimulated antidromic wavefront that collides with the circulating orthodromic wavefront of the VT. The stimulated orthodromic wavefront then propagates through the circuit resetting the circuit. (Modified from [6])

Reentry can be due to an anatomic substrate when there is a distinct relationship of the reentrant pathway to the underlying tissue structure such as dense scar and functional when the reentrant circuit occurs without clearly defined anatomic borders. Both conditions likely coexist to some extent in some SVTs and VTs. Entrainment mapping is used for regular, organized, monomorphic SVTs and VTs to both confirm the mechanism and specifically in VT to adequately localize the critical site of slow conduction that will result in termination of VT by catheter ablation.

Criteria for Transient Entrainment [7] 1. During tachycardia, while pacing at a constant rate that is faster than the rate of the spontaneous tachycardia, the demonstration of constant fusion beats in the ECG, except for the last captured beat

When a ventricular premature beat is introduced during a tachycardia when the His bundle is refractory, if there is a functional bypass tract conducting retrogradely, then the atrium will be pre-excited. This is unequivocal proof of an accessory pathway since there is no other way that the impulse could reach the atrium. Entrainment of AVRT can be performed by ventricular pacing (VP) at a rate faster than the tachycardia, in which case there plausibly are two wavefronts attempting to depolarize the ventricles: the stimulated orthodromic wavefront and the tachycardia antidromic wavefront that proceeds the paced beat. The collision between the antidromic stimulated wavefront and the orthodromic wavefront from the preceding beat may occur in ventricular myocardium or in the AV conduction system, depending on the pacing rate. If the collision occurs in ventricular myocardium, then the paced QRS complexes will be fused. Figure 5.4 shows an orthodromic AVRT with a cycle length (CL) of 310 msec. During AVRT, a 10-beat pacing train from the right ventricular apex (RVA) is delivered at a CL of 270 msec. After which, AVRT continues. During overdrive VP, the atria are accelerated to a cycle length of 270 msec. and the QRS complexes are fused. The last stimulated beat conducts over the AP depolarizing the atria and returning to the ventricles over the normal AV conduction system without fusion, because there is no new stimulated wavefront to collide with, but with a longer St-V interval. These features meet the first criterion for entrainment: constant fusion at a constant pacing CL and the last beat is entrained but not fused. The presence of fusion is the key

52 Fig. 5.3 Progressive fusion. Legend: From top to bottom, ECG leads 1, II, III, V1, V6, and RV electrogram in panels A and B. Panel A shows pacing at 310 msec; after pacing is stopped, VT continues at 335 msec. Panel B shows pacing at 280 msec. Note progressive fusion at faster pacing rate when compared to panel A. When pacing is stopped, VT continues at 335 msec. (Courtesy of Dr. William G. Stevenson)

5 The Concept of Entrainment

a

200 ms

I

II III V1 V6

310

335

RV

b

I

II III V1 V6

280 RV

element that proves the tachycardia was entrained and is called manifest entrainment. Manifest entrainment establishes that the ventricle is a part of the SVT circuit and for all practical purposes rules out AVNRT and AT as the mechanism of tachycardia. Furthermore, eccentric activation during VP similar to SVT further establishes conduction over the accessory pathway. However, overdrive VP is usually ideal for differentiation between AT and AVNRT/AVRT. If the post-pacing response is A-A-V, the diagnosis is AT, while if it is A-V, the diagnosis is either AVNRT or AVRT. If the QRS complex is fused, then AVRT is established excluding AVNRT. However, it turns out that QRS fusion has a low sensitivity when performed from the right ventricular apex. In orthodromic AVRT circuit employing left-sided anomalous pathways (APs), which account for the majority of AVRT cases, fusion could not be demonstrated when entrained by overdrive pacing from the RVA [8]. On the other hand, when the

335

VP site was located closer to the AP, fusion was demonstrable [9, 10]. In these studies, manifest entrainment occurred after overdrive pacing from the RVA in 13 of 14 patients with septal APs [10] and after LV pacing in 6 of 6 patients with left-sided accessory pathways and in no patient after overdrive pacing from the RVA [9]. Besides the QRS morphology, evidence of fusion may also be apparent in intracardiac recordings.

