Heart Disease in Children [1 ed.] 9781616682255, 9781607415046

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Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

CARDIOLOGY RESEARCH AND CLINICAL DEVELOPMENTS SERIES

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

HEART DISEASE IN CHILDREN

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information herein. This digital document is sold with the Publishers, clear understanding the publisher is not engaged in Heart Disease in Children,contained edited by Marius D. Oliveira, and William S. Copley, Nova Science Incorporated,that 2009. ProQuest Ebook

CARDIOLOGY RESEARCH AND CLINICAL DEVELOPMENTS SERIES Focus on Atherosclerosis Research Leon V. Clark (Editor) 2004 ISBN: 1-59454-044-6 Cholesterol in Atherosclerosis and Coronary Heart Disease Jean P. Kovala (Editor) 2005 ISBN: 1-59454-302-X Frontiers in Atherosclerosis Research Karin F. Kepper (Editor) 2007 ISBN: 1-60021-371-5 Cardiac Arrhythmia Research Advances Lynn A. Vespry (Editor) 2007 ISBN: 1-60021-794-X

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Heart Disease in Women Benjamin V. Lardner and Harrison R. Pennelton (Editors) 2009 ISBN: 978-1-60692-066-4 Cardiomyopathies: Causes, Effects and Treatment Peter H. Bruno and Matthew T. Giordano (Editors) 2009 ISBN: 978-1-60692-193-7 Transcatheter Coil Embolization of Visceral Arterial Aneurysms Shigeo Takebayashi, Izumi Torimoto and Kiyotaka Imoto (Editors) 2009. ISBN: 978-1-60741-439-1 Heart Disease in Men Alice B. Todd and Margo H. Mosley (Editors) 2009 ISBN: 978-1-60692-297-2

Angina Pectoris: Etiology, Pathogenesis and Treatment Alice P. Gallos and Margaret L. Jones (Editors) 2009 ISBN: 978-1-60456-674-1 Coronary Artery Bypasses Russell T. Hammond and James B Alton (Editors) 2009 ISBN: 978-1-60741-064-5 Congenital Heart Defects: Etiology, Diagnosis and Treatment Hiroto Nakamura (Editor) 2009 ISBN: 978-1-60692-559-1 Atherosclerosis: Understanding Pathogenesis and Challengefor Treatment Slavica Mitrovska, Silvana Jovanova Inge Matthiesen and Christian Libermans 2009 ISBN: 978-1-60692-677-2 Practical Rapid ECG Interpretation (PREI) Abraham G. Kocheril and Ali A. Sovari 2009 ISBN: 978-1-60741-021-8 Heart Transplantation: Indications and Contraindications, Procedures and Complications Catherine T. Fleming (Editor) 2009. ISBN 978-1-60741-228-1 Handbook of Cardiovascular Research Jorgen Brataas and Viggo Nanstveit (Editors) 2009. ISBN: 978-1-60741-792-7 Heart Disease in Children Marius D. Oliveira and William S. Copley (Editors) 2009 ISBN: 978-1-60741-504-6

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

CARDIOLOGY RESEARCH AND CLINICAL DEVELOPMENTS SERIES

HEART DISEASE IN CHILDREN

MARIUS D. OLIVEIRA AND

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

WILLIAM S. COPLEY EDITORS

Nova Biomedical Books New York Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Copyright © 2009 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Library of Congress Cataloging-in-Publication Data Heart disease in children / [edited by] Marius D. Oliveira and William S. Copley. p. ; cm. Includes bibliographical references and index. ISBN 978-1-61668-225-5 (e-Book) 1. Pediatric cardiology. I. Oliveira, Marius D. II. Copley, William S. [DNLM: 1. Heart Diseases. 2. Adolescent. 3. Child. WS 290 H4346 2009] RJ421.H37 2009 618.92'12--dc22 2009027756

Published by Nova Science Publishers, Inc.    New York Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Contents

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Preface

vii

Chapter I

Congenital Primary Arrhythmias in Children Z. A. Bhuiyan, T. S. Momenah and A.A.M. Wilde

Chapter II

The Impact of Congenital Heart Disease on Brain Development and Neurodevelopmental Outcome An N. Massaro and Mary T. Donofrio

Chapter III

PDA in the Preterm Infant Afif EL-Khuffash, Kevin Walsh and Eleanor Molloy

Chapter IV

Fetal Arrhythmias Maurizio Mongiovì and Salvatore Pipitone

Chapter V

Pharmacological Therapy in Children with Congenital Long-QT Syndrome Tarik El Houari, Rachida Bouhouch, Ibtissam Fellat and Mohamed Arharbi

Chapter VI

Chapter VII

Chapter VIII

1

43 75 113

139

Diagnostic Difficulties of Myocarditis in Children and Their Medico-Legal Aspects Klára Törő, László Losonczi and György Fekete

149

Apparent Life-Threatening Event (ALTE) and Wolff-ParkinsonWhite Syndrome: Is There a Connection? Thomas Erler and Albrecht Grunske

157

Congenital Heart Disease and Necrotizing Enterocolitis Peter J. Giannone, Wendy A. Luce, Juli M. Richter, and Craig A. Nankervis

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165

vi Chapter IX

Chapter X

Chapter XI

Contents BMPR2 Sequence Analysis in a Down Syndrome Population with Congenital Heart Disease Clifford L. Cua, Lora J.H. Bean, Gloria Zender, Trang Pham, Stephanie L. Sherman, Kenneth Dooley and Kim L. McBride Arterial Duct Stenting in Congenital Heart Disease with DuctDependent Pulmonary Circulation Giuseppe Santoro, Chiara Marrone, Giovanbattista Capozzi, Gianpiero Gaio, Carola Iacono, Marianna Carrozza, Raffaella Esposito, Carmela Morelli, Maria Giovanna Russo, and Raffaele Calabrò Rare Reason for Myocardial Infarction in Adolescence: Anomalous Origin of the Left Main Coronary Artery in Association with Combined Prothrombotic Defects Martin Koestenberger

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Index

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

171

177

197 205

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Preface Up to one-third of American children have high cholesterol. Compared with their counterparts in many other countries, American children and adolescents also have higher blood cholesterol levels and higher intakes of saturated fatty acids and cholesterol. There is also evidence now that atherosclerosis, a build up of plaque in the arteries, starts in childhood. However, most of the risk factors that affect children can be controlled early in life, lowering the risk of heart disease later in life. This book examines new developments in the field. Included is a review on neurologic abnormalities associated with congenital heart disease (CHD), the diagnosis and management of a patent ductus arteriosus (PDA), one of the most common cardiovascular abnormalities in preterm neonates and an analysis of fetal cardiac rhythm. Also looked at are therapeutic options for children who suffer from congenital long QT syndrome (CLQTS) and myocarditis, which could be a cause of sudden death in infants, children and adolescents. This book also further explores necrotizing enterocolitis (NEC), the most common gastrointestinal disease in infancy and the correlation between children with Down syndrome and congenital heart disease. Chapter 1 - Approximately, 10% of deaths of children, after their first year of life are sudden; sudden deaths in children and young adults account for about 1:20 000 to 1:50 000 per year [1-2]. Primary electrical cardiac disorders comprise a significant percentage of deaths in these children and young adults [3-6]. In 50% of cases of Sudden Cardiac Death (SCD) or aborted SCD victims between 1-18 yrs, a genetic basis of the disease has been reported [4-5]. Pathophysiology and Genetic basis of these primary arrhythmia disorders are quite complex and researchers have just started to unravel the intricate and complex process of arrhythmogenesis. First reports linking mutations in genes causative to primary arrhythmias were reported between 1995 and 1997 from the laboratory of Dr. Mark T. Keating and Dr. Pascal Guicheney [7-12]. Thereafter, during the last 13 years, authors have observed potential discoveries linking mutations in cardiac ion channels, gap junction protein encoding genes with a wide variety of inherited arrhythmia syndromes [13]. As to the structure of heart, three layers of tissues, epicardium, myocardium and the endocardium form the outer to inner layers of the heart. Cardiac myocytes are the major functioning cells in the heart and are extensively linked so that impulses propagate rapidly and uniformly. Individual cardiomyocytes are separated from each other by a specialised boundary called the intercalated disc, where gap junction proteins, desmosomes and ion

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

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Marius D. Oliveira and William S. Copley

channels are located [14]. Gap junctions consist of tightly packed connexins which permit intercellular exchange of small molecules and excitatory current flow between neighbouring cells. Desmosomes alongwith adherens junctions are responsible for the mechanical attachments of individual cardiomyocytes. All these components of the intercalated disc are topologically segregated and serve distinct functions. Well coordinated crosstalks between the structural and electrical components of the heart are required for proper cardiac function [14-17]. Disruption in this communication could predispose the heart to arrhythmias with or without any structural defects in the heart [14-17]. Chapter 2 - Advances in medical and surgical management have led to improved survival in patients with congenital heart disease (CHD). While improving short-term morbidity and mortality are essential goals, optimizing neurodevelopmental outcome and quality of life for survivors are equally important in this high-risk population. Surviving infants with CHD are at significant risk for neurodevelopmental impairment, either as a result of in utero physiological effects of abnormal circulation; associated congenital brain anomalies; neurodevelopmental compromise before, during and after surgical repair; or combinations of all of these factors. This chapter will review the following topics: 1) neurologic abnormalities detectable prior to surgery, 2) peri- and intraoperative neuroprotective strategies, and 3) reported neurodevelopmental outcomes for patients with CHD. Chapter 3 - There is limited consensus on the diagnosis and management of a patent ductus arteriosus (PDA) in preterm neonates. PDA remains one of the most common cardiovascular abnormalities in preterm neonates occurring in about a third of infants below 30 weeks gestation and up to 60% of infants less than 28 weeks. Shunting from the systemic to the pulmonary circulations is defined as ductal steal and results in systemic hypoperfusion and pulmonary overcirculation. This may explain the association between PDA and necrotizing enterocolitis (NEC), renal dysfunction, intraventricular haemorrhage (IVH), pulmonary haemorrhage and increased ventilator dependence. However, early medical therapy using non-steroidal anti-inflammatory drugs such as indomethacin and, more recently, ibuprofen have not reduced the incidence of PDA-associated complications. Echocardiography remains the gold standard for diagnosing a PDA and all clinical trials of targeted therapy to date have relied on echocardiography to grade the severity of the PDA. This has not resulted in improved outcomes. A haemodynamically significant PDA is associated with lower blood flow volumes in the abdominal aorta and lower mean blood flow velocities in the celiac, superior mesenteric, renal and cerebral arteries despite a rising left ventricular output (LVO). However, echo alone cannot reliably predict PDA-associated complications. Biochemical markers such as Pro-B-type natriuretic peptide (NTpBNP) and cardiac troponin T (cTnT) may aid in identifying high risk infants. cTnT and NTpBNP may be superior to echocardiography alone in predicting the occurrence of severe IVH and death in preterm infants. The use of biochemical markers such as NTpBNP and cTnT in conjunction with echocardiography may provide a basis for targeted treatment in infants with a PDA, and reduce the incidence of PDA-related complications. Chapter 4 - This chapter will describe the analysis of fetal cardiac rhythm, present a discussion of the pathophysiology of arrhythmias and their effect on the fetal circulatory

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

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Preface

ix

system, and describe the latest methods for the diagnosis of tachyarrhythmias and a treatment algorithm of cardiac arrhythmias during fetal life. The normal fetal cardiac rhythm is characterized by a regular heart rate ranging between 100 and 160–180 beats/min with a normal 1:1 atrio-ventricular electromechanical relationship during each cardiac cycle. Fetal rhythm disturbances are diagnosed in at least 2% of pregnancies during routine ultrasound scanning and are common reasons for referral to a fetal cardiologist. Arrhythmias are most frequently due to multiple atrial premature contractions, of little clinical relevance in more than 90% of cases. About one in 200 fetuses with frequent atrial ectopy will develop supraventricular tachycardia, either in fetal life or in the newborn period; the risk of supraventricular tachycardia increases to about 10% when ectopy is re-entrant or complex. Fetal tachycardia occurs in approximately 0.5% of all pregnancies and is related to sinus tachycardia, atrial flutter and supraventricular tachycardia as the main aetiology. Appropriate management depends on accurate diagnosis and fetal echocardiography remains the main tool to diagnose and discern the mechanism of tachyarrhythmia, to study the impact on cardiac function, to exclude cardiac pathology, and to survey the fetal heart during anti-arrhythmic treatment. In addition to M-mode and flow Doppler, new ultrasounds techniques such as myocardial deformation imaging have become available. Infrequently, the tachyarrhythmias become sustained with a high risk for hydrops fetalis, neurological morbidity and fetal death. For the compromised fetus, the mortality rate ranges from 8% to 27% and the delivery of an immature, hydropic infant has equally unacceptable morbidity and mortality. In these cases there is a consensus treatment with drug therapy. The recognition of the type of tachyarrhythmia allows the choice of specific drug therapy and improves the chance for success. Approximately 75–85% of fetuses with sustained tachycardia and mild heart failure respond to transplacental antiarrhythmic therapy. To avoid the limits of placenta transfer of antiarrhythmic drugs when transplacental therapy fails, direct fetal therapy has been used. Sustained bradyarrhythmias relate to sinus bradycardia, atrial bigeminy or, from the most common cause, to complete atrio-ventricular block (CAB). CAB may present in fetuses with normal cardiac structure, and normally appears after 20 weeks of gestation in mothers with autoimmune conditions associated with high titres of anti-Ro/La autoantibodies that cross the placenta to cause immune-related inflammatory damage. Isolated fetal CAB has a significant mortality rate, particularly in association with fetal hydrops, poor ventricular function and low heart rates. CAB may be associated with either complex congenital heart malformations involving the atrio-ventricular junction of the heart; with worse outcome, typically left atrial isomerism; or corrected transposition of the great arteries. Treatment of a fetus with irreversible atrio-ventricular nodal damage is proposed, primarily to augment fetal cardiac output and to mitigate or prevent concomitant myocardial inflammation. Published studies have demonstrated a significant improved outcome with transmaternal dexamethasone and beta stimulation. Chapter 5 - The congenital long QT syndrome (CLQTS) is a genetic channelopathy that affects sodium and calcium kinetics, resulting in prolonged ventricular repolarization. This channelopathy is associated with increased propensity to syncope, malignant ventricular arrhythmias and sudden arrhythmic death in children with normal cardiac structure. Recently,

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Marius D. Oliveira and William S. Copley

the published data from the International LQTS Registry have established risk factors for sudden cardiac death and aborted cardiac arrest in children. β-blockers are the first-line drug therapy for congenital long-QT syndrome in children. Several β-blockers (propranolol, atenolol, nadolol, metoprolol,) were used in CLQTS with a significant reduction of cardiac events in patients with LQT1 and LQT2 mutations, but no evident reduction in those with LQT3 mutations. Infrequently, additional Drugs (mexiletine and flecainide) were used in children with CLQTS. The implantable cardioverter defibrillator and left cervicothoracic sympathetic denervation are other therapeutic options in children who remain symptomatic despite β-blocker therapy. Genetic factors may be used to improve risk stratification in genotyped patients and to predict the response to β-blockers. Chapter 6 - Myocarditis could be a cause of sudden death in infants, children and adolescents. The epidemiology of fatal myocarditis in the general population has remained largely uncharacterized, because the clinical presentation and findings of myocarditis are highly variable and because the definite diagnosis is based on autopsy. Discrepancies between clinical symptoms, diagnostic difficulties and post mortem detection of myocarditis of infants and children may result malpractice court cases. Common areas of children malpractice suits include cases involving myocarditis. Defensive strategies to deter litigation in myocarditis in children include the use of standard forms, good documentation, and full evaluation of diagnostic procedures. The improvements in the quality of diagnostic techniques and post mortem methods may result a decreasing infant and child mortality represent an effective strategy to prevent malpractice. Chapter 7 - The indications for use of home monitors are still a controversial point of discussion among pediatricians. The authors report the case of a six-week-old male white baby who was admitted after an apparent life-threatening event. The diagnostic examinations did not explain the circumstances. The baby was discharged in a good state of health with a home monitor. A few days later, the infant was readmitted because of prolonged monitor alarm due to tachycardia. WPW syndrome was diagnosed, and necessary intervention was performed early enough. The diagnosis of connatal arrhythmia was made thanks to the use of a home monitor during a tachycardiac attack, whereas polysomnographia and other examinations proved to be negative. Connatal arrhythmia can be overlooked by polysomnographia and therefore requires a more careful cardiological examination and diagnostic procedure. In a few carefully chosen cases, however, the use of a monitor can be judicious and helpful. The use of a monitor—with the necessary compliance of the parents—after an unexplained apparent life-threatening event (ALTE) is advisable. Chapter 8 - Both necrotizing enterocolitis (NEC) and congenital heart disease (CHD) are significant causes of morbidity and mortality in neonates. NEC is the most common gastrointestinal disease in infancy, afflicting up to 15% of all infants born at less than 30 weeks gestational age or at C) and one was a non-synonymous change (c.554G>A; p.S185N), both in exon 5. Neither variant was found among 144 ethnically matched normal control chromosomes. The p.S185N change involves a highly conserved amino acid, but was predicted to be a benign change by the PolyPhen program, Conclusion: BMPR2 unlikely plays a major role in the formation of atrioventricular septal defects in Down syndrome individuals. Further studies are needed to determine the etiology of congenital heart disease in patients with Down syndrome. Chapter 10 - Congenital heart diseases with duct-dependent pulmonary blood flow are a wide spectrum of malformations characterized by high morbidity and mortality in neonatal age. Despite current trends toward early primary repair, surgical systemic-to-pulmonary artery shunt is still an invaluable palliative option in some high-risk patients with cyanotic congenital heart defects. However, maintaining the arterial duct patency by stent implantation has been proposed as an effective alternative to surgical systemic-to-pulmonary artery shunt in neonates with duct-dependent pulmonary circulation who are unsuitable for primary repair or in whom there is anticipated spontaneous improvement of oxygen saturation as the pulmonary vascular resistance decreases. This paper highlights history, methodology and results of this innovative and minimally-invasive palliative option. Chapter 11 - An adolescent is presented with clinical features of an acute myocardial infarction including signs of a cardiogenic shock and loss of consciousness. Angiography revealed a complete obstruction of the left main coronary artery. Coronary-aorto bypass graft was undertaken immediately. A cardiac CT demonstrated an anomalous origin of the left main coronary artery from the right coronary sinus of the aorta. It followed a short interarterial course between the aorta and the main pulmonary artery supplying the anterior descending and circumflex coronary arteries. A thrombophilic state with a heterozygote genotype for prothrombin G20210 mutation, a C677T methylenetetrahydrofolate reductase gene mutation, and a protein C type 1 deficiency was detected. No other embolic source could be identified. This instructional patient recovered with persistent left ventricular dysfunction and is now anticoagulated with warfarin. Combined prothrombotic defects in combination with additional risk factors like coronary anomalies can lead to MI even in children and adolescents. Therefore, to my opinion the diagnostic work up should include a complete thrombophilia screening.

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

In: Heart Disease in Children Editors: M. D. Oliveira and W. S. Copley

ISBN: 978-1-60741-504-6 © 2009 Nova Science Publishers, Inc.

Chapter I

Congenital Primary Arrhythmias in Children Z. A. Bhuiyan1, T. S. Momenah2 and A.A.M. Wilde3 1

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Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Netherlands. 2 Department of Pediatric Cardiology, Prince Sultan Cardiac Center, Riyadh, Saudi Arabia. 3 A. A.M. Wilde, Department of Cardiology and Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Netherlands.

Approximately, 10% of deaths of children, after their first year of life are sudden; sudden deaths in children and young adults account for about 1:20 000 to 1:50 000 per year [1-2]. Primary electrical cardiac disorders comprise a significant percentage of deaths in these children and young adults [3-6]. In 50% of cases of Sudden Cardiac Death (SCD) or aborted SCD victims between 1-18 yrs, a genetic basis of the disease has been reported [4-5]. Pathophysiology and Genetic basis of these primary arrhythmia disorders are quite complex and researchers have just started to unravel the intricate and complex process of arrhythmogenesis. First reports linking mutations in genes causative to primary arrhythmias were reported between 1995 and 1997 from the laboratory of Dr. Mark T. Keating and Dr. Pascal Guicheney [7-12]. Thereafter, during the last 13 years, we have observed potential discoveries linking mutations in cardiac ion channels, gap junction protein encoding genes with a wide variety of inherited arrhythmia syndromes [13]. As to the structure of heart, three layers of tissues, epicardium, myocardium and the endocardium form the outer to inner layers of the heart. Cardiac myocytes are the major functioning cells in the heart and are extensively linked so that impulses propagate rapidly and uniformly. Individual cardiomyocytes are separated from each other by a specialised boundary called the intercalated disc, where gap junction proteins, desmosomes and ion channels are located [14]. Gap junctions consist of tightly packed connexins which permit intercellular exchange of small molecules and excitatory current flow between neighbouring

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

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Z. A. Bhuiyan, T. S. Momenah and A.A.M. Wilde

cells. Desmosomes alongwith adherens junctions are responsible for the mechanical attachments of individual cardiomyocytes. All these components of the intercalated disc are topologically segregated and serve distinct functions. Well coordinated crosstalks between the structural and electrical components of the heart are required for proper cardiac function [14-17]. Disruption in this communication could predispose the heart to arrhythmias with or without any structural defects in the heart [14-17].

Cardiac Channelopathies Ion channels are pore-forming protein complexes that provide controlled inward and outward ionic currents across the cell membranes, which is critical for cardiac contractility, rhythm generation and propagation. Channelopathies could be either congenital (often resulting from mutation/s in various genes) or acquired (resulting from autoimmune attack or drug effect on an ion channel). A large number of dysfunctions are caused by mutations in genes coding for cardiac ion channels: Long QT syndrome (LQTS), Jervell and LangeNielsen syndrome (JLN-S), Short QT syndrome (SQTS), Sick sinus syndrome (SSS), Isolated Cardiac Conduction defect (ICCD), Brugada syndrome (BrS), and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) are the presently known cardiac channelopathies.

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Long QT Syndrome (LQTS) Congenital LQTS is an inherited disorder defined by prolongation of the QT interval. Patients with all forms of LQTS are predisposed to the ventricular tachyarrhythmia torsades de pointes (TdP) leading to recurrent syncope or sudden cardiac death. In many cases, syncope or sudden death could be the first and the only manifestation. Prevalence of LQTS is likely to be between 1/2,500 and 1/3,000 live births [18]. The ECG hallmark of the LQTS is prolongation of the QT interval (corrected for heart rate i.e. QTc). In children age-dependent (and gender dependent) values are relevant. Values above 480 ms in the absence of an identified cause are generally considered highly suspect for LQTS. In adults, normal values of QTc are 440ms in males and 450 ms in females. The molecular basis of LQTS is heterogeneous and to date, mutations in at least 12 different genes have been reported in LQTS patients (table 1). Presently, ~70% of LQTS patients are reported to have a mutation in one of the 12 reported genes. Among the presently known 12 types of LQTS, the most common are LQT1, LQT2 and LQT3, caused by mutations in cardiac ion channel genes KCNQ1, KCNH2 and SCN5A, respectively. Mutations in these three genes constitute more than 90% of genotyped patients, both in adults and in children [713,19]. Among the remaining nine genes ANK2, CAV3, and AKAP9 are regulatory/chaperone genes, KCNE1, KCNE2, KCNJ2, SCN4B and SNTN-1 genes encode the ancillary subunits of major ion channels and CACNA1C encodes the pore forming α-subunit of the cardiac L-type calcium channel (table 1). Mutations in these 9-genes constitute 10% of the presently genotyped LQTS.

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

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Table 1. Summary of genes and chromosomal loci (where genes are not known) for LQTS Disease name LQT1

Diseases causing gene (encoded protein) KCNQ1 (KvLQT1)

Functional effect

Arrhythmia onset

Resting ECG

ECG at onset of arrhythmia

QT change with exercise

Response to βblockers

Extracardia c features

decreased IKs

emotinal or physical stress, swimming, diving emotinal or physical stress, sudden loud noise rest, sleep

broad based T wave

tachycardia

relative increase

yes

no

low-aplitude T wave with notching

with pause

some shortening

no

long isoelectric ST segment

pause? bradycardia

adequate shortening

yes, less than LQT1 response ns

ns

bradycardia, atrial arrhythmia

ns

ns

ns

no

ns auditory/acoustic stimulus like alarm clock noise, door ringing bell exercise

ns ns

ns ns

ns ns

yes ns

no no

large U-wave, extrasystoles very long QT interval ns

ns

ns

no

yes*

ns

ns

ns

yes**

ns

ns

ns

ns

LQT2

KCNH2 (HERG)

decreased IKr

LQT3

SCN5A (α-subunit of sodium channel, Nav1.5) Ank-B/ANK2 (ANK2)

increased late sodium current

LQT4

LQT5 LQT6

KCNE1 (minK) KCNE2 (miRP1)

LQT7

KCNJ2 (Kir2.1) CACNA1C (α-1 subunit of ICa-L) CAV3 (CAV3)

LQT8 LQT9

disruption of localization and posttranslational stability of Na+/Ca2+ exchanger decreased IKs decreased IKs

decrased IK1 increased L-type calcium current increased late sodium current

ns ns

no

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Table 1. (Continued). Disease name LQT10

Diseases causing gene (encoded protein) SCN4B (NaVβ4)

LQT11 LQT12

AKAP9 SNTN1 (SNTN1)

JLNS

biallelic mutations in KCNQ1 or KCNE1 biallelic mutations in KCNQ1

LQT1 (recessive)

Functional effect

Arrhythmia onset

Resting ECG

ECG at onset of arrhythmia

QT change with exercise

Response to βblockers

Extracardia c features

increased late sodium current decreased IKs Increased late sodium current loss of IKs

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns ns

ns ns

ns ns

see LQT1

ns

ns

ns

yes

ns

near absence of IKs

see LQT1

ns

ns

ns

yes

ns

ns: not specified *skeletal muscle periodic paralysis, cleft palate, low set ears, short stature. ** syndactyly, baldness at birth, small teeth, and occasionally cardiac structural malformations, autism, mental retardation, facial dysmorphic features.

Congenital Primary Arrhythmias in Children

5

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LQT1 Mutations in the KCNQ1 gene cause the commonest form of LQTS referred to as LQT1, comprising around 50% of the total genotyped LQTS patients. KvLQT1 (encoded by KCNQ1) along with its β-subunit minK (encoded by KCNE1) co-assemble to form the cardiac K+ channel (figure 1), which is responsible for the slowly activating delayed rectifier outward K+ current (IKs). In this form of the disease, syncope or sudden death is triggered by adrenergic drives e.g. emotional stress, physical exertion, diving, swimming [20]. Schwartz et al. (2001) reported that LQT1 patients, both children and adults, experienced the majority of their events (62%) during physical activities and only 3% during rest/sleep [21]. Swimming is a typical trigger for cardiac events in these patients. Pathogenic mutations in the KCNQ1 could be located all over the coding exons (including their intronic junctions). Patients between 7-20 yrs age with mutations at the transmembrane domains are susceptible to higher risk of LQTS-related cardiac events and have greater sensitivity to sympathetic stimulation [22-23]. Homozygous or compound heterozygous mutations in the KCNQ1 gene are rare, but when present, could cause the recessive type of the disease, JLN-S, with few exceptions [2431]. Clinical phenotypes in JLN-S patients are severer (also longer QTc) than the dominant LQT1, and the cardiac manifestations appear more frequently during the early childhood [32]. Patients with JLN-S suffer additionally from bilateral sensorineural deafness. JLN-S causing homozygous KCNQ1 mutations are predominantly truncating (except several missense mutations), leading to complete loss/absence of the functional KvLQT1 protein and IKs channel. This IKs is also present in the inner ear and is required to maintain normal hearing. In some exceptional cases, homozygous/compound heterozygous KCNQ1 mutation carriers could still have some residual IKs functions left, these patients suffer only from arrhythmias but not from deafness.

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Z. A. Bhuiyan, T. S. Momenah and A.A.M. Wilde

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Figure 1. Ionic currents contributing to the ventricular action potential (A) and schematic representation of a cardiomyocyte displaying (only) those proteins involved in the pathogenesis of inherited arrhythmia syndromes (B). In panel A, the action potential is aligned with its approximate time of action during the ECG. In panel B, ankyrin-B, an adapter protein involved in the long QT syndrome type 4, is not depicted. (Reproduced with modification and permission from authors, Wilde AA and Bezzina CR. 2005).

LQT2 LQT2 is equally prevalent as LQT1, accounting for 35-40% of genotyped LQT patients. Mutations in the KCNH2 gene are responsible for the LQT2 form of LQTS. KCNH2 encodes for the HERG protein, and mutations could cause reduction in the rapid component of the delayed rectifier repolarizing current (IKr). This reduction of the IKr contributes to lengthening of the QT interval (figures 1 and 2). 29% of the syncopal attacks in LQT2 occur during rest/sleep and only 13% of the syncopal attacks were reported during exercise [21]. Sudden startling noises e.g. alarm clock noise, telephone ringing often trigger syncopal events in these patients [21, 33]. Patients with mutations in the pore forming region of the HERG (encoded by KCNH2) gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations [34]. In neonates, 2:1 Atrioventricular block (AVB) is preferentially associated with KCNH2 mutations [35]. Homozygous mutations in KCNH2 are rare and when present, patients suffer from a severe form of LQT, with 2:1 AV block and severe ventricular arrhythmias, well before and immediately after birth [36-39]. Homozygous nonsense KCNH2 mutation carriers could have arrhythmia as early as during the intrauterine stages of life [36-37].

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LQT-3 LQT3 accounts for C) and one was a non-synonymous change (c.554G>A; p.S185N), both in exon 5. Neither variant was found among 144 ethnically matched normal control *

Corresponding author: Clifford Cua, MD; Assistant Professor of Pediatrics; Heart Center; Nationwide Children’s Hospital; 700 Children’s Hospital; Columbus, OH 43205-2696; [email protected]; Phone – 614-722-2530; Fax – 614-722-2549

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chromosomes. The p.S185N change involves a highly conserved amino acid, but was predicted to be a benign change by the PolyPhen program, Conclusion: BMPR2 unlikely plays a major role in the formation of atrioventricular septal defects in Down syndrome individuals. Further studies are needed to determine the etiology of congenital heart disease in patients with Down syndrome.

Keywords: Down syndrome; Congenital heart disease; Bone morphogenetic protein receptor.

Introduction

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Down syndrome (DS) is a common genetic disorder with national estimates of approximately 1/750 live-births [1]. Children with DS may have multiple medical issues including congenital heart defects (CHD). CHD incidence in newborns with Down syndrome is estimated to be approximately 50% with the most common defects being atrioventricular septal defects (AVSD) or ventricular septal defects[2,3]. Recent animal studies have shown that various bone morphogenetic proteins and bone morphogenetic receptors (BMPR) are involved in the formation of the fetal heart. Animal models that had dysregulation of this pathway either died in utero during gastrulation or had abnormal cardiac structures involving the atrioventricular or outflow tract areas[4]. Cardiac abnormalities described in these models include atrioventricular septal defects[2], ventricular septal defects, abnormal semilunar valves, truncus arteriosus, double outlet right ventricle, and interrupted aortic arch. The goal of this preliminary study was to determine if there was an increased prevalence of BMPR2 mutations in DS children with congenital heart defects.

Methods The Investigational Review Board approved this study. DNA was obtained from samples collected through several other projects[5]. Samples with trisomy 21 (DS) and atrioventricular septal defect (AVSD) were selected for this study. Patients with translocations, mosaic trisomy 21, or trisomy 21 plus another chromosome abnormality were excluded. Race was determined by report of the mother. BMPR2 DNA sequence (NCBI Ref Seq ID number NM_001204) was downloaded from Ensembl database (release 49). The entire coding sequence of the BMPR2 gene, consisting of 13 exons and their intron/exon boundaries was investigated by denaturing high pressure liquid chromatography (dHPLC). Seventeen polymerase chain reaction (PCR) primer pairs were used to generate amplicons for analysis (initial PCR primer sequences and dHPLC parameters kindly provided by Dr. Bart Janssen, University of Heidelberg, Germany)[6]. Amplicons were run on the WAVE MD system (Transgenomic Inc) at two different melting temperatures chosen through the Navigator software to optimize peak separation. Those sample amplicons with abnormal chromatograms were directly sequenced using Big Dye

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Terminator chemistry and the ABI 3700 capillary sequencer (Applied Biosystems Inc.) to identify base pair changes. Several bioinformatic tools were used to assess the sequence variants. Identified missense changes were analyzed in the program Polyphen (http://genetics.bwh. harvard.edu/pph/) to predict deleterious changes(1). Cross species sequence conservation of nonsense mutations was performed on reference sequence data using CLUSTAL-W alignment. Finally, we used the program RESCUE-ESE to see if any variants lay in an exon splice enhancer.

Results

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A total of 49 samples, 25 female, were analyzed. All samples were from Caucasian patients and all patients had a complete AVSD. Seven patients, four females, had echocardiographic evidence of PHTN; however, no cardiac catheterization data were available to verify the echocardiographic findings. We found deviations from the reference sequence in 14 patients, including one patient documented to have pulmonary hypertension (PHTN) (table 1). Three previously described single nucleotide polymorphisms (SNP) were identified: rs10714063, rs7575056, and rs2228545. The two intronic variants rs10714063 and rs7575056 appear to be in linkage disequilibrium, as the minor alleles of each SNP were always present in the same individuals. The SNP rs2228545 (c.2324G>A) causes the amino acid substitution p.S775N. Allele frequency data on the occurrence of rs7575056 and rs2228545 in the general Caucasian population were available from the NCBI website (http://www.ncbi.nlm.nih.gov/SNP). Frequencies were equal to the allele frequencies in our DS cohort. Table 1. BMPR2 Sequence Variants Variant position refSNP ID Amino acid change N PHTN Study frequency Population frequency

IVS3 43delT rs10714063

IVS4 +64, C/T rs7575056

Exon 5, c.554g>a

Exon 5, c.600a>c

p.S185N

p.L200

Exon 12, c.2324g>a rs2228545 p.S775N

9 0 0.09

9 0 0.09

1 0 0.01

4 0 0.04

3 1 0.03

Unk

0.138

Unk

Unk

0.05

C = cysteine, IVS = intervening sequence, L = leucine, N = asparagine, PHTN = pulmonary hypertension, SNP = single nucleotide polymorphism, T = threonine, Unk = unknown.