Atrioventricular-Nodal Reentrant Tachycardia (AVNRT) Entrainment of AVNRT by overdrive VP is difficult to prove. For VP to entrain AVNRT, the stimulated wavefront must occur early enough that it can travel retrogradely up the His–Purkinje system and reach the circuit in the AVN. If at that point an excitable gap is present, the

Entrainment of Different Tachycardias

53

I III V1 V5

HRA d 270

310

HIS d

CS 9,10 CS 7,8 CS 5,6 CS 3,4 CS 1,2

RVa d

fig. 5.4 Entrainment of AVRT. Legend: From top to bottom—ECG leads 1, 11, V1; high right atrial electrogram (HRAd); His bundle (HBd); and CS electrograms. Note that during Vp pacing and AVRT, the activation of CS 7,8 occurs earlier (right paraseptal pathway). Note that

during V pacing, there is entrainment of tachycardia as evidenced by the CL of AA interval which is advanced to the rate of pacing. Post- pacing the St-V interval is prolonged, and the tachycardia resumes its cycle length of 310 msec. slower than the pacing cycle length

orthodromic wavefront will advance the AVNRT circuit (and atrial activation), while the antidromic wavefront will collide with the orthodromic wavefront from the preceding beat inside the AVN. Importantly, fusion cannot be present because the antidromic and the orthodromic wavefronts collide in the AV node and the QRS morphology will be entirely that of a paced beat. If the AVNRT was entrained, then the cycle length of AVNRT will be advanced to that of the pacing cycle length, and the tachycardia will continue when pacing is stopped with a longer Ae-H interval (i.e., the interval from the retrograde atrial echo to the His bundle electrogram). Because the QRS complex during entrainment is not fused, direct proof of entrainment is not available, so this is called concealed entrainment (Fig. 5.5). This explanation holds true in patients where there is a distal common pathway in the AVN; however, it may not hold true in those patients in whom the retrograde limb is an insulated His atrial tract. Irrespective, currently for a variety of other methods of differentiation, such as concentric versus eccentric retrograde activation sequence, entrainment mapping does not seem to be necessary in the diagnosis of AVNRT and AVRT. However, it can be useful in separating septal bypass tracts from AVNRT [10].

trial Flutter and Macro-reentrant Atrial A Tachycardias Since Waldo’s description of entrainment of atrial flutter, the circuit of right atrial counterclockwise and clockwise atrial flutter has been well defined and is amenable to successful ablative therapy with what is commonly referred to as an “isthmus line.” Further proof that the sub-Eustachian isthmus bounded by the inferior vena cava and the tricuspid annulus is the area of slow conduction critical in maintaining “typical” AF comes from entrainment mapping (Fig. 5.6). Surgical procedures such as mitral valve repair in association with the Maze procedure can create left atrial flutter circuits around the mitral valve. Entrainment of such flutters is useful in diagnosing reentry and selecting appropriate ablation sites (Fig. 5.7). The advent of pulmonary vein isolation with ablation of complex fractionated atrial electrograms (CFAEs) and other ablation lines for the treatment of atrial fibrillation has created additional circuits resulting in macro- reentrant flutter circuits in the left atrium that often need ablation. In such patients, in addition to electro-anatomic 3-D mapping, entrainment maneuvers are often helpful in not only delineating the circuit but also guiding ablation (Fig. 5.8). Furthermore, entrainment is useful in distinguish-

54

5 The Concept of Entrainment S1: 505

I II aVF V1 V6

HRA

506 msec

HIS d

HIS p

506 msec

CS 1,2 CS 3,4 CS 5,6 CS 7,8 CS 9,10

706 msec

517 msec

RVa

Fig. 5.5 Transient entrainment in AVNRT. Legend: From top to bottom: ECG lead 1, 11, aVF, V1, V6; high right atrial electrogram (HRA), His bundle, distal and proximal (HISd and HISp); coronary sinus (CS

from distal to proximal) and right ventricular electrogram (RVA). Note that ventricular pacing advances the AA intervals. Post-pacing, the St-V increases due to AH prolongation and the tachycardia CL resumes

Halo

CS

Fig. 5.6 Entrainment in typical (counterclockwise flutter). Legend: From top to bottom: ECG leads iii and V1, pacing artifact, recordings from Halo catheter (shown in red) followed by CS recording (proximal to distal, shown in blue). The entrainment is carried out from the abla-

tion catheter at isthmus site. The flutter CL was 337 msec. Note the counterclockwise activation of the AFL. Pacing with the stimulation electrode at the cavotricuspid isthmus at 300 msec produced a PPI interval of 331 msec (PPI–TCL = 6 msec)