We also identified two novel changes in the coding region, one of which results in an amino acid substitution. The c.600A>C variant does not cause an amino acid change (p.L200). We queried this sequence region with the program RESCUE- ESE, and the variant does not appear to lie in an exon splice enhancer. The c.554G>A (p.S185N) nucleotide

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change in exon 5 is highly evolutionarily conserved across multiple vertebrate species (from primates to fish) with the exception of the Stickleback fish. The program PolyPhen, a tool which predicts possible impact of an amino acid substitution on the structure and function of a human protein using straightforward physical and comparative considerations, indicated that p.S185N was likely a benign change. Neither of these changes was found in 144 ethnically matched normal control chromosomes.

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Discussion DS is one of the most common genetic disorders and the most viable of the trisomies[2,3]. DS patients may present with multiple medical issues with CHD as one of the more common[2]. CHD in Down syndrome is likely to have a genetic component [7-13]. Recent data has shown that BMP’s and/or BMPR’s play an important role in both heart embryology as well as pulmonary vascular physiology[2]. In this preliminary study to determine if whether DS patients with CHD had an increased prevalence of BMPR2 mutations, we noted one novel missense variant (p.S185N) and one novel synonymous coding sequence change (p.L200). We also noted a previously described missense variant (p.S775N) in our cohort. The significance of these changes is unknown. Neither the p.S185N nor the p.L200 variants, to our knowledge, has been previously described, nor has the functional significance of the p.S185N variant been studied. Both the p.S185N and the p.L200 variants involve highly conserved sequence. The p.S185N variant, however, was predicted to be a benign change in the POLYPHEN program. One study noted that the c.2324G>A (SNP rs2228545), which causes the amino acid substitution p.S775N, did not appear to contribute a reduction in vasoreactivity. Similar to our data, this allele does not appear to be overrepresented compared to the frequency in the general population, suggesting this is not likely to be a pathogenic change. Functional studies will need to be performed to understand if the two novel variants identified here contribute to the pathogenesis of CHD in individuals with Down syndrome. Additionally, common or rare nucleotide variants outside the coding and immediate flanking regions could influence BMPR2 function. This possibility needs to be addressed in a larger case / control study. These findings suggest the BMPR2 gene is unlikely to play a major role in the etiology of CHD in this population. Since all the patients had an AVSD, no comment can be made if BMPR2 may play a role in other types of CHD. In animal models, mutations in this gene family caused abnormalities in both the endocardial cushions as well as the conotruncal area[7-9]. Conotruncal defects such as double outlet right ventricles, interrupted aortic arches, or truncus arteriosus, are rarely observed in DS. Since tetralogy of Fallot lesions may be observed[2], further studies in DS patients with Tetralogy of Fallot will be needed to determine if BMPR2 plays a role in that specific cardiac defect. Limitations of this study include its small sample size, but this study was meant to be a preliminary investigation. The samples studied were only in a Caucasian population with an AVSD. A recent study has shown differential rates of AVSD incidence by ethnicity in DS[2].

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This implies that genetic background plays a role in CHD susceptibility, an issue not addressed in this study. In conclusion, BMPR2 sequence variants were found in a minority of DS Caucasian patients with atrioventricular septal defects. BMPR2 is unlikely to play a major role in the formation of atrioventricular septal defects in DS individuals. Further studies are needed to determine the etiology of the various congenital heart defects in patients with DS.

Acknowledgments Presentation: Pediatric Academic Society Meeting, May 2008. Grant: We gratefully acknowledge the many families whose participation has made this study possible. This work was supported by The Research Institute at Columbus Children's Hospital (#224707), NIH R01 HD38979, NIH P01 HD24605, F32 HD046337, Children's Healthcare of Atlanta Cardiac Research Committee and by the technical assistance of the General Clinical Research Center at Emory University (NIH/NCRR M01 RR00039).

References [1]

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[2]

[3] [4]

[5]

[6] [7] [8] [9]

Improved national prevalence estimates for 18 selected major birth defects--United States, 1999-2001. MMWR Morb. Mortal. Wkly. Rep. 2006;54:1301-5. Freeman SB, Bean LH, Allen EG, et al. Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project. Genet. Med. 2008;10:173-80. Kallen B, Mastroiacovo P, Robert E. Major congenital malformations in Down syndrome. Am. J. Med. Genet. 1996;65:160-6. Kaneko K, Li X, Zhang X, Lamberti JJ, Jamieson SW, Thistlethwaite PA. Endothelial expression of bone morphogenetic protein receptor type 1a is required for atrioventricular valve formation. Ann. Thorac. Surg. 2008;85:2090-8. Grunig E, Koehler R, Miltenberger-Miltenyi G, et al. Primary pulmonary hypertension in children may have a different genetic background than in adults. Pediatr. Res. 2004;56:571-8. Kent WJ, Sugnet CW, Furey TS, et al. The human genome browser at UCSC. Genome Res. 2002;12:996-1006. Delot EC. Control of endocardial cushion and cardiac valve maturation by BMP signaling pathways. Mol. Genet. Metab. 2003;80:27-35. Delot EC, Bahamonde ME, Zhao M, Lyons KM. BMP signaling is required for septation of the outflow tract of the mammalian heart. Development. 2003;130:209-20. Keyes WM, Logan C, Parker E, Sanders EJ. Expression and function of bone morphogenetic proteins in the development of the embryonic endocardial cushions. Anat. Embryol. (Berl) 2003;207:135-47.

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[10] Schneider MD, Gaussin V, Lyons KM. Tempting fate: BMP signals for cardiac morphogenesis. Cytokine Growth Factor Rev. 2003;14:1-4. [11] Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat. Genet. 2000;26:81-4. [12] Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J. Med. Genet. 2000;37:741-5. [13] Machado RD, Pauciulo MW, Thomson JR, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am. J. Hum. Genet. 2001;68:92-102.

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In: Heart Disease in Children Editors: M. D. Oliveira and W. S. Copley

ISBN: 978-1-60741-504-6 © 2009 Nova Science Publishers, Inc.

Chapter X

Arterial Duct Stenting in Congenital Heart Disease with Duct-Dependent Pulmonary Circulation Giuseppe Santoro*, Chiara Marrone, Giovanbattista Capozzi, Gianpiero Gaio, Carola Iacono, Marianna Carrozza, Raffaella Esposito, Carmela Morelli, Maria Giovanna Russo, and Raffaele Calabrò

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Division of Cardiology, 2nd University of Naples, “Monaldi” Hospital, Naples, Italy

Abstract Background Congenital heart diseases with duct-dependent pulmonary blood flow are a wide spectrum of malformations characterized by high morbidity and mortality in neonatal age. Despite current trends toward early primary repair, surgical systemic-to-pulmonary artery shunt is still an invaluable palliative option in some high-risk patients with cyanotic congenital heart defects. However, maintaining the arterial duct patency by stent implantation has been proposed as an effective alternative to surgical systemic-to-pulmonary artery shunt in neonates with ductdependent pulmonary circulation who are unsuitable for primary repair or in whom there is anticipated spontaneous improvement of oxygen saturation as the pulmonary vascular resistance decreases. This paper highlights history, methodology and results of this innovative and minimally-invasive palliative option.

* Correspondence to: Giuseppe Santoro, MD, E-mail: [email protected], Phone/Fax +39-081-7064275, Via Vito Lembo, 14, 84131 – Salerno, ITALY Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

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Methods and Results Technical improvement of stents and delivery systems made arterial duct stenting a safe and feasible tool for short-term palliation of duct-dependent neonates and young infants. Arterial duct stenting is usually performed under general anesthesia or deep sedation. Following duct morphology evaluation, the stent is chosen to completely cover the entire ductal length and dilated to about 75% of the proposed surgical shunt. The procedure can be performed from arterial or venous approach and is successfully completed in the vast majority of cases. Procedural failure mainly depends on ductal tortuosity typical of complex cono-truncal anomalies as tetralogy of Fallot or pulmonary atresia with ventricular septal defect. The morbidity rate ranges from 8 to 11% and mainly consists in stent embolization or thrombosis and arterial access injury. The midterm fate of the stented duct is spontaneous, slow and progressive closure within a few months, although stent re-dilatation or stent-in-stent implantation can be easily and successfully performed whenever the clinical conditions warrant this. Arterial duct stenting promotes a more uniform and significant pulmonary artery growth than surgical shunt over a mid-term follow-up.

Conclusions Arterial duct stenting is a technically feasible, safe and effective palliation in congenital heart disease with duct-dependent pulmonary circulation. The stented arterial duct is less durable than a conventional surgical shunt although it shows high efficacy in promoting the global pulmonary artery growth.

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Introduction Congenital heart diseases with duct-dependent pulmonary blood flow are a wide spectrum of malformations resulting in severe pulmonary hypo-perfusion and thus in high morbidity and mortality in neonatal age. Incidence of these anomalies ranges from 0.02/1000 live births of pulmonary atresia with ventricular septal defect, to 0.057/1000 live births of tricuspid atresia, to 0.06/1000 live births of Ebstein’s anomaly of tricuspid valve and finally to 0.074/1000 live births of pulmonary atresia with intact ventricular septum (Keane JF, Nadas Pediatric Cardiology 2006). It has long been realized that patients with ductdependent pulmonary circulation would greatly benefit from arterial duct patency in view of spontaneous improvement or later lower-risk surgical repair. Thus, arterial duct stabilization has been attempted with various techniques over time.

Arterial Duct Histology Arterial duct is unique when compared with other vascular structures. Indeed, the arterial duct media mainly consists of muscular fibers spiraling in opposite directions and thereby encircling the channel, different from the medial layer of nearby great vessels that is composed primarily of elastic tissue. In addition, the arterial duct intima is thicker than that of the boundary arteries, and consists mainly of an endothelial layer and loose connective

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tissue (Ruiz CE, Circulation 1999). Also the responsive behavior of the ductal cell layers to different stimuli is unique. Indeed, the anatomical closure of the arterial duct requires that normally quiescent luminal endothelial and medial smooth muscle cells migrate into the subendothelial space to produce intimal mounts that eventually coalesce, thereby causing the vessel closure. This migratory process requires the exposure of multiple integrin receptors that lack in both smooth muscle cells and endothelial cells during prenatal life. However, both types of cells change their phenotype in early postnatal period and express a full repertoire of integrins (Clymans RI, Pediatr Res 1996), that trigger physiological remodeling. Thus, arterial duct remodeling differs from what observed in other arteries or veins subjected to traumatic insult. In addition, this response to injuries might be different in duct-dependent systemic blood flow as opposed to duct-dependent pulmonary blood flow, but these differences have so far not completely understood

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Physiology Natural history of severe cyanotic congenital heart disease mainly relies on the adequacy of the pulmonary blood supply. Reliable sources of pulmonary blood flow are arterial duct, systemic-to-pulmonary collateral arteries and plexuses of bronchial or pleural arteries. In most case, these latter are negligible and the arterial duct is the only source of pulmonary flow. Thus, its closure may lead to critical hypoxia within a few days of life and eventually to death if an alternative source of pulmonary blood supply is not provided. Arterial duct stabilization may be achieved for a short period by continuous intravenous prostaglandin E infusion that inhibits ductal smooth muscle contraction. However, this treatment may be maintained just for a short period and a stable pulmonary blood flow source must be provided within a few weeks. Goal of palliation of cyanotic congenital heart disease has always been to provide a controlled pulmonary blood flow. Historically, the Blalock-Taussig shunt was the first proposed option in infants with cyanotic congenital heart disease. It consists in direct end-to-side anastomosis (classic Blalock-Taussig shunt) or interposition of a tube graft between subclavian artery and the ipsilateral pulmonary artery (modified Blalock-Taussig shunt)(Blalock A, JAMA 1945). Over time, other systemic-to-pulmonary artery shunts have been proposed, including that from descending aorta to the left pulmonary artery, or Potts procedure (Potts WJ, JAMA 1946) or from ascending aorta to the right pulmonary artery, or Waterston procedure (Waterston DJ, Rozhl Chir 1962). In these latter options, the size and angulations of the prosthetic conduit must be carefully controlled to avoid pulmonary artery distortion and hypertension. Complication rate of Blalock-Taussig shunt is much lower than other types of systemic-to-pulmonary shunts, although pleural effusion, chylothorax, phrenic and vagal nerve palsy, distortion and differential growth of the pulmonary arteries (Fig. 1) are seldom reported and potentially increase morbidity and mortality of the subsequent corrective surgery (Alwi M, J Am Coll Cardiol 2004; Tamisier D, Ann Thorac Surg 1990). Also, it has been described a high incidence of late sudden death in patients who received Blalock-Taussig shunt, which is only partly explained by the limited life span of the shunt (Fermanis GG, Eur J Cardiothorac Surg 1992). To avoid these drawbacks, several surgical modifications have been proposed including central shunt between the aortic arch branches

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and the main pulmonary artery (Potapov EV, Ann Thorac Surg 2001). However, this latter option needs median sternotomy and cardiopulmonary by-pass that may be particularly challenging in small-sized or critical patients. Thus, mini-invasive percutaneous approaches have been suggested, mainly directed to arterial duct stabilization.

…

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(a)

(b)

(c) Figure 1. Mid-term complications following surgical Blalock-Taussig shunt (asterisk). A, stenosis at the site of shunt insertion with distal hypoplasia of the segmental pulmonary artery branches (arrows). B, pinching of the right pulmonary artery presumably due to shunt retraction. C, differential growth of the main pulmonary arteries. Abbreviations: LPA, left pulmonary artery; MPA, main pulmonary artery; RPA, right pulmonary artery

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Percutaneous Palliation

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Historical Perspective The idea of using the patent arterial duct as a native systemic-to-pulmonary communication first came up in 1974, when Lakier et al. reported that surgical formalin infiltration of the arterial duct with formaldehyde prevented its spontaneous post-natal closure without any apparent adverse effects in late gestational lambs (Lakier JB, Pediatr Res 1974). This technique inhibited the constriction of the ductal smooth muscle cells secondary to destruction of the whole medial layer, as confirmed on post-mortem histology. Rudolph et al. extended this concept to newborns with cyanotic congenital heart disease, whose arterial duct was exposed at thoracotomy and infiltrated with 10% buffered formaldehyde (Rudolph AM, N Engl J Med 1975). All infants improved clinically due to increase of systemic arterial saturation that was maintained over a short-term follow-up. This idea was later pursued by introducing transcatheter techniques such as balloon angioplasty, but the long-term results of this approach were disappointing (Lund G, Circulation 1983; Lund G, Circulation 1984). Early studies described the in-vivo balloon dilatation of the arterial duct in newborn pigs, resulting in ductal patency confirmed up to 6 weeks at autopsy. In these specimens, the histology showed splitting of the internal elastic layer and media, areas of haemorrhage confined to the media, and preservation of the adventitia (Lund G, Circulation 1983). However, the injury to the media and endothelium resulted in irregular ductal stenoses that hampered a wide clinical application of this approach (Abrams SE, Arch Dis Child 1994; Gibbs JL, Circulation 1995). Ductal flow stabilization by stent implantation inside the arterial duct to achieve a longer-time patency, was first described in the early ‘90s in newborns lambs (Coe JY, J Am Coll Cardiol 1991; Moore JW, Cardiovasc Interv Radiol 1991). These pre-historic studies showed the feasibility and efficacy of this approach without procedural complications and side effects. However, preliminary reports of human application of endovascular arterial duct stenting were published only a few years later. The initial attempts of neonatal arterial duct stenting in duct-dependent pulmonary circulation using early generation, rigid, bare stents deployed by bulky, stiff wires, balloons, and sheaths frequently resulted in life-threatening complications such as worsening cyanosis, bleeding, vessel rupture, duct spasm or acute stent thrombosis. The first implantation was reported by Gibbs in 2 neonates with pulmonary atresia (Gibbs JL, Br Heart J 1992), who died suddenly after the procedure as a consequence of pulmonary artery perforation and cardiac perforation, respectively. However, this preliminary report stated that the stenting procedure was technically feasible and provided an adequate short-term palliation resulting in balanced, central perfusion of both pulmonary arteries. In 1998, Schneider et al. reported a series of 21 neonates and infants (age range 1-65 days) submitted to Palmaz stent implantation (Schneider M, Eur Heart J 1998). The procedure was successful in all patients without major procedural complications, but 2 in-hospital deaths were recorded, due to septicaemia and low cardiac output respectively. Overall morbidity was 10.5% but an in-stent stenosis due to intimal proliferation was found in 11 of the 13 patients submitted to control angiography and required the stent re-dilatation in 5 of them. Over a mean follow-up of 8.7 months, a significant pulmonary artery growth was shown in all patients without any pulmonary artery