Entrainment of Different Tachycardias

55

232 msec 258 BPM

225 msec 267 BPM

196 msec 305 BPM

196 msec 305 BPM

Fig. 5.7 Entrainment of left atrial flutter post MVR and Maze. Legend: Recordings with a multielectrode catheter. The CL of the flutter is 225 msec. Pacing at 196 msec entrains the flutter at the mitral isthmus site with a PPI of 232 msec. Post-pacing the flutter continues with an

identical CL as the flutter CL of PPI interval of 225 msec. Ablation at the site was associated with termination of left atrial mitral annular flutter

Fig. 5.8 Left atrial flutter after PVI entrained from the roof. Legend: Multiple electrograms with a multielectrode catheter. The CL of the flutter is 442 msec. Pacing at a CL of 420 msec at the left atrial roof (A1A2) results in entrainment of the flutter. Note that the post-pacing

interval is 448 msec with resumption of the flutter. Ablation at the site with a roof line resulted in termination of the left atrial flutter. (Courtesy of Dr. Subarao Choudhry)

56

ing right atrial macro-reentrant tachycardias from left atrial tachycardias. To distinguish one from the other, Miyazaki H et al. [11] studied 180 patients with organized reentrant AT, with entrainment performed at the high RA, proximal coronary sinus (CS), and distal CS. The difference between the post-pacing interval (PPI) and tachycardia cycle length (TCL) was calculated at each site. The actual location of the AT reentrant circuit was determined by mapping and ablation. An algorithm predicting AT regions was developed from 104 ATs in the first 90 patients (group I) and prospectively evaluated in a validation cohort of 106 ATs in the second 90 patients (group II). They found that in group I, PPI–TCL difference 50 msec. at the high RA distinguished RA from LA reentrant circuits. For RA tachycardias, PPI– TCL difference at the proximal CS distinguished common flutter from lateral RA circuits. For LA circuits, PPI–TCL difference at the proximal and distal CS distinguished peri- mitral reentry from reentry involving the right pulmonary veins and septum. In group II, an algorithm based on PPI– TCL difference 50 msec. at the high RA, proximal CS, or distal CS had sensitivity of 94%, specificity of 88%, and predictive accuracy of 93% for predicting the successful ablation region. This study suggests that limited entrainment from sites accessible from the RA can expeditiously point to the AT location to guide more detailed mapping and potentially avoid unnecessary trans-septal punctures in some patients. However, it should be noted that in most patients, it is possible to surmise the origin of AT based on prior history of surgery, prior ablation for AF, and P wave morphology of the AT. Furthermore, even if the AT is entrained from the distal CS, ablation will usually require insertion of the ablative catheter in the left atrium via a trans-septal puncture. Additionally, their algorithm was unable to adequately distinguish ATs that can be ablated from the region adjacent to the right pulmonary veins from those that require ablation in the septum. Furthermore, it is noteworthy that attempts at entrainment of ATs can terminate tachycardia or initiate a new tachycardia. In addition to entrainment mapping, currently, high- density 3-D activation and propagation color-coded mapping is available to guide ablative therapy of macro-reentrant atrial tachycardias. To assess the comparative role of these two systems, Pathik K et al. [12] studied 15 patients with right ATs. Based on high-definition (HD)-3-D mapping, 27 circuits were observed: 12 peri-tricuspid, 2 upper loop reentry, 10 lower loop reentry, and 3 lateral wall circuits. With entrainment, all 12 peri-tricuspid and 2 upper loop reentry were active, while lower loop reentry was confirmed in only 3 of 10, and none of the 3 lateral wall circuits. The mean percentage of tachycardia cycle length covered by active circuits was 98% ± 1% vs. 97% ± 2% for passive circuits. In

5 The Concept of Entrainment

8 of 15 patients, 13 examples of unexpectedly long post- pacing intervals were observed at entrainment sites located distal to localized zones of slow conduction seen on HD-3-D mapping. This study suggests that HD-3-D mapping may point to “visual reentry” due to passive circuitous propagation rather than a critical reentrant circuit. Thus, establishing that entrainment mapping is complimentary to HD-3-D mapping, which by itself may identify passive circuits not suitable for ablation.

Ventricular Tachycardia Some of the most important work on entrainment of VT comes from the elegant studies of Stevenson W and coworkers [6, 13–19]. With entrainment mapping, they delineated an anatomic–electrophysiologic corridor of scar-related VT not only identifying reentry as the mechanism but also deciphering “the isthmus of slow conduction,” highly useful in the successful ablation of postinfarction VT, as well as characteristics of the inner loop, exit site, and bystander pathways. Entrainment is possible in VT, since the majority of large scar-related post-MI recurrent monomorphic VTs have an excitable gap (Fig. 5.2) [6]. Like in all entrainment mapping studies, VP is done slightly faster than the cycle length of the tachycardia (TCL). The depolarizing pacing stimulus captures the myocardium via the excitable gap, creating an activation wavefront in two directions in the reentrant circuit: the orthodromic wavefront that travels in the same direction as the tachycardia circuit and the antidromic wavefront that travels in the reverse direction and collides with a returning orthodromic wavefront (Figure 5.2b), resetting the tachycardia [6]. The resetting continues until cessation of pacing or development of block somewhere in the circuit. When pacing is stopped, there is an increase of the tachycardia rate to the pacing rate (post-pacing interval or PPI) with resumption of the intrinsic VT rate [20]. The presence of criteria previously mentioned confirms entrainment and includes: 1. Fixed fusion of the paced complexes at a constant pacing rate [21]. Figure 5.9 shows entrainment with fusion associated with termination of VT in 5.3 seconds. 2. Progressive fusion (Fig. 5.3) if pacing is carried out at progressively faster pacing rates when the surface QRS complexes will ultimately resemble paced QRS. 3. Conduction block within an orthodromic site that is associated with termination of tachycardia followed by activation of that site by a paced wavefront from an antidromic direction [22].

Entrainment of Different Tachycardias Fig. 5.9 Entrainment with fusion. Legend: Top panel shows ECG leads 1, 11, aVF, V1, and V6. VP resulted in fusion seen in the second to last paced beat; best seen in V6. Note the PPI is almost identical to the VT CL. The electrogram at the pacing site (ABL D) occurred 52 msec before the QRS complex (exit site). RF delivery at the site terminated VT in 5.3 sec (lower panel)

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Entrainment & Near Identical Pace Map II

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VT Termination 5.3sec after RF Application 200 mm Hg P1 P1

When pacing is carried out outside the exit site of the reentrant circuit, entrainment can occur but without QRS fusion. However, entrainment can be detected from local electrograms. Such entrainment is referred to as concealed entrainment. If the pacing site is close to the isthmus site and proximal to the exit site, entrainment can also occur without fusion, and the QRS morphology will remain the same as the VT-QRS. Such entrainment is referred to as

entrainment with concealed fusion. Examples of entrainment of epicardial VT and VT in RV dysplasia are shown in Figs. 5.10 and 5.11. It is noteworthy that unlike reentrant VT, focal VTs due to abnormal automaticity, triggered activity, or micro-reentrant in mechanism do not manifest fixed fusion with overdrive VP and are usually suppressed in automatic foci or accelerated as in triggered activity.

58 Fig. 5.10 Epicardial VT: mid-diastolic potentials/ concealed entrainment with long ST-QRS. Legend: From top to bottom in both panels, ECG leads and recordings from ablation catheter (d, p), right ventricle (RVA), stimulus and blood pressure recording. The blue arrows point to mid-diastolic activity during VT. The bottom panel shows concealed entrainment during pacing at 420 msec. Termination of pacing is associated with a PPI of 460 msec and identical to the CL of VT. RF application at the site resulted in termination of VT

5 The Concept of Entrainment I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 ABL d ABL p RVa Stim 2

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As noted above, the simple demonstration of entrainment alone does not indicate the location of the pacing site relative to the reentry circuit. Several other measurements [19] can help locate components of the reentry circuit, which include the following: • PPI after entrainment • Stimulus to QRS interval (S-QRS) during entrainment and its relationship to electrogram to QRS (EGM-QRS) during VT and its relationship to the VT CL

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Post-pacing Interval After Entrainment The PPI is the interval from the last captured stimulus to the next local electrogram at the pacing site. It is a measure of the proximity of a pacing site to the reentry circuit [13]. Pacing sites within the reentry circuit will yield a PPI that is close in duration to the tachycardia cycle length (TCL). This is because the stimulated orthodromic wavefront completes one revolution around the circuit. Thus, the interval from the last stimulus that captures the electrogram at the