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distortion.. However, different results were reported by Gibbs in 11 infants (age range 4-78 days), 10 of them with pulmonary atresia and 1 with tricuspid atresia and restrictive ventricular septal defect (Gibbs JL, Circulation 1999). The stenting procedure was successful in 7 patients (63%). Procedural failures were due to ductal tortuosity in 2 cases and fatal ductal spasm in other 2 cases. Among the survivors, 2 died suddenly without any clear cause and 1 further patient died due to acute stent thrombosis confirmed at autopsy. Thus, only 3 patients survived over a mid-term follow-up, 2 of them with absent central pulmonary arteries. These results prompted the authors to conclude that trans-catheter ductal stenting in duct-dependent pulmonary blood flow was justified only in the rare subgroup of pulmonary atresia and disconnected pulmonary arteries served by bilateral ducts, who were at high-risk for surgical palliation. Over time, technical improvement of stents and delivery systems made percutaneous arterial duct stenting safer and more feasible tool in short-term palliation of duct-dependent neonates and young infants. Following these preliminary experiences, several series were reported concerning the mid-term follow up of this approach. Michel-Behnke et al. treated 21 newborns and infants (age range 1-50 days) with balloon-expandable stents (Michel-Behnke I, Cathet Cardiovasc Interv 2004), reporting minor complications in 5 patients (24%), in 3 cases the stent embolization, in 1 patient the stent thrombosis and, finally, in 1 patient occlusion of the arterial access. The re-intervention was required in 9 patients (43%) because of significant re-stenosis and an aorto-pulmonary shunt was needed in further 3 cases (15%). However, the overall survival rate at 6 years was 86%, prompting the authors to conclude that this transcatheter approach was technically feasible and might be the first-choice option for short-term palliation of duct-dependent neonates. During the same period, Alwi et al. attempted the arterial duct stenting in 56 patients with a median age of 2.3 months (range 7 days-2.8 years)(Alwi M, J Am Coll Cardiol 2004). In five patients (8.9%), the procedure was abandoned because of the very proximal origin of the arterial duct from the aortic arch, or its extreme tortuosity. There was no mortality related to the procedure and also the morbidity rate was negligible. Over a follow-up period of 9.6 months (range 3.2 months-2.4 years), 9 patients underwent surgical shunt or stent re-dilatation due to sub-acute stent trombosis or intra-stent stenosis. In addition, 7 patients showed the worsening of preexisting branch PA stenoses and 5 of them were referred to surgical shunt. Thus, overall freedom from re-intervention was 89% and 55% at six months and one year, respectively. Thus, this report confirmed the feasibility and short-term efficacy of this approach in neonates and young infants, suggesting that the arterial duct morphology predicted the risk of re-stenosis and need for re-intervention. Based of this experience, the authors stated that an absolute contraindication to this technique was the stenosis of the main pulmonary branches at the site of duct insertion. In 2004, Gewillig et al. reported a series of 10 selected neonates and infants with duct-dependent pulmonary circulation (age range 1-42 days) and short and straight duct who were submitted to stent implantation (Gewillig M, J Am Coll Cardiol 2004). The procedure was successfully completed in all cases without any complication, but 3 patients needed anti-congestive therapy early after stenting due to pulmonary overflow. At control cardiac catheterization after 4.7 months, an adequate growth of the pulmonary arteries was observed. There were no cases of acute stent occlusion but a luminal narrowing of the duct was found in all patients, prompting to re-dilatation in 1 case. Similar results were reported by Santoro et al. in a series of 26 patients, mostly at high-risk for conventional

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surgical shunt or with an anticipated short-term need of pulmonary flow support (Santoro G, Heart 2008). In this report, the success rate was nearly 93% and the procedural failures were mainly due to ductal tortuosity. Morbidity rate was 8.3% and no fatality cases were reported. According to previously published series, the stented arterial duct tended to be less durable than a conventional surgical shunt due to ductal tissue prolapse through the stent struts and intra-stent endothelial hyperplasia, with spontaneous, slow and progressive closure within a few months.

Indication

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The choice of arterial duct stenting in alternative to surgical shunt strongly depends on the local policy of any single centre as well as the technical skill and propensity of the interventional cardiologist and pediatric cardiac surgeon. However, the percutaneous approach is nowadays widely deemed as a safer and more “physiologic” option with respect to a Blalock-Taussig shunt in that results in a better distribution of the pulmonary blood flow (Alwi M, J Am Coll Cardiol 2004; Gewillig M, J Am Coll Cardiol 2004; Gibbs JL, 1992; Santoro G, Heart 2008). In addition, the shunt magnitude may be more finely tailored to the single patient’s size and anatomy (Abrams SE, Int J Cardiol 1993) and, in the case of very low-weight neonates, the stent diameter may be progressively increased by serial balloon dilatations to adapt the shunt magnitude to the patient growth. However, the inclusion criteria to a stenting program could be roughly set as follows: a) Patients with high-risk profile for conventional surgery. It should be considered at high-risk a low-weight and/or critically-ill neonate due to significant co-morbidities or with unusual anatomic arrangement of the pulmonary arteries (for example, with the arterial duct serving a discontinuous pulmonary artery (Fig. 2) or with bilateral ducts serving isolated pulmonary arteries (Fig. 3) (Butera G, J Interv Cardiol 2008; Santoro G, Tex Heart Inst J 2005; Santoro G, Ped Cardiol 2008). b) Patients with anticipated need for a short-term support to the pulmonary circulation. This condition could be supposed in those patients with pulmonary atresia and intact ventricular septum after successful radio-frequency pulmonary valve perforation or in critically cyanosed neonates due to Ebstein’s anomaly of the tricuspid valve and functional pulmonary atresia. In the former case, the elective stenting of the arterial duct has to be performed some few days after catheter valvotomy after failure to wean from prostaglandin infusion. Stenting of the arterial duct might be indicated in critically cyanotic, duct-dependent patients with Ebstein’s anomaly of tricuspid valve who are unresponsive to pulmonary vasodilator therapy with prostaglandin infusion, inhaled nitric oxide and high-frequency ventilation (Santoro G, J Cardiovasc Med 2008; Santoro G, Ped Cardiol 2008). Finally, this approach could be advisable also in complex cardiac malformations with uni-ventricular physiology destined to the Fontan operation, in which the stented duct could act just as a bridge toward an early cavo-pulmonary anastomosis, at the same time supporting an adequate and balanced pulmonary artery growth.

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Giuseppe Santoro, Chiara Marrone, Giovanbattista Capozzi et al. c) Elective alternative to systemic-to-pulmonary artery shunt in low-risk neonates in whom early surgical repair may be planned. This anatomic arrangement is typical of complex congenital heart malformations in which no need for prosthetic conduits at corrective surgery might be anticipated. In fact, the mid-term fate of the stented duct is that of spontaneous, slow and progressive closure within a few months, although stent re-dilatation or stent-in-stent implantation can be quite easily performed whenever the clinical conditions warrant this

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(a)

(b)

(c) Figure 2. Percutaneous stenting of a left arterial duct serving an isolated left pulmonary artery. A, aortic angiography in postero-anterior view imaging the right aortic arch with mirror image branching of epiaortic vessels. A left-sided arterial duct arises from the innominate artery and serves the discontinuous left pulmonary artery. B, the arterial duct is stented with a coronary stent, resulting in stabilization of the arterial duct-left pulmonary artery complex (C) Abbreviations: AD, arterial duct; LPA, left pulmonary artery

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(c) Figure 3. Stenting of bilateral arterial ducts serving discontinuous pulmonary arteries. A, Aortic angiography showing the anatomic pattern of the ascending aorta and its main branches as well as the bilateral arterial ducts arising from the underside of the right aortic arch (right duct) and the base of the innominate artery (left duct). B, Bilateral stenting procedure from the right carotid artery. C, Final angiographic result after implantation of multiple chromium-cobalt coronary stents. Abbreviations: LAD, left arterial duct; RAD, right arterial duct.

Contraindications Apart the classic contraindications to angiography as contrast-medium allergy, or to prosthesis implantation as active endocarditis, arterial duct stabilization by percutaneous stent implantation should be avoided in the case of pulmonary artery stenosis at the site of duct

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insertion since this problem may worsen early after stent implantation (Alwi M, J Am Coll Cardiol 2004; Elzenga NJ, Int J Cardiol 1986). As previously reported, relative contraindications may also be considered the extreme ductal tortuosity or an anticipated longterm palliation. Paradoxically, arterial duct closure should not be considered an absolute contraindication to the stenting procedure, provided the channel be re-canalized (Marrone C, Int J Cardiol 2009; Santoro G, Ped Cardiol 2008)(Figgs. 4, 5). This goal may be achieved with pharmacological and/or mechanical tools, as local infusion of prostaglandin through end-hole catheters located inside the ductal ampulla or manipulation of chronic-occlusion coronary guide-wires

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(a)

(b)

(c) Figure 4. Re-canalization and stenting of an occluded arterial duct. A, Aortic angiography in lateral view showing the complete closure of the arterial duct (asterisk). B, It is re-canalized with a coronary guide-wire (arrow) after local infusion of prostaglandins through an end-hole catheter and stabilized with a coronary stent (C). Abbreviations: Ao, descending aorta. PA, main pulmonary artery

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(b)

(c) Figure 5. Re-canalization and stenting of a 3 month-old infant with tetralogy of Fallot and isolated left pulmonary artery arising from an occluded left arterial duct. A, Aortic angiography in postero-anterior view showing the right aortic arch with mirror-image branching of the epi-aortic vessels and the complete closure of a left-sided arterial duct arising from the base of the innominate artery. B, the duct has been re-canalized with a chronic-occlusion coronary guide-wire and stabilized with a coronary stent, thereby re-opening the left pulmonary artery (C). Abbreviations: AD, arterial duct. Ao, ascending aorta. LPA, left pulmonary artery.

Interventional Procedure Arterial duct stenting is usually performed under general anesthesia or deep sedation. Prophylactic antibiotic treatment is recommended. Vascular access is mostly obtained

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through 5 Fr venous sheaths and/or 3-4 Fr arterial sheaths. In complex anatomic arrangements, it could be advisable to image the anatomic arrangement of the aorta, arterial duct and pulmonary arteries by the venous route and then to perform the interventional procedure from the arterial site, choosing the straightest course to the duct from carotid, axillary, umbilical or femoral arteries. Standard intravenous heparin is given (100 IU/kg) after vessel cannulation and anti-platelet therapy is recommended (acetylsalicylic acid, 3-5 mg/Kg/day) after stent deployment, to maintain long-term ductal patency. Arterial duct profiling is usually obtained in multiple views, to reduce any foreshortening or mis-sizing of the channel. Ductal morphology usually predicts the technical difficulty of stent implantation. Short and straight ducts are typically observed in patients with critical pulmonary stenosis or atresia and may be easily stented using the femoral artery approach (Fig. 6). However, long and tortuous ducts are frequently found in cono-truncal malformations such as tetralogy of Fallot, pulmonary atresia with ventricular septal defect, heterotaxia or other complex cardiac malformations with pulmonary obstructions, and are the major cause of procedural failure (Fig. 7). It is advisable to abandon the procedure whenever the duct shows multiple, sharp bends in different planes (Fig. 8), in the belief that multiple bends in a single plane could still be reasonable straightened once the stiffer part of a coronary guide-wire is passed across the vessel, but this would not be the case in different planes. Finally, the arterial duct may serve discontinuous pulmonary arteries, more frequently arising from the innominate or subclavian artery. In this case, the arterial duct is relatively straight and may easily stented, provided an optimal orientation from the arterial side is chosen. Prostaglandin infusion should be stopped some few hours before the procedure, in order to grip the stent at deployment. This trick is even more critical in the case of straight ducts that less firmly maintain the stent after deployment. Conversely, in the case of long and tortuous ducts, ductal constriction is less important in that the multiple bends do themselves act as stable constrictors. In choosing a stent, important features are length, diameter and design. Ideally, the stent should have high trackability, open-cell design and as less metallic mass as possible, in order to reduce the endothelial reactive hyperplasia. Most of these technical characteristics are found in the newest chromium-cobalt coronary stents that may be deployed through 3 or 4Fr sheaths. Covering the full length of the arterial duct is fundamental to avoid any post-procedure ductal spasm and should be ideally obtained using a single stent. Thus, the chosen stent should be slightly longer than the ductal length. Choosing the stent length is relatively easy in straight ducts, while it may be challenging in tortuous ducts. In this latter case, the arterial duct length may change when it is straightened by a rigid guide-wire, thereby making very difficult the choice of the stent length. In this setting, it could be advisable to introduce inside the duct serially longer coronary angioplasty balloons using the catheter markers to precisely evaluate the effective ductal length by repeat angiographies. The diameter of the stent should be chosen individually, based on the size of the patient and the expected time for which the palliation is needed. However, it should be always about 75% of the proposed surgical shunt size in the belief that it acts more as a central shunt than a Blalock-Taussig shunt. After deployment of the stent, repeat angiographies should be performed in multiple views to exclude any incomplete coverage of the duct as well as to evaluate any potential stent-related pulmonary artery stenosis.

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Figure 6. A-D, Procedural steps in percutaneous stenting of a straight arterial duct (arrow). It is imaged from the aortic site (A), negotiated using a coronary guide-wire (B) and stabilized with a highflexibility coronary stent (C), with significant increase of the pulmonary artery blood flow (D).Abbreviations: DA, descending aorta; LPA, left pulmonary artery; PA, main pulmonary artery; RPA, right pulmonary artery.

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(a)

(b)

(c) Figure 7. A-C, Stenting procedure of a long, tortuous arterial duct (asterisk) in a complex congenital heart disease. In this case, the arterial approach from the left subclavian artery was deemed as the straightest course to negotiate and stabilize the arterial duct (A). The length of the stent is chosen after the angiographic evaluation of the duct straightened by a stiff coronary guide-wire (arrow)(B). Following the stent deployment the duct is significantly straightened and widely patent (C). Abbreviations: AA, ascending aorta; DA, descending aorta; left pulmonary artery; LPA, left pulmonary artery; RPA, right pulmonary artery

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(a)

(b) Figure 8. Arterial duct considered unsuitable for percutaneous stent implantation. Note the extreme tortuosity of the channel (asterisks) that shows multiple bends in different orthogonal planes. Abbreviations: LPA, left pulmonary artery; RPA, right pulmonary artery

Follow-Up Acute or early stent occlusion has not so far been reported in literature and even the overall rate of sub-acute stent thrombosis is very low, even if the stent diameter is usually smaller than the proposed surgical shunt (Boshoff DE, Expert Rev Cardiovasc Ther 2007; Santoro G, Heart 2008). However, the stented arterial duct tends to be less durable than a conventional surgical shunt due to ductal tissue prolapse through the stent struts and intrastent endothelial hyperplasia, as reported in several studies (Alwi M, J Am Coll Cardiol 2004; Coe JY, J Am Coll Cardiol 1991; Gibbs JL, Circulation 1999; Rosenthal E, Br Heart J

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1992; Santoro G, Heart 2008). Indeed, the mid-term fate of the stented duct is that of spontaneous, slow and progressive closure within a few months, although stent re-dilatation or stent-in-stent implantation can be easily and successfully performed. However, newer technologies, such as drug-eluting or more flexible, covered stents might broaden the application of this therapeutic strategy and improve long-term patency of the stented duct. Several studies reported an effective long-term stent patency provided large stent (>5 mm) were used, but, in this case, an early anti-congestive treatment had to be provided due to the shunt magnitude. However, despite an usually lower durability with respect to conventional surgical shunt, the stented duct showed high efficacy in promoting the global pulmonary artery growth (Fig. 9)(Alwi M, J Am Coll Cardiol 2004; Gewillig M, J Am Coll Cardiol 2004; Michel-Behnke I, Cathet Cardiovasc Interv 2004; Santoro G, Heart 2008). In addition, a preliminary report showed a more uniform development of the main pulmonary branches after neonatal arterial duct stenting than following Blalock-Taussig shunt (Santoro G, Cathet Cardiovasc Interv 2008).

(a)

(b)

Figure 9. Pulmonary artery growth following arterial duct stenting. A, in this 1.9 kg neonate, severely hypoplastic pulmonary arteries showed a significant development after 6 months from the arterial duct (asterisk) stabilization (B).Abbreviations: DA, descending aorta; LPA, left pulmonary artery; MPA, main pulmonary artery; RPA, right pulmonary artery

Conclusions In conclusion, arterial duct stenting using low-profile, high-flexibility, pre-mounted coronary stents is a technically feasible, safe and effective palliation in a high percentage of cases. It is advisable either in surgically high-risk neonates or in low-risk patients whenever a short-term pulmonary blood flow support is anticipated. Indeed, the stented arterial duct either supports the spontaneous physiologic improvement process or promotes a significant

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growth of the pulmonary artery over a mid-term follow-up. In addition, it warrants a more homogeneous pulmonary blood flow than a Blalock-Taussig shunt thereby resulting in a more balanced growth of the pulmonary artery bed. Thus, it could be proposed as the firstchoice approach in short-term palliation of these malformations in view of a spontaneous improvement or an early and safer corrective surgery, although its use should still be restricted to single centers with special expertise and experience.