Entrainment of Different Tachycardias

59

Fig. 5.11 Entrainment in right ventricular dysplasia and termination of VT with RFA. Legend: ECG leads and recording from ablation catheter (d, p), right ventricular apex (RVA) and stimulus. Top panel shows pacing at 412 msec which results in concealed entrainment with a PPI of

474 msec with resumption of VT at a CL of 472 msec. Lower panel shows termination of VT with application of RF current at the site with slowing of the rate of VT before termination. Note the presence of an epsilon wave (arrow) in sinus rhythm

pacing site is equal to the revolution time through the circuit and corresponds to the TCL [6]. When entrainment is performed outside the circuit, the last pacing stimulus to the subsequent electrogram at the pacing site is a composite

of the conduction time from the pacing site to the circuit, plus conduction through the circuit, and back to the pacing site. Consequently, the PPI will be considerably longer than the TCL and will depend on the distance from the pacing

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5 The Concept of Entrainment

site/sites outside the circuit. The difference between the PPI and TCL (PPI – TCL) within 30 msec. is suggestive that the pacing site was in the VT circuit. This finding is associated with increased likelihood of VT termination with RF ablation [13].

Stimulus to QRS Interval During entrainment with concealed fusion, the S-QRS interval indicates conduction time from the pacing site to the reentry circuit exit. For sites within the reentry circuit, the S-QRS interval will equal the EGM-QRS interval, and the PPI will approximate the VT CL (Fig. 5.12). If pacing from a bystander site entrains VT with concealed fusion, the S-QRS interval typically exceeds the EGM-QRS interval during VT, and the PPI exceeds the VT CL. When pacing within the isthmus denoted by a mid- diastolic potential results in termination of VT without global capture (Fig. 5.13), RF delivery will usually be associated with termination of VT. Based on the combination of fusion, PPI, and S-QRS during VT, Stevenson WG et al. [6] (Fig. 5.14, top panel) developed a classification of reentry circuit sites includ-

ing isthmus sites as well as exit site and outer or inner loop sites, and bystander sites, using the Figure-of-8 model of re-entrant VT (Fig. 5.14, bottom panel). Entrainment at central and p roximal isthmus sites will produce concealed fusion and an S-QRS matching the EGM-QRS. However, as the pacing site is moved further from the exit, to more proximal sites in the circuit, the S-QRS interval increases. The percentage of S-QRS to VT CL (S-QRS/VT CL × 100) has been used to characterize sites as exit, central, or proximal isthmus on the basis of the ratio being less than or equal to 30%, 31%–50%, and 51%– 70%, respectively (Fig. 5.14, lower panel). These designations were arrived at empirically, based on the observation that VT was infrequently interrupted at S-QRS greater than 70% of the VT CL sites (inner loops) [6]. RF ablation is frequently effective in interrupting VT at central and proximal sites [6]. Inner loop sites have a long S-QRS during entrainment (>70% of VT CL) and show concealed fusion (Fig. 5.12). The S-QRS interval is as long as the pacing site is proximal to isthmus. Ablation at inner loops is less effective than isthmus sites [6]. When pacing from the exit site, the stimulated orthodromic wavefront will propagate away from the cir500 ms

I II III aVR aVF aVL

398

V1 V2 V3 V4 V5 450

V6

472 ABL d

450

450

472

ABL p RVa d

Fig. 5.12 Entrainment at inner loop site. Legend: The ablation catheter is located at an inner loop site. The surface electrogram demonstrates concealed fusion with a post-pacing interval that is equivalent to the VT

cycle length of 472 msec. However, the stimulus to QRS is long (398 msec) and represents 84% of the VT cycle length. This is a characteristic of an inner loop site. (Courtesy of Dr. Srinivas Dukkipati)

Stimulus to QRS Interval

cuit exit producing a QRS configuration identical to the VT (concealed entrainment). The PPI will also match the TCL. The S-QRS interval during entrainment will match the EGM-QRS interval during VT. At such sites, the S-QRS is short (1. This is because the atrium and ventricle are activated nearly simultaneously; however, depending on the conduction via the fast pathway, the atrium can be activated before the ventricular myocardium (Figs. 6.4 and 6.5). The commonest variant of AVNRT is the reverse of the slow/fast, i.e., a fast/slow tachycardia (Fig. 6.1 panel b), wherein the retrograde P wave occurs before the QRS with a P1-R/R- P1 ratio of