References [1] [2]

[3]

[4] [5]

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[6]

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[13]

Abrams SE, Walsh KP. Arterial duct morphology with reference to angioplasty and stenting. Int J Cardiol 1993; 40: 27-33 Abrams SE, Walsh KP, Diamond MJ, Clarkson MJ, Sibbons P. Radiofrequency thermal angioplasty maintains arterial duct patency. An experimental study. Circulation 1994; 90: 442-448 Alwi M, Choo KK, Latiff HA, Kandavello G, Samion H, Mulyadi MD. Initial results and medium term follow up of stent implantation of patent ductus arteriosus in ductdependent pulmonary circulation. J Am Coll Cardiol 2004; 44: 438-445 Blalock A, Taussig H. The surgical treatment of malformations of the heart in which there is pulmonary stenosis or pulmonary atresia. J Am Med Ass 1945; 128: 189-202 Boshoff DE, Michel-Behnke I, Schranz D, Gewillig M. Stenting the neonatal arterial duct. Expert Rev Cardiovasc Ther 2007; 5: 893-901 Butera G, Santoro G, Calabrò R, Carminati M. Percutaneous treatment of ductal origin of the distal pulmonary artery in low-weight newborns. J Inv Cardiol 2008; 20: 354356. Clymans RI, Goetzman BW, Chen YQ, Mauray F, Kramer RH, Pytela R, Schnapp LM. Changes in endothelial cell and smooth muscle cell integrin expression during closure of the ductus arteriosus: an immuno-histochemical comparison of the fetal, preterm newborn and full-term newborn rhesus monkey ductus. Pediatr Res 1996; 40: 198-208 Coe JY, Olley PM. A novel method to maintain ductus arteriosus patency. J Am Coll Cardiol 1991; 18: 837-841 Elzenga NJ, Gittenberger-de Groot AC. The ductus arteriosus and stenoses of the pulmonary arteries in pulmonary atresia. Int J Cardiol 1986; 11: 195-208 Fermanis GG, Ekangaki AK, Salmon AP et al. Twelve year experience with the modified Blalock-Taussig shunt in neonates. Eur J Cardiothorac Surg 1992; 6: 586589 Gewillig M, Boshoff DE, Dens J, Mertens L, Benson LN. Stenting the neonatal arterial duct in duct-dependent pulmonary circulation: new techniques, better results. J Am Coll Cardiol 2004; 43: 107-112 Gibbs JL, Rothman MT, Rees MR, Parsons JM, Blackburn ME, Ruiz CE. Stenting of the arterial duct: a new approach to palliation for pulmonary atresia. Br Heart J 1992; 67: 240-245 Gibbs JL. Stenting of the arterial duct. Arch Dis Child 1995; 72: 196-197

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[14] Gibbs JL, Uzun O, Blackburn MEC, Wren C, Hamilton L, Watterson KG. Fate of the stented arterial duct. Circulation 1999; 99: 2621-2625 [15] Keane JF, Lock JE, Fyler DC. Nadas’ Pediatric Cardiology, II edition, 2006. Saunders Elsevier [16] Lakier JB, Heymann MA, Rudolph AM. Inhibition of closure of the ductus arteriosus. Pediatr Res 1974; 8:351-360 [17] Lund G, Cragg A, Rysavy J, Castaneda F, Salomonowitz E, Vlodaver Z, CastenedaZuniga W, Amplatz K. Patency of the ductus arteriosus after balloon dilatation: an experimental study. Circulation 1983;68: 621-627 [18] Lund G, Rysavy J, Cragg A, Salomonowitz E, Vlodaver Z, Zuniga WC, Amplatz K. Long-term patency of the ductus arteriosus after balloon dilatation: an experimental study. Circulation 1984; 69: 772-774 [19] Marrone C, Santoro G, Palladino MT, Caianiello G, Russo MG, Calabrò R. Hybrid palliation in complex congenital heart malformation with duct-dependent isolated pulmonary artery. Int J Cardiol 2009 (In press) [20] Michel-Behnke I, Akiturch H, Thul J, Bauer J, Hagel KJ, Schanz D. Stent implantation in the ductus arteriosus for pulmonary blood supply in congenital heart disease. Cathet Cardiovasc Interv 2004; 61: 242-252 [21] Moore JW, Kirby WC, Lovett EJ, O’ Neill JT. Use of an intravascular prosthesis (stent) to establish and maintain short-term patency of the ductus arteriosus in new born lambs. Cardiovasc Interv Radiol 1991; 14: 299-301 [22] Potapov EV, Alexi-Maskishvili VV, Dahnert I, Ivanitskaia EA, Lange PE, Hetzer R. Development of pulmonary arteries after centrala orto-pulmonary shunt in newborns. Ann Thorac Surg 2001; 71: 899-906 [23] Potts WJ, Smith S, Gibson S. Anastomosis of the aorta to a pulmonary. Certain types in congenital heart disease. J Am Med Ass 1946; 132: 627-631 [24] Rosenthal E, Qureshi SA. Editorial: stent implantation in congenital heart disease. Br Heart J 1992; 67: 211-212 [25] Rudolph AM, Heymann MA, Fishman N, Lakier JB. Formalin infiltration of the ductus arteriosus. A method for palliation of infants with selected congenital cardiac lesions. N Engl J Med 1975; 292: 1263-1268 [26] Ruiz CE, Bailey LL. Stenting the ductus arteriosus: a "wanna be" Blalock-Taussig. Circulation 1999; 99: 2608-2609 [27] Santoro G, Bigazzi MC, Palladino MT, Russo MG, Carrozza M, Calabrò R. Transcatheter palliation of tetralogy of Fallot with pulmonary artery discontinuity. Tex Heart Inst J 2005; 32: 102-104 [28] Santoro G, Caianiello G, Russo MG, Calabrò R. Stenting of bilateral arterial ducts in complex congenital heart disease. Ped Cardiol 2008; 29: 842-845 [29] Santoro G, Gaio G, Caianiello G, Palladino MT, Farina G, Carrozza M, Russo MG, Calabrò R. Pulmonary artery growth after palliation of congenital heart disease with duct-dependent pulmonary flow: arterial duct stenting vs surgical shunt. Cathet Cardiovasc Interv 2008; 71: O2.

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[30] Santoro G, Gaio G, Palladino MT, Carrozza M, Iacono C, Russo MG, Caianiello G, Calabrò R. Transcatheter ductal stenting in critical neonatal Ebstein’s anomaly. J Cardiovasc Med 2008; 9: 419-422 [31] Santoro G, Gaio G, Palladino MT, Carrozza M, Russo MG, Calabrò R. Neonatal Patent Ductus Arteriosus Recanalization and “Stenting” in Critical Ebstein’s Anomaly. Ped Cardiol 2008; 29: 176-179 [32] Santoro G, Gaio G, Palladino MT, Iacono C, Carrozza M, Esposito R, Russo MG, Caianiello G, Calabrò R. Stenting of the arterial duct in newborns with duct-dependent pulmonary circulation. Heart 2008; 94: 925-929 [33] Schneider M, Zartner P, Sidiropouluos A, Konertz W Hausdorf G. Stent implantation of the arterial duct in newborns with duct-dependent circulation. Eur Heart J 1998; 19: 1401-1409 [34] Tamisier D, Vouhe PR, Vermant F, Leca F, Massoat C, Neveux J. Modified Blalock Taussig shunts: results in infants less than 3 months of age. Ann Thorac Surg 1990; 40: 797-802 [35] Waterston DJ. The treatment of Fallot’s tetralogy in children under one year of age. Rozhl Chir 1962; 41: 181-183

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ISBN: 978-1-60741-504-6 © 2009 Nova Science Publishers, Inc.

Chapter XI

Rare Reason for Myocardial Infarction in Adolescence: Anomalous Origin of the Left Main Coronary Artery in Association with Combined Prothrombotic Defects Martin Koestenberger*

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Division of Pediatric Cardiology, Department of Pediatrics, Medical University Graz, Graz, Austria

Abstract An adolescent is presented with clinical features of an acute myocardial infarction including signs of a cardiogenic shock and loss of consciousness. Angiography revealed a complete obstruction of the left main coronary artery. Coronary-aorto bypass graft was undertaken immediately. A cardiac CT demonstrated an anomalous origin of the left main coronary artery from the right coronary sinus of the aorta. It followed a short interarterial course between the aorta and the main pulmonary artery supplying the anterior descending and circumflex coronary arteries. A thrombophilic state with a heterozygote genotype for prothrombin G20210 mutation, a C677T methylenetetrahydrofolate reductase gene mutation, and a protein C type 1 deficiency was detected. No other embolic source could be identified. This instructional patient recovered with persistent left ventricular dysfunction and is now anticoagulated with warfarin. Combined prothrombotic defects in combination with additional risk factors like coronary anomalies can lead to MI even in children and adolescents. Therefore, to my opinion the diagnostic work up should include a complete thrombophilia screening.

Keywords: myocardial infarction; adolescent; coronary anomaly; prothrombotic defects. *

Correspondence to: Martin Koestenberger, MD; Department of Paediatrics; Medical University Graz; Auenbruggerplatz 30; A-8036 Graz, Austria; Tel.: +43 316 385 2605; Fax: +43 316 385 2619; E-mail: [email protected] or [email protected] This study was supported by grants from the “Franz-Lanyar-Stiftung”.

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Abbreviations MI CT MTHFR ECG CK CK-MB NT-proBNP LMT RCA CABG LAD LCX RCA ACE

myocardial infarction computed tomography methylenetetrahydrofolate reductase electrocardiography creatine kinase creatine kinase-myocardial band N-terminal fragment pro-brain natriuretic peptide left main trunk right coronary artery coronary-aorto bypass graft left anterior descending artery left circumflex coronary artery right coronary artery angiotensin-converting enzyme

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Introduction Myocardial infarction (MI) is uncommon in previous asymptomatic adolescents [1]. In this age group various case reports describe sudden cardiac events like MI secondary to coronary anomalies [2], drug use [3], and heritable thrombophilia [4]. A patent foramen ovale associated with heritable thrombophilia has also been discussed as triggering mechanism [5]. Anomalous origin of the left coronary artery from the right coronary sinus is known to be a cause of sudden death in adolescents [6]. Rarely, a combination of a heterozygote genotype for prothrombin G20210 mutation and a heterozygote genotype for C677T methylenetetrahydrofolate reductase (MTHFR) gene mutation, and a Protein C type 1 deficiency can be important risk factors for spontaneous thrombosis in childhood and adolescents [7-9]. Although infrequent a combination of MTHFR gene mutation and prothrombin G20210 mutation as a cause of MI has been reported [4]. However, only rare data exist about an association of protein C deficiency and the development of MI [10]. To the best of my knowledge no data exist about the combination of risk factors given in this instructional case.

Case Report A 15 year old boy, without any previous cardiac history experienced acute chest pain and dyspnoea while playing football. On admission he still suffered from pain but in decreased intensity. The ECG showed sinus rhythm with ST elevation in lead I, aVL and in V2-V6. The myocardial enzymes were significantly increased: troponin T was 11.900 ng/ml (normal values: 0–0.05 ng/ml), myoglobin was 2014 ng/ml (normal values: 0-80 ng/ml) and CK-MB was 1376 U/L (normal values: 0-13 U/L). Further laboratory investigations were as follows:

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creatine phospokinase was 17600 U/L (normal values: 0-160 U/L), aspartate transaminase was 1832 U/L (normal values: 0-43 U/L), red blood cells, white blood cells, hemoglobin, renal function, standard coagulation markers, and NT-proBNP were within the normal limits. Urine drug screens were negative. Echocardiography showed a markedly decreased left ventricular function and the left main trunk (LMT) could not be visualized. Emergency cardiac catheterization revealed a normal right coronary artery (RCA), but the LMT was completely obstructed, as shown in figure 1, and stenting by cardiac catheterization was not possible. Clinically, the patient showed signs of a cardiogenic shock and loss of consciousness. In an emergency operation the proximal part of the left coronary system was found to be completely occluded and the initial attempted mechanical recanalization and rapid restoration of coronary flow failed. Therefore coronary-aorto bypass graft (CABG) was performed to both the left anterior descending artery (LAD) and left circumflex coronary artery (LCX). Postoperative course was uncomplicated. Postoperative treatment consisted of a combination of diuretics, beta-blockers and ACE inhibitors as well as anticoagulant treatment with unfractionated heparin and aspirin. Thrombophilia studies established a heterozygote genotype for prothrombin G20210 mutation and a heterozygote genotype for C677T MTHFR gene mutation. Protein C activity and antigen were reduced to 36 % and 45 %, respectively. Protein S activity was normal. Factor V Leiden mutation was absent, as was lupus anticoagulant and anticardiolipin anticoagulants. Doppler evaluation of the abdominal and lower limb veins and arteries were normal. Contrast transesophageal echocardiography excluded a paradoxical embolic event via a patent foramen ovale. The mother was heterozygote for prothrombin G20210 mutation and heterozygote for factor V Leiden but has not experienced venous thrombosis to date. A postoperative computed tomography (CT) angiography using the 64-slice CT technology demonstrated an anomalous origin of the hypoplastic LMT from the right coronary sinus. It followed a short interarterial course between the aorta and the main pulmonary artery supplying the anterior descending and circumflex coronary arteries, as shown in figure 2. Serial echocardiography demonstrated persistent impaired left ventricular function. The ECG 2 weeks following the MI exhibited pathologic deep Q-waves in aVL, V1-V6, and negative T-waves in V3-V6. Due to the CABG and the combined prothrombotic defects anticoagulant treatment with warfarin was started.

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Figure 1. Coronary angiography. (a) Hand injection into the right coronary sinus only showed the right coronary artery but not the left main trunk (LMT). (b) Hand injection into the left coronary sinus without visualization of the LMT. Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

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Figure 2. (a) Axial scan at the level of the left main coronary artery, the hypoplastic left main coronary artery arising from the right coronary sinus with an abnormal course between the aorta and the main pulmonary trunk. (b) Axial scan at the level of the RCA, regular origin of the RCA, the hypoplastic LAD and LCX.

Discussion Possible causes that can lead to MI in children and adolescents are Kawasaki disease, known atherosclerotic disease, drug abuse, sickle cell disease or myocarditis and therefore have to be excluded [1]. In addition, spontaneous, iatrogenic or paradoxical coronary artery embolism can result in MI in adolescents [5]. However, the most common cause of an acute MI in children and adolescents is an anomaly of the coronary arteries. The left coronary

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artery arising from the right coronary sinus is a rare but dangerous congenital coronary anomaly that can lead to sudden death in adolescents and young adults [6]. The course of the LMT between the aorta and the main pulmonary trunk in combination with physical exercise is known to be associated with sudden cardiac death [11]. In children and adolescents presenting with an acute MI immediate cardiac catheterization is mandatory. If coronary abnormalities are detected a 64-slice CT, a method that has recently been shown to accurately detect obstructive coronary artery disease [12], is helpful in the diagnosis of an abnormal coronary artery course like in this patient. Therefore, in my opinion the diagnostic work up should also include a complete thrombophilia screening. As shown in various studies, the prothrombin G20210 and a C677T MTHFR gene mutation, and deficiencies of protein C are important risk factors for thrombosis in childhood and adolescents [8, 13]. The prevalence of the prothrombin G20210 and the C677T MTHFR gene mutation in the normal population is 1.3 % and 10.4 % respectively [7, 8]. The prevalence of the combined prothrombotic defects given in our case so far is not reported in the literature. Although the results of Doggen et al [14] in adults indicate that the importance of the prothrombin G20210A mutation is restricted to individuals who have additional cardiovascular risk factors it has recently been shown for adolescents that this gene mutation seems to be the only prothrombotic risk factor associated with the risk of developing MI in that age group [10]. In this instructional case, the MI occurred in an adolescent who is heterozygous for the prothrombin G20210 and the C677T MTHFR gene mutation, and has also a protein C type 1 deficiency. I assume that coronary occlusion in this patient occurred due to the combination of physical activity, multiple heritable prothrombotic defects and the hypoplastic anomalous origin LMT from the right coronary sinus with an abnormal course between the aorta and the main pulmonary trunk.

Conclusion MI in children and adolescents is rare and continues to be a diagnostic challenge. Combined prothrombotic defects in combination with additional risk factors like coronary anomalies can lead to MI even in this group of patients. Thus, to my opinion heritable thrombophilia should always be investigated thoroughly in adolescents who present with MI even if a coronary anomaly is present.

References [1] [2]

[3]

Desai A, Patel S, Book W. Myocardial infarction in adolescents: do we have the correct diagnosis? Pediatr. Cardiol. 2005; 26: 627-31. Schoebel F, Heintzen M, Jax W, et al. Acute myocardial infarction with origin of the left circumflex artery from the right (anterior) aortic sinus with retroaortic course to the left atrioventricular sulcus. Am. J. Cardiol. 1996; 78: 720-21. Erbilen E, Ozhan H, Akdemir R, Yazici M. A case of myocardial infarction with sumatriptan use. Pediatr. Cardiol. 2005; 26: 464-66.

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[6]

[7]

[8]

[9]

[10]

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[11]

[12]

[13]

[14]

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Gotsman I, Mosseri M. Acute myocardial infarction in a young woman with normal coronary arteries and a combined thrombophilia. Int. J. Cardiol. 2005; 99: 483-84. Carano N, Agnetti A, Hagler D, Tchana B, Squarcia U, Bernarsconi S. Acute myocardial infarction in a child: possible pathogenic role of patent foramen ovale associated with heritable thrombophilia. Pediatrics. 2004; 114: 255-8. Basso C, Maron B, Corrado D, Thiene G. Clinical profile of congenital coronary artery anomalies with origin from the wrong aortic sinus leading to sudden death in young competitive athletes. J. Am. Coll. Cardiol. 2000; 35: 1493-501. Nowak-Gottl U, Straeter R, Heinecke A, et al. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Blood. 1999; 94: 3678-82. Junker R, Koch H, Auberger K, Muenchow N, Ehrenforth S, Nowak-Gottl U for the Childhood Thrombophilia Group. Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia. Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2568-72. Koestenberger M, Nagel B, Gamillscheg A, Temmel W, Cvirn G, Beitzke A. Myocardial infarction in an adolescent: Anomalous origin of the left main coronary artery from the right coronary sinus in association with combined prothrombotic defects. Pediatrics. 2007; 120: 424-7. Rallidis L, Belesi C, Manioudaki H, et al. Myocardial infarction under the age of 36: prevalence of prothrombotic disorders. Thromb. Haemost. 2003: 90: 272-8. Kannam H, Satou G, Gandelman G, et al. Anomalous origin of the left main coronary artery from the right sinus of Valsalva with an intramural course identified by transesophageal echocardiography in a 14 year old with acute myocardial infarction. Cardiol. Rev. 2005; 13: 219-22. Mollet N, Cademartiri F, van Mieghem C, et al. High-resolution spiral computed tomography coronary angiography in patients referred for diagnostic conventional coronary angiography. Circulation. 2005; 112: 2318-23. Ehrenforth S, Junker R, Koch H, Kreuz W, Muenchow N, Scharrer I, Nowak-Gottl U for the Childhood Thrombophilia Group. Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Eur. J. Pediatr. 1999; 158: S97-S104. Doggen C, Cats V, Bertina R, Rosendaal F. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin G20210A. Circulation. 1999; 97: 1037-41.

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Index

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A AA, 6, 10, 30, 31, 32, 33, 36, 37, 38, 39, 40, 41, 71, 136, 148, 168, 169, 190 abnormalities, ix, x, xiii, 19, 24, 29, 43, 44, 45, 46, 47, 51, 52, 53, 56, 59, 60, 61, 64, 65, 66, 70, 75, 117, 120, 134, 135, 144, 167, 168, 171, 172, 174, 202 absorption, 84, 106, 127 AC, 30, 37, 39, 69, 134, 148, 169, 193 accessory pathway, 123, 128 accounting, 6, 123 accuracy, 47, 91, 128 ACE, 154, 198, 199 ACE inhibitors, 154, 199 acetaminophen, 151 acetate, 137 acetylcholine, 170 achievement, 64 acid, xiii, 20, 26, 28, 29, 54, 55, 76, 88, 172, 173, 174, 188 acidosis, 55, 101, 102, 114, 129, 154 acoustic, 3, 8 actin, 92 action potential, 6, 8, 9, 10, 15, 16, 144 action potential (AP), 10 activation, 9, 15, 56, 92, 116, 170 acute, xiii, 45, 51, 61, 71, 92, 111, 151, 152, 153, 154, 163, 170, 181, 191, 197, 198, 201, 203 acute ischemic stroke, 111 adaptation, 67 adenosine, 128 ADH, 95 adherens junction, x, 2 adhesion, 167 adjunctive therapy, 144 adjustment, 94 administration, 20, 60, 96, 128, 132, 133, 142

adolescence, 146, 155 adolescents, ix, xii, xiii, 30, 134, 135, 149, 151, 168, 197, 198, 201, 202 adult, 78, 88, 108 adults, ix, 1, 2, 5, 7, 9, 16, 19, 53, 58, 59, 93, 99, 145, 146, 155, 168, 175, 202 adventitia, 78, 181 AE, 37, 38, 107, 108 aetiology, xi, 113, 123, 125, 131, 132 AF, 82, 108, 109, 162 agent, 16, 95, 101, 102, 128, 133, 143 agents, 128, 133, 144, 148, 151, 154 agonist, 104 aid, x, 75, 84, 89 air, 97 AJ, 30, 31, 32, 35, 36, 37, 41, 65, 66, 69, 135, 145, 146, 147, 169 AL, 33, 34, 35, 36, 39, 71, 164 alertness, 60 algorithm, xi, 58, 59, 113 alkalinity, 54 allele, 7, 52, 173, 174 alleles, 173 allergy, 185 alpha, 54, 61, 69, 78, 110 alternative, xiii, 16, 21, 56, 94, 95, 177, 179, 183, 184 amino, xiii, 20, 29, 54, 88, 107, 172, 173, 174 amino acid, xiii, 20, 29, 54, 88, 172, 173, 174 Amiodarone, 127, 128, 137 amplitude, 11, 12, 16, 23, 26, 117, 120 ampulla, 186 Amsterdam, 1 anastomosis, 179, 183 anatomy, 115, 183 anger, 24 angiography, 181, 184, 185, 186, 187, 199, 200, 203 angioplasty, 181, 188, 193

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206 angiotensin-converting enzyme, 198 animal models, xiii, 60, 76, 171, 174 animal studies, 79, 89, 172 animals, 54, 59 anisotropy, 45 anomalous, xiii, 73, 197, 199, 202 antagonist, 76, 142 antagonists, 76, 146 antiarrhythmic, xi, 13, 114, 125, 126, 128, 133, 143 antibiotic, 35, 153, 154, 187 antibody, 131, 132, 152 anticardiolipin, 199 anticoagulant, 152, 199 anticoagulants, 199 antidepressants, 16, 18 antidiuretic, 109 antidiuretic hormone, 109 antigen, 199 antihistamines, 16, 18 anti-inflammatory drugs, x, 75, 94 anti-platelet, 94, 188 antiviral, 152 aorta, x, xiii, 46, 47, 48, 50, 53, 75, 76, 80, 81, 82, 85, 86, 89, 117, 128, 137, 153, 166, 179, 185, 186, 187, 188, 189, 190, 192, 194, 197, 199, 201, 202 aortic stenosis, 52 aortic valve, 52, 116, 130 apnea, 158, 161, 162, 163, 164 Apolipoprotein E, 52, 68 apoptosis, 76 apoptotic, 98, 111 application, 84, 94, 140, 162, 181, 192 Arabia, 1 arachidonic acid, 76 arrest, xii, 8, 14, 17, 19, 24, 28, 54, 55, 56, 57, 59, 60, 64, 69, 70, 71, 72, 73, 74, 129, 139, 140, 145, 146, 162, 167, 170 arrhythmia, ix, xii, 1, 3, 4, 6, 7, 9, 12, 13, 14, 20, 22, 23, 24, 30, 33, 34, 35, 38, 114, 115, 116, 120, 125, 127, 129, 133, 140, 145, 151, 152, 157 arrhythmias, ix, x, 1, 2, 5, 7, 9, 14, 18, 19, 20, 22, 23, 30, 31, 36, 38, 40, 113, 114, 115, 116, 118, 120, 121, 124, 128, 129, 131, 133, 134, 135, 136, 137, 140, 141, 144, 145, 146, 151, 154 arrhythmogenesis, ix, 1, 37 arterial vessels, 47 arteries, ix, x, xi, xiii, 45, 47, 65, 68, 73, 74, 75, 80, 85, 93, 114, 152, 178, 179, 180, 182, 183, 185, 188, 192, 193, 194, 197, 199, 201, 203

Index artery, xiii, 47, 50, 57, 59, 67, 70, 76, 79, 81, 82, 83, 84, 85, 86, 87, 89, 101, 102, 106, 131, 135, 166, 169, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 197, 198, 199, 200, 201, 202, 203 Asia, 16 aspartate, 45, 199 asphyxia, 108, 111 aspirin, 199 assessment, 60, 67, 73, 82, 84, 85, 87, 88, 107, 115, 117, 120, 121, 123, 162 asthma, 142, 158 asymmetry, 44, 60 asymptomatic, 18, 24, 39, 40, 103, 131, 198 atherosclerosis, ix, 78 athletes, 203 atresia, 55, 178, 181, 183, 188, 193 atria, 47, 116, 118, 123, 124, 129, 162 atrial fibrillation, 7, 15, 19, 37 atrial flutter, xi, 113, 115, 117, 121, 123, 124, 126, 128, 133, 134, 136 atrial premature contraction, xi, 113, 115, 129 atrio-ventricular, xi, 113, 114, 115, 116, 118, 123, 125, 128, 129, 131, 132 atrioventricular block, 9, 137, 138, 152 atrioventricular node, 123 atrium, 85, 86, 89, 100, 116, 117, 119, 122, 123, 124, 130 atrophy, 52, 53 attacks, 6, 8, 15, 22 auditory stimuli, 34 Austria, 161, 197 autism, 4, 8, 34 autoantibodies, xi, 114, 131, 132 autoantibody, 138 autoimmune, xi, 2, 114, 152 autoimmune disease, 152 autopsy, xii, 52, 149, 150, 155, 181 autosomal dominant, 19, 20, 22 autosomal recessive, 40, 141 availability, 54, 88, 97, 145, 161 averaging, 115 avoidance, 57, 60 awareness, 56

B babies, 44, 46, 51, 52, 53, 55, 59, 64, 65, 97, 105, 161 bacteria, 151, 152, 154

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Index bacterial, xii, 150, 165 balloon angioplasty, 181 barrier, 127, 142 basal ganglia, 52, 53 base pair, 172 behavior, 55, 64, 70, 164, 178 behavioral difficulties, 56 bell, 3, 8, 13 beneficial effect, 141 benefits, 57, 98, 105 benign, xiii, 121, 129, 172, 174 beta-blockers, 34, 199 bias, 64 binding, 9, 16, 89, 142 biochemistry, 69 biomarker, 107, 111 biomarkers, 53 biometric, 45 biopsy, 152, 153 birth, xii, 4, 6, 8, 23, 24, 44, 45, 51, 76, 77, 89, 94, 95, 97, 104, 105, 109, 110, 116, 121, 123, 128, 131, 133, 165, 167, 168, 169, 175 birth weight, xii, 24, 45, 94, 97, 104, 105, 109, 110, 165, 167, 168, 169 births, 2, 131, 172, 178 birthweight, 112 BIS, 58, 71 bleeding, 95, 97, 98, 181 blindness, 96 blocks, 131, 144, 147, 151 blood, ix, x, xiii, 44, 45, 46, 47, 48, 49, 50, 51, 54, 55, 58, 59, 66, 67, 68, 69, 75, 76, 78, 80, 81, 82, 84, 85, 86, 87, 88, 92, 95, 100, 103, 104, 105, 106, 109, 111, 116, 125, 127, 142, 151, 152, 158, 162, 166, 167, 169, 177, 178, 179, 182, 183, 189, 192, 194, 199 blood flow, x, xiii, 44, 45, 46, 47, 48, 49, 50, 51, 54, 55, 58, 59, 66, 67, 68, 69, 75, 78, 80, 81, 82, 84, 85, 86, 87, 95, 103, 104, 105, 106, 109, 116, 125, 151, 166, 167, 169, 177, 178, 179, 182, 183, 189, 192 blood pressure, 80, 85, 88, 100, 105 blood supply, 78, 80, 179, 194 blood-brain barrier, 142 body temperature, 54 bone morphogenetic proteins, 172, 175 borderline, 20, 154 Bose, 105 Boston, 55, 56, 58, 61, 62, 64, 65, 71 boys, 11

207

bradyarrhythmia, 20 bradycardia, xi, 3, 7, 9, 13, 15, 17, 19, 20, 24, 32, 39, 40, 100, 101, 114, 129, 130, 131, 163, 164 brain, x, 24, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 66, 67, 68, 69, 70, 72, 80, 84, 87, 98, 107, 111, 142, 198 brain abnormalities, 44, 45, 51, 52, 53, 59 brain damage, 72 brain development, 44, 45, 46, 49, 51, 53, 66 brain growth, 47 brain injury, 44, 45, 52, 53, 57, 59, 66, 98 brain natriuretic peptide, 107, 198 brainstem, 52 branching, 184, 187 breast feeding, 158 breathing, 24, 159, 161, 163 breeding, 152 bronchitis, 158 bronchoalveolar lavage, 110 bronchopulmonary dysplasia, 104, 110, 161 bronchus, 85 browser, 175 Brugada syndrome, 2, 14, 16, 17, 28, 33, 38, 39, 145, 147 bundle branch block, 16, 17 bypass, xiii, 44, 54, 55, 56, 57, 59, 61, 64, 69, 70, 71, 72, 74, 166, 167, 169, 170, 197, 198, 199 bypass graft, xiii, 197, 198, 199

C Ca2+, 3, 8, 13, 17, 20, 147, 148 caesarean section, 24, 126, 133 calcium, xi, 2, 3, 7, 8, 13, 16, 20, 34, 38, 77, 92, 94, 139, 140, 148 calcium channels, 77 calibration, 12, 21 calreticulin, 40 campaigns, 158 candidates, 98 capillary, 172 Carbon, 69 cardiac arrest, xii, 8, 14, 28, 129, 139, 140, 145, 146 cardiac arrhythmia, xi, 19, 30, 33, 34, 35, 38, 113, 115, 120, 134, 135, 136, 140, 145 cardiac catheterization, 57, 173, 182, 199, 202 cardiac dysrhythmia, 134 cardiac enzymes, 152 cardiac function, x, xi, 2, 68, 113, 116, 133 cardiac muscle, 92, 108

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208 cardiac myocytes, 108 cardiac operations, 72 cardiac output, xi, 51, 68, 79, 106, 114, 115, 125, 128, 167, 169, 181 cardiac pacemaker, 39 cardiac surgery, 19, 52, 54, 57, 66, 68, 71, 72, 73, 166, 167 cardiogenic shock, xiii, 151, 154, 197, 199 cardiologist, xi, 88, 113, 120, 183 cardiology, 88, 139 cardiomyocytes, ix, 1, 16, 35 Cardiomyocytes, 8 cardiomyopathy, 31, 39, 131, 151, 153, 156 cardiopulmonary, 24, 44, 54, 55, 56, 59, 69, 70, 71, 72, 74, 158, 162, 166, 167, 169, 170, 180 cardiopulmonary bypass, 44, 54, 55, 56, 59, 69, 70, 71, 72, 74, 166, 167, 169, 170 cardiovascular disease, 140 Cardiovascular disease, 68 cardiovascular risk, 202, 203 cardiovascular system, 66, 147 carrier, 10, 11, 18, 23, 26 catecholamine, 20, 29, 40, 114, 151 catecholamines, 142 catheter, 182, 183, 186, 188 catheterization, 57, 173, 182, 199, 202 catheters, 186 Caucasian, 173, 174 Caucasian population, 173, 174 cDNA, 27 CE, 35, 40, 162, 178, 193, 194 cell, 2, 16, 51, 53, 54, 76, 77, 78, 92, 152, 178, 188, 193, 201 cell death, 78 cell line, 53 cell lines, 53 cell membranes, 2 cell surface, 16, 78 cellular adhesion, 167 central nervous system, 52, 55, 71, 142 cerebral arteries, x, 47, 75, 80 cerebral blood flow, 44, 45, 48, 49, 50, 51, 54, 55, 59, 66, 67, 68, 69, 80, 95, 105 cerebral blood volume, 84 cerebral blood volume (CBV), 84 cerebral cortex, 49 cerebral damage, 68 cerebral function, 69 cerebral hypoperfusion, 59 cerebral hypoxia, 60

Index cerebral ischemia, 53, 68 cerebral palsy, 96 cerebrovascular, 58, 68 Chagas disease, 151 channel blocker, 14, 16, 141, 143, 146 channelopathy, xi, 139, 140 channels, ix, x, 1, 2, 7, 8, 9, 10, 15, 16, 30, 34, 38, 77, 104, 142, 143, 146, 147, 148 child mortality, xii, 149, 155 childhood, ix, 5, 11, 14, 20, 30, 72, 140, 153, 155, 198, 202, 203 chlamydia, 158 cholesterol, ix choreoathetosis, 45, 55, 61, 69 chromatograms, xiii, 171, 172 chromatography, xiii, 171, 172 chromium, 185, 188 chromosome, 19, 20, 33, 40, 52, 88, 172 chromosomes, xiii, 172, 174 chronic hypoxia, 67 chylothorax, 179 circulation, x, xiii, 43, 46, 47, 48, 50, 53, 56, 67, 69, 70, 80, 84, 85, 87, 88, 91, 98, 103, 153, 177, 178, 182, 183, 193, 195 CK, 198 CL, 70, 72, 73, 105, 163, 168 classification, 115, 120, 128 cleft palate, 4, 8 clinical examination, 168 clinical presentation, xii, 15, 149, 150, 166 clinical symptoms, xii, 23, 149, 150, 152, 153, 154 clinical trial, x, 18, 55, 71, 75, 144, 147 clinical trials, x, 18, 75, 144 clinician, 94 cloning, 30, 34, 145 closure, 52, 76, 77, 78, 79, 82, 84, 89, 90, 93, 94, 95, 96, 97, 99, 100, 103, 104, 106, 109, 110, 178, 179, 181, 184, 186, 187, 192, 193, 194 clozapine, 151 CNS, 52, 58, 60 Co, xii, 134, 136, 137, 138, 157 CO2, 54, 58 coagulation, 199, 203 coarctation, 52, 153 cobalt, 185, 188 cocaine, 16, 151 Cochrane, 94, 96, 97, 103, 104, 109, 110 coding, xiii, 2, 5, 31, 171, 172, 173, 174 codon, 27 cognitive test, 64

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Index cognitive testing, 64 cohort, 53, 56, 59, 61, 64, 65, 88, 91, 98, 99, 132, 141, 173, 174 collaboration, 88 collateral, 179 colon, 166 colonization, xii, 165 common findings, 52 communication, x, 2, 130, 155, 181 co-morbidities, 183 complement, 49, 152 complexity, 58, 61, 127 compliance, xii, 79, 104, 157 complications, x, 56, 72, 75, 80, 94, 95, 96, 97, 98, 99, 127, 133, 152, 180, 181 components, x, 2 composition, 30 compounds, 14 computed tomography, 152, 198, 199, 203 concentration, 20, 53, 54, 84, 88, 96, 106, 127, 142 concordance, 72 conductance, 148 conduction, 16, 17, 18, 19, 23, 28, 30, 32, 33, 39, 115, 123, 124, 126, 128, 129, 132, 152 conduction block, 124 conductivity, 120 confounders, 80 confusion, 156 congenital heart block, 138 congenital heart disease, ix, x, xii, xiii, 43, 44, 45, 48, 50, 51, 52, 60, 65, 66, 67, 68, 69, 73, 74, 131, 132, 134, 153, 165, 167, 168, 169, 170, 171, 172, 178, 179, 181, 190, 194 congestive heart failure, 127, 134, 151 Congress, vi connective tissue, 131, 178 consciousness, xiii, 22, 24, 158, 161, 197, 199 consensus, x, xi, 38, 75, 76, 113, 115, 127, 128 conservation, 173 continuity, 116 continuous positive airway pressure, 100 contractions, xi, 113, 115, 116, 134 control, xiii, 22, 25, 26, 27, 28, 29, 45, 48, 60, 78, 97, 125, 162, 166, 169, 171, 174, 181 control group, 97 controlled trials, 126 conversion, 16, 126, 127, 128, 133 conversion rate, 128 convulsion, 23, 24 cooling, 54, 123

209

Coping, 163 coronary angioplasty, 188 coronary arteries, xiii, 93, 197, 199, 201, 203 coronary artery disease, 202 corpus callosum, 52 correlation, ix, 11, 31, 37, 59, 85, 89, 90, 92, 146, 154 correlations, 70 corticosteroid therapy, 138 costs, 120 coughing, 151 COX-1, 76 COX-2, 76 CPAP, 100 CPB, 57, 60, 166 CPI, 48, 50 CPR, 24 CR, 6, 10, 30, 36, 37, 38, 39, 110 cranial nerve, 61 C-reactive protein, 152 creatine, 152, 153, 198, 199 creatine kinase, 152, 153, 198 creatinine, 97, 101 critical period, 49 critically ill, xiii, 57, 98, 99, 107, 165 cross-linking, 92 cross-sectional, 50 CT, xiii, 13, 24, 34, 134, 197, 198, 199, 202 CT scan, 24 C-terminal, 20, 34, 41 culture, 77 cyanosis, 44, 151, 181 cyanotic, xiii, 22, 45, 66, 74, 158, 161, 166, 177, 179, 181, 183 cycling, 41 cyclooxygenase, 76, 109 cyclooxygenases, 104 cysteine, 173 cytokine, 53 cytokines, 167 cytomegalovirus, 151, 152 cytoplasm, 152 cytosolic, 17, 20, 92

D Dallas, 150, 153, 154, 155 danger, 152, 153 database, 150, 172 de novo, 8, 15

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210 deafness, 5, 22, 23 death, ix, x, xi, xii, 2, 5, 8, 13, 14, 15, 16, 20, 30, 31, 33, 34, 36, 37, 38, 40, 45, 75, 78, 95, 96, 98, 99, 103, 109, 113, 115, 125, 127, 131, 132, 139, 140, 141, 143, 145, 146, 149, 150, 151, 152, 155, 158, 161, 163, 179, 198, 202, 203 death rate, 14, 143 deaths, ix, 1, 9, 16, 97, 126, 128, 132, 150, 165, 181 decision making, 58, 71 decisions, 163 defects, x, xiii, 2, 7, 13, 39, 45, 50, 51, 65, 66, 68, 70, 71, 73, 116, 168, 171, 172, 174, 175, 177, 197, 199, 202, 203 defibrillator, xii, 14, 18, 21, 139, 144, 145 deficiency, xiii, 16, 153, 197, 198, 202 deficit, 101, 102 deficits, 56, 64, 65 definition, 80, 103, 150 deformation, xi, 113, 117 degradation, 89 dehydrogenase, 17, 36, 38 delivery, xi, 9, 24, 51, 55, 60, 65, 108, 111, 112, 113, 121, 126, 131, 132, 133, 178, 182 demographics, 138 denervation, xii, 37, 40, 139, 148 depolarization, 38, 77 depressed, 167 depression, 142 derivatives, 144 dermatomyositis, 151 destruction, 131, 181 detection, xii, 47, 58, 60, 68, 92, 97, 115, 117, 149, 150 developing brain, 44, 111 developmental delay, 51, 56 developmental disabilities, 70 developmental process, 78 dexamethasone, xi, 110, 114, 133, 138 diabetes, 142 Diamond, 193 diarrhea, 151 diastole, 47, 48, 80, 120, 129 diastolic blood pressure, 85 differential diagnosis, 152 differential rates, 174 differentiation, 129 diffusion, 45, 78 diffusion tensor imaging, 45 diffusion tensor imaging (DTI), 45 digitalis, 154, 160

Index dilated cardiomyopathy, 151, 153, 156 dilation, 48, 69 disability, 54, 60 discomfort, 150 discontinuity, 194 diseases, xiii, 67, 151, 152, 153, 161, 177, 178 disequilibrium, 173 dislocation, 140 disorder, 2, 8, 14, 19, 20, 22, 34, 38, 59, 129, 140, 172 dispersion, 37, 143, 144, 145, 146, 147 dissociation, 54, 116, 123, 125 distress, 95, 105, 106, 108, 111, 112, 114, 129, 162 distribution, 15, 127, 183 diuretic, 88, 95 diuretics, 199 diving, 3, 5, 22 dizziness, 15, 19, 29 DNA, 25, 26, 27, 28, 29, 152, 172 doctors, 154 dogs, 143 dopamine, 154 Doppler, xi, 46, 47, 48, 50, 53, 57, 59, 67, 68, 71, 82, 85, 86, 87, 100, 105, 106, 113, 116, 117, 118, 121, 122, 123, 125, 131, 134, 135, 136, 137, 169, 199 dosage, 142, 154 Down syndrome, ix, xiii, 171, 172, 174, 175 drug abuse, 201 drug therapy, xi, xii, 113, 126, 127, 128, 139, 162 drug treatment, 126, 127 drug use, 143, 198 drug-induced, 9, 35, 143, 147 drugs, x, xi, 9, 13, 14, 75, 84, 94, 98, 114, 125, 126, 127, 128, 134, 142, 144, 151, 154 ductus arteriosus, ix, x, 46, 47, 75, 76, 77, 81, 82, 86, 89, 98, 100, 103, 104, 105, 106, 107, 108, 109, 110, 111, 193, 194 durability, 192 duration, 8, 9, 10, 11, 15, 47, 55, 56, 69, 70, 71, 72, 96, 97, 115, 124, 125, 128, 140, 144 dysplasia, 31, 104, 110, 161 dysregulation, xiii, 171, 172

E ears, 4, 8 edema, 151, 152, 153 EEG, 23, 45, 56, 57, 58, 59, 61, 158, 162 EEG activity, 56

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

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Index effusion, 131, 179 EKG, 162 elderly, 19 electrical conductivity, 120 electrocardiogram, 9, 38, 120, 121, 160, 163 electroencephalogram, 71 electroencephalography, 57 electrographic seizures, 71 electrolyte, 14, 34 electrolyte imbalance, 14, 34 electrolytes, 13, 23 electron, 77 electrophoresis, 137 electrophysiology, 15, 116, 123 ELISA, 152 EM, 30, 73, 134, 137 emboli, 96, 178, 182 embolism, 201 embolization, 178, 182 embryology, 174 emission, 152 emotional, 5, 13, 20, 29, 141, 162 emotional distress, 162 employment, 120 encoding, ix, 1, 8, 16, 24, 175, 176 endocarditis, 185 endocardium, ix, 1 endocrinological, 158 endothelial cell, 78, 167, 170, 179, 193 endothelial cells, 78, 167, 170, 179 endothelium, 167, 181 energy, 94 enterocolitis, ix, x, xii, 75, 80, 100, 165, 168, 169 environment, 47 environmental factors, 11 enzymes, 152, 198 eosinophilia, 151 eosinophils, 152 EP-2, 76 epicardium, ix, 1 epidemiology, xii, 149, 150, 156 epilepsy, 22 epileptic seizures, 158 epinephrine, 13, 37, 144 Epstein-Barr virus, 151 ER, 103 ester, 35, 36, 38 estimating, 143 ET, 40, 69, 138 ethnicity, 174

211

etiology, xiii, 46, 167, 172, 174, 175 Europe, 158, 161 evoked potential, 58 evolution, 85, 87, 131 examinations, xii, 13, 24, 45, 60, 92, 116, 153, 154, 157, 158, 162 excitation, 92, 160, 162, 163 excretion, 95, 109 executive function, 56 executive functioning, 56 exercise, 3, 4, 6, 7, 9, 11, 13, 14, 20, 21, 22, 29, 73, 202 exertion, 5, 24 exons, xiii, 5, 25, 171, 172 expertise, 76, 193 exposure, 77, 84, 91, 98, 99, 179 externalizing, 64 externalizing behavior, 64 extrasystoles, 3, 12, 21, 29, 120, 121, 129

F FA, 34, 39, 71 failure, xi, 48, 66, 78, 94, 102, 104, 108, 113, 126, 127, 143, 147, 149, 150, 151, 153, 154, 155, 178, 183, 188 failure to thrive, 151 false alarms, 161 false positive, 152 familial, 28, 39, 125, 136, 175 family, 7, 9, 13, 15, 16, 18, 22, 23, 24, 25, 26, 27, 29, 33, 78, 152, 158, 161, 174, 176 family history, 9, 15, 22, 29 family members, 9, 13, 16, 18 fatigue, 19 fatty acid, ix fatty acids, ix FD, 104 fears, 158 feeding, 24, 44, 61, 73, 151, 158, 166, 169 females, 2, 11, 91, 150, 173 fetal, ix, x, xi, 7, 9, 13, 15, 19, 23, 32, 33, 44, 46, 47, 48, 50, 51, 53, 67, 68, 76, 89, 92, 104, 113, 114, 115, 116, 120, 121, 123, 124, 125, 126, 127, 128, 129, 131, 132, 133, 134, 135, 136, 137, 138, 172, 193 fetal brain, 47, 67 fetal death, xi, 113, 115, 125, 132 fetal distress, 129 fetal tissue, 76

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Index

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212 fetus, xi, 19, 24, 44, 46, 47, 50, 67, 68, 69, 76, 77, 89, 92, 113, 114, 115, 116, 119, 120, 121, 123, 124, 125, 126, 127, 128, 129, 131, 132, 133, 134, 135, 136, 137 fetuses, xi, 23, 45, 46, 47, 48, 49, 50, 51, 53, 67, 68, 113, 114, 121, 124, 125, 126, 127, 128, 129, 131, 132, 133, 136 fever, 16, 18, 28, 151 fibers, 178 fibrillation, 7, 15, 16, 19, 20, 29, 37, 134 fibronectin, 96, 110 fibrosis, 19, 96, 154 filament, 92 Finland, 155 Finns, 33 fish, 173 FL, 168, 169 flexibility, 189, 192 flow, x, xi, xiii, 1, 44, 45, 46, 47, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 66, 67, 68, 69, 70, 71, 74, 75, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 95, 100, 101, 102, 103, 104, 105, 106, 109, 113, 116, 117, 118, 125, 137, 151, 166, 167, 169, 170, 177, 178, 179, 181, 183, 189, 192, 194, 199 flow rate, 56, 58, 79 fluid, 89, 94, 95, 110 fluorinated, 132, 138 football, 22, 198 foramen, 46, 47, 76, 117, 198, 199, 203 foramen ovale, 46, 47, 76, 117, 198, 199, 203 Ford, 74 formaldehyde, 181 Fox, 30, 35, 138 FP, 35 freedom, 182 Friday, 148 frontal lobe, 47 frontal lobes, 47 FS, 108

G G protein, 76 gamma globulin, 138 ganglia, 52, 53 ganglion, 14 gas, 54 gases, 54 gastric, 101 gastrointestinal, ix, xii, 95, 96, 165

gastrointestinal bleeding, 95 gastrulation, 172 GC, 69, 109 GE, 169 gender, 2, 9, 11, 36, 140 gene, xiii, 3, 4, 5, 6, 7, 8, 13, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 108, 140, 145, 146, 148, 172, 174, 176, 197, 198, 199, 202, 203 gene expression, 108 general anesthesia, 178, 187 general knowledge, 60 generation, 2, 56, 92, 181 genes, ix, 1, 2, 3, 8, 9, 10, 11, 13, 15, 16, 17, 19, 20, 22, 31, 140, 145, 148 genetic abnormalities, 68 genetic disorders, 174 genetic factors, 52 genetic testing, 36 genetics, 140, 173 genome, 175 genotype, xiii, 11, 23, 36, 37, 41, 68, 140, 141, 144, 146, 197, 198, 199 genotypes, 11, 35, 141, 144, 146 Germany, 65, 157, 161, 172 germline mutations, 175, 176 gestation, x, xi, 9, 15, 23, 24, 47, 48, 49, 50, 75, 76, 86, 94, 96, 97, 98, 104, 114, 117, 118, 119, 121, 122, 123, 124, 125, 126, 130, 131, 132, 133 gestational age, xii, 49, 94, 95, 114, 115, 120, 124, 125, 132, 165, 167 Gibbs, 181, 183, 191, 193, 194 girls, 11 GL, 67, 136 glial, 53, 68 globulin, 138, 154 glucocorticoids, 138 glutamic acid, 26 glycerol, 17, 36, 38 glycogen, 153 goal-directed, 88, 107 goals, x, 43, 44 gold, x, 75, 80, 85 gold standard, x, 75, 80, 85 government, vi grades, 96, 129 grandparents, 158 grants, 197 groups, 50, 54, 55, 56, 64, 79, 90, 91, 93, 94, 95, 96, 102, 103, 120, 124, 133, 150, 161

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Index growth, 44, 45, 47, 48, 66, 67, 169, 178, 179, 180, 181, 183, 192, 193, 194 gut, 80, 166 gyri, 49

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H HA, 108, 163, 169, 193 haematocrit, 84 haemoglobin, 84 half-life, 142 handling, 162 haploinsufficiency, 176 haplotype, 25, 27 haplotypes, 25, 27 HE, 137, 138 headache, 24 healing, 154 health, xii, 157, 158, 160, 169 hearing, 5, 22, 23, 41, 65, 96 hearing impairment, 22, 96 heart, ix, x, xi, xii, xiii, 1, 2, 9, 13, 14, 19, 20, 23, 24, 29, 30, 31, 34, 43, 44, 45, 46, 48, 49, 50, 51, 52, 55, 56, 57, 60, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 79, 88, 89, 92, 100, 101, 102, 108, 113, 114, 115, 116, 118, 120, 123, 124, 125, 126, 127, 128, 129, 131, 132, 133, 134, 135, 136, 137, 138, 140, 143, 147, 148, 149, 150, 151, 153, 154, 155, 159, 160, 161, 162, 163, 165, 166, 167, 168, 169, 170, 171, 172, 174, 175, 177, 178, 179, 181, 184, 190, 193, 194 Heart, 1, v, vii, viii, 1, 24, 28, 30, 31, 32, 34, 36, 37, 38, 40, 41, 43, 46, 48, 49, 60, 62, 66, 72, 108, 111, 114, 120, 129, 134, 135, 136, 137, 138, 148, 152, 155, 156, 163, 165, 171, 177, 181, 183, 191, 193, 194, 195 heart block, 129, 137, 138 heart disease, ix, x, xii, xiii, 19, 30, 31, 43, 44, 45, 48, 49, 50, 51, 52, 60, 65, 66, 67, 68, 69, 73, 74, 126, 131, 132, 134, 138, 140, 153, 165, 167, 168, 169, 170, 171, 172, 177, 178, 179, 181, 190, 194 heart failure, xi, 108, 113, 126, 127, 134, 143, 147, 149, 150, 151, 153, 154, 155 heart rate, xi, 2, 14, 19, 24, 29, 79, 113, 114, 115, 116, 120, 123, 124, 125, 128, 129, 131, 132, 133, 134, 135, 136, 148, 161, 163 heart transplantation, 151 hematochezia, 166 hematocrit, 54, 55, 59, 61 hemiparesis, 64

213

hemodynamic, 44, 46, 52, 57, 64, 67, 107, 126, 134, 169 hemodynamic effect, 67 hemodynamics, 61, 65, 67, 109 hemoglobin, 51, 54, 58, 199 hemorrhage, 52, 104, 105, 110, 111, 112 hemorrhagic stroke, 111 hepatitis, 151, 152 hepatomegaly, 151 heritability, 30 Hermes, 103 herpes, 151 herpes simplex, 151 heterogeneity, 60, 148 heterogeneous, 2, 15 heterozygosity, 32, 39 heterozygote, xiii, 197, 198, 199 heterozygotes, 20 high pressure, xiii, 171, 172 high risk, x, xi, 14, 16, 75, 93, 109, 113, 127, 131, 132, 162, 167 high-frequency, 102, 183 high-risk, x, xiii, 37, 43, 47, 48, 53, 65, 141, 161, 177, 182, 183, 192 histamine, 167 histidine, 54 histochemical, 193 histological, 150, 152, 153 histology, 181 histopathology, 154 HIV, 151, 152 holoprosencephaly, 52 homeostasis, 144 homogenous, 92 hormone, 95, 107, 109 hospital, 24, 28, 60, 96, 154, 158, 160, 161, 162, 166, 181 hospital death, 181 hospital stays, 166 hospitalization, 162 hospitals, 155 HPLC, 40, 172 HR, 168 human, 26, 32, 34, 35, 39, 46, 47, 48, 49, 54, 59, 67, 68, 77, 92, 94, 104, 107, 108, 134, 146, 173, 175, 181 human brain, 68 human cerebral cortex, 49 human genome, 175 human milk, 94

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Index

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214 humans, 59 Hungarian, 150, 156 Hungary, 149, 150 hybrid, 57 hydration, 86, 89 hydrogen, 54 hydrops, xi, 113, 114, 115, 124, 125, 126, 127, 128, 131, 132, 133, 134, 135, 136, 137, 138 hydroxyl, 54 hyperemesis, 158 hyperemesis gravidarum, 158 hyperplasia, 183, 188, 191 hypersensitivity, 151 hypertension, 47, 94, 96, 107, 110, 153, 173, 175, 179 hyperthermia, 60, 72 hypertrophy, 131 hypokalemia, 9 hypoperfusion, x, 44, 53, 59, 75, 80 hypoplasia, 180 hypotension, 55, 101 hypothermia, 54, 55, 69, 70, 72, 73, 98, 167, 169 hypothesis, 56 hypothyroidism, 13 hypotonia, 44, 60, 158 hypoxemia, 49, 50 hypoxia, 48, 51, 52, 57, 59, 60, 67, 76, 78, 104, 114, 129, 153, 167, 179 hypoxia-ischemia, 53 hypoxic, 52, 55, 60 hypoxic-ischemic, 55

I iatrogenic, 201 IB, 69 ibuprofen, x, 75, 77, 94, 95, 96, 97, 99, 109, 110 ICD, 14, 15, 21, 23, 145, 150 id, xii, 24, 157, 158 identification, 33, 87, 123, 140, 154 idiopathic, 19, 148 IFN, 78 IgG, 152 IKr, 3, 6, 7, 17, 30, 34, 144 IKs, 3, 4, 5, 7, 9, 17, 23, 30, 31, 33 IL-1, 53 IL-10, 53 IL-6, 53, 78 ileum, xii, 165

imaging, xi, 45, 47, 48, 52, 70, 84, 106, 113, 117, 135, 152, 184 imaging modalities, 45 imbalances, 14 immunoassays, 92 immunoglobulin, 132 immunohistochemical, 156 immunohistochemistry, 154 immunosuppressive, 133, 138 immunosuppressive agent, 133 impairments, 65 implants, 132 in situ, 47 in utero, x, 37, 43, 45, 47, 77, 116, 133, 135, 136, 138, 172 in vivo, 143 inactivation, 37 inactive, 89 incidence, x, xiii, 7, 15, 45, 50, 51, 52, 53, 54, 55, 56, 60, 61, 66, 72, 75, 79, 80, 96, 97, 98, 99, 124, 127, 131, 132, 133, 140, 144, 150, 155, 165, 166, 167, 171, 172, 174, 175, 179 inclusion, 183 independence, 99 indication, 58, 85, 86, 158 indices, 47, 48, 50, 125 indium, 152 indomethacin, x, 75, 76, 79, 94, 95, 96, 97, 98, 104, 109, 110 induction, 126 infancy, ix, xii, 71, 73, 133, 165 infants, ix, x, xii, 13, 14, 43, 44, 45, 48, 51, 53, 54, 56, 57, 60, 65, 66, 67, 68, 69, 71, 72, 75, 76, 78, 82, 84, 85, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 134, 135, 149, 151, 154, 157, 158, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 178, 179, 181, 194, 195 Infants, 13, 53, 55, 66, 78, 80, 93, 105, 109, 163, 164, 166 infarction, xiii, 108, 152, 197, 198, 202, 203 infection, 78, 104, 114, 132, 150, 158 infections, 151, 153 infectious, 150, 151, 153, 154, 156 infectious disease, 150 infectious diseases, 150 inferior vena cava, 46 inflammation, xi, 96, 104, 114, 132, 152, 154, 167, 170

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Index inflammatory, x, xi, 56, 57, 75, 78, 94, 114, 131, 132, 149, 154, 166, 167, 170 inflammatory cells, 154 inflammatory disease, 149 inflammatory mediators, 78, 167 inflammatory response, 167 influenza, 151, 152 infrared, 59, 84, 106 infrared light, 84 infrared spectroscopy, 57, 58, 71, 84, 106 ingestion, 114 inheritance, 19, 20 inherited, ix, 1, 2, 6, 15, 20, 28, 30, 38, 144, 145, 148, 176 inherited disorder, 2 inhibition, 30, 76, 143 inhibitor, 38, 77, 95, 110 inhibitors, 76, 104, 109 inhibitory, 142 inhibitory effect, 142 initiation, 88, 125, 135 injection, 128, 137, 200 injuries, 179 injury, vi, xii, 19, 52, 53, 55, 57, 58, 59, 60, 68, 72, 92, 93, 99, 111, 152, 165, 166, 167, 178, 181 inner ear, 5, 23 innominate, 57, 184, 185, 187, 188 insertion, 47, 180, 182, 186 insight, 64 instability, 57, 64, 89, 98, 102 instruction, 158 insulation, 115 integrin, 179, 193 integrins, 179 integrity, 167 intelligence, 52, 70 intelligence quotient, 52 intensive care unit, 55, 110 interaction, 9 interactions, 140 interferon, 78 interleukin, 78 International Classification of Diseases, 150 interval, 2, 3, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 20, 22, 23, 24, 25, 26, 28, 31, 37, 116, 120, 124, 129, 136, 137, 140, 142, 143, 144, 145, 148 intervening sequence, 173 intervention, xii, 18, 44, 52, 59, 65, 157, 162, 169, 182 intestine, xii, 165

215

intima, 178 intracerebral, 111 intracerebral hemorrhage, 111 intracranial, 52 intramuscular, 128 intramyocardial, 129 intraoperative, x, 43, 44, 53, 54, 55, 57, 58, 98 intraperitoneal, 128 intrauterine growth retardation, 45, 67 intravascular, 89, 137, 194 intravenous, 95, 138, 179, 188 intrinsic, 53, 77, 80 intron, xiii, 25, 28, 171, 172 invasive, xiii, 134, 177, 180 iodine, 128 ion channels, ix, x, 1, 2 ionic, 2 ions, 54, 92, 140 ipsilateral, 179 IQ, 52, 56, 62, 63, 64, 65 IQ scores, 64, 65 IR, 104 Ireland, 75, 155 irritability, 151 IRS, 59 ischaemia, 19, 71, 93 ischemia, 53, 68, 152, 166, 167 ischemic, 52, 53, 60, 99, 111, 150, 203 ischemic stroke, 99, 203 isoenzymes, 56 isoforms, 92, 108 isolation, 85, 86 Israel, 40 Italy, 113, 177 IVH, x, 75, 80, 94, 95, 96, 97, 99, 100, 103

J JAMA, 72, 146, 155, 179 Japan, 7, 31, 155 JI, 136 JT, 164, 169, 194 judge, 92 Jun, 105, 108, 109, 110, 111, 138 juvenile rheumatoid arthritis, 151

K K+, 5, 7, 13, 23, 36, 38, 41, 104, 144, 147, 148

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Index

216 Kawasaki disease, 201 KH, 107, 110 kidney, 80 kinase, 35 kinetics, xi, 15, 108, 139 King, 104 KL, 155 knockout, 32

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L LA, 36, 68, 70, 71, 73, 85, 86, 89, 90, 91, 93, 99, 100, 101, 102, 132 labour, 104, 126 lamina, 79 laminar, 79 language, 56, 64, 65 language skills, 65 late-onset, 78 leakage, 170 leaks, 97 learning, 64 left atrium, 85, 86, 89, 100, 116, 130 left ventricle, 46, 76, 86, 116, 118, 119, 121, 122, 148, 152 left ventricular, x, xiii, 46, 47, 48, 50, 51, 75, 79, 82, 83, 84, 91, 99, 105, 106, 130, 153, 163, 167, 197, 199 Lesion, 45 lesions, 45, 48, 50, 52, 58, 64, 66, 73, 88, 165, 166, 167, 174, 194 lethargy, 44 leucine, 173 leukocyte, 167 leukocytes, 167 life span, 179 lifestyle, 73 life-threatening, xii, 31, 129, 140, 141, 144, 157, 158, 161, 162, 163, 164, 181 ligand, 89 limitation, 58, 116 limitations, 61, 66, 120, 146 Lincoln, 73 linear, 49, 52, 67 linkage, 173 lipid, 142, 170 Lipid, 104 Lipoprotein, 203 liquid chromatography, xiii, 171, 172 listening, 164

lithium, 151 litigation, xii, 149, 155 liver, 80 LM, 34, 71, 138, 155, 193 localization, 3, 34 locus, 20 London, 36, 38, 39, 69, 138 loss of consciousness, xiii, 22, 24, 197, 199 losses, 23 low birthweight, 112 low platelet count, 98 low risk, 103, 141 low temperatures, 54 lumen, 78 luminal, xii, 165, 179, 182 lung, 79, 96, 98, 104, 161 lung disease, 79, 98, 104, 161 lungs, 76, 80 lupus, 131, 138, 151, 152, 199 lupus anticoagulant, 152, 199 lupus erythematosus, 131, 138, 151 LV, 48, 86, 99, 162 lysine, 96, 110

M machinery, 85 macrophages, 78 magnetic, vi, 52, 70, 120, 134 magnetic field, 120 magnetic resonance, 52, 70 magnetic resonance imaging, 52, 70 maintenance, 127 males, 2, 11, 91 malignant, xi, 38, 40, 139, 151 malpractice, xii, 149, 150, 154, 155 management, ix, x, xi, 18, 35, 37, 43, 53, 54, 57, 59, 60, 61, 65, 69, 75, 76, 86, 88, 89, 92, 94, 103, 107, 109, 110, 111, 112, 113, 115, 121, 126, 128, 134, 135, 136, 148, 155, 163, 164 manipulation, 54, 55, 186 mantle, 52 marriage, 25, 27 marriages, 22 Marx, 134 maternal, 33, 47, 98, 104, 114, 127, 128, 132, 133, 134, 138 matrix, 112 maturation, 175 MB, 33, 39, 198

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

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Index MCA, 81 MDI, 55, 56 measurement, 47, 80, 84, 85, 86, 105, 106, 120 measures, 45, 58, 84, 165 mechanical ventilation, 55, 104, 106 media, 78, 178, 181 median, 64, 90, 94, 98, 126, 180, 182 mediators, 78, 167, 170 medication, 18, 23, 154 medications, 18, 58 medicine, 65, 76, 155 melatonin, 164 melting, 172 melting temperature, 172 membranes, 2, 140 memory, 56, 64, 65 mental retardation, 4, 8, 52, 64 messenger RNA, 77, 89 meta-analysis, 95, 96, 109 metabolic, 14, 70, 101, 102 metabolic acidosis, 101, 102 metabolism, 127, 128 methylenetetrahydrofolate reductase, xiii, 197, 198, 203 methylprednisolone, 72, 132 Mexican, 9 Mg2+, 13 mice, 89 microcephaly, 52, 64 microcirculation, 55, 69, 106 microorganisms, 154 microvascular, 84 migration, 49, 78, 167 military, 155 milk, 94 minority, 174 mirror, 184, 187 miscarriage, 24 miscarriages, 23 mitochondria, 77 mitochondrial, 77, 104 mitral, 100, 102, 118, 126, 152 mitral valve, 118 mixing, 48, 50 ML, 31, 32, 34, 35, 36, 41, 73, 74, 145, 163 modalities, 45 modality, 58, 97 models, xiii, 37, 60, 76, 143, 147, 161, 171, 172, 174 modifier gene, 11 modulation, 148

217

molecules, x, 1, 31, 167 monoclonal, 152 monoclonal antibody, 152 monocyte, 104 monocytes, 78 monotherapy, 127 Montenegro, 71 morbidity, x, xi, xii, xiii, 43, 44, 70, 94, 97, 98, 111, 113, 115, 123, 125, 127, 136, 138, 165, 167, 177, 178, 179, 181 Morocco, 139 morphogenesis, 175 morphology, 16, 20, 24, 69, 140, 144, 178, 182, 188, 193 mortality, x, xi, xii, xiii, 43, 44, 48, 55, 59, 60, 93, 94, 95, 96, 97, 99, 111, 112, 113, 114, 115, 123, 124, 125, 126, 127, 131, 132, 133, 138, 143, 149, 154, 155, 161, 165, 166, 167, 169, 177, 178, 179, 182 mortality rate, xi, 113, 114, 143, 154, 161, 166 mortality risk, 112, 126 mosaic, 172 mothers, xi, 111, 114, 131, 132, 137, 138 motion, 117, 135 motor function, 56 motor skills, 64 mouse, 26, 34, 89 movement, 59 MPA, 180, 192 MRI, 13, 23, 45, 52, 53, 59, 66, 152 MRS, 45 MS, 72, 108, 164 MTHFR, 198, 199, 202 mucosa, 167 multifocal atrial tachycardia, 124, 125 murmur, 85, 86 muscle, 4, 8, 20, 77, 78, 92, 104, 108, 150, 155, 161, 162, 170, 179, 181, 193 muscle cells, 77, 78, 104, 179, 181 muscle contraction, 20, 77, 92, 108, 179 muscles, 108 mutant, 35, 38, 143 mutation, xiii, 2, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38, 39, 40, 41, 52, 140, 143, 147, 197, 198, 199, 202, 203 mutations, ix, xii, xiii, 1, 2, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, 19, 20, 22, 23, 30, 31, 32, 34, 36, 37, 38, 39, 40, 139, 140, 145, 148, 171, 172, 173, 174, 175, 176

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Index

218 MV, 47, 48, 105, 138 myocardial biopsy, 152, 153 myocardial infarction, xiii, 108, 197, 198, 202, 203 myocardial ischemia, 152 myocarditis, ix, xii, 114, 131, 138, 149, 150, 151, 152, 153, 154, 155, 156, 201 myocardium, ix, 1, 9, 51, 91, 92, 99, 117, 128, 148, 150, 151, 152, 153, 154 myocyte, 150 myocytes, ix, 1, 88, 147 myofibrillar, 92 myoglobin, 198 myosin, 92

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N Na+, 3, 16, 38, 142, 143, 148 N-acety, 45 natural, 32, 54, 96, 115, 125, 126, 131, 132, 133, 138, 155 near-infrared spectroscopy, 57, 58, 71, 106 NEC, ix, x, xii, 75, 80, 94, 95, 96, 97, 98, 100, 102, 165, 166, 167 necrosis, 52, 78, 150, 152, 153 neonatal, xiii, 19, 33, 57, 66, 67, 70, 71, 73, 76, 87, 88, 89, 92, 97, 98, 104, 107, 110, 111, 125, 127, 131, 132, 133, 134, 137, 165, 167, 168, 177, 178, 181, 192, 193, 195 neonatal intensive care unit, 110 neonate, 24, 57, 68, 86, 89, 92, 102, 133, 183, 192 neonates, ix, x, xii, xiii, 6, 7, 32, 54, 66, 68, 70, 71, 72, 75, 76, 77, 89, 93, 94, 96, 97, 107, 108, 110, 111, 112, 131, 165, 166, 167, 168, 169, 170, 177, 178, 181, 183, 184, 192, 193 neonatologists, 88 nerve, 61, 142, 179 nervous system, 9, 52, 55, 71, 142 Netherlands, 1 neurobehavioral, 44 neurodegeneration, 98, 111 neuroimaging, 44, 45, 52, 53 neuroimaging techniques, 52 neurological injury, 53, 54, 56, 57, 59, 66 neurologist, 22 neuromotor, 60, 66 neuromuscular diseases, 19 neuronal migration, 49 neurons, 49 neuroprotection, 60 neuroprotective, x, 43, 44, 60

New York, v, vi, 24, 67, 68, 164 NICU, 158 Nielsen, 2, 30, 31, 32, 41, 141 NIH, 175 NIRS, 57, 58, 59, 60, 84 nitric oxide, 96, 167, 183 nitric oxide (NO), 167 NMDA, 111 NMDA receptors, 111 NNT, 97 NO, 167 noise, 3, 6, 8, 13 non-invasive, 84, 117 nonsense mutation, 173 non-smokers, 161 non-steroidal anti-inflammatory drugs, x, 75, 94 norepinephrine, 111 normal, xi, xiii, 2, 5, 7, 8, 9, 12, 13, 16, 20, 22, 23, 25, 27, 29, 45, 47, 48, 49, 50, 51, 52, 56, 59, 61, 64, 65, 67, 78, 86, 113, 114, 118, 120, 125, 126, 129, 130, 131, 132, 133, 134, 139, 144, 160, 162, 167, 171, 174, 198, 199, 202, 203 normal development, 78 normalization, 144 norms, 65 NPR, 89 NS, 30, 110, 134 NSAIDs, 97 N-terminal, 20, 89, 108, 109, 111, 198 nutrient, 95 nutrients, 78

O OB, 103, 105, 109 obese, 116 observations, 131 obstruction, xiii, 48, 50, 51, 153, 197 occlusion, 182, 186, 187, 191, 202 odds ratio, 51, 78, 97, 98 oedema, 79, 85, 96, 101 online, 59 open heart surgery, 56, 66, 70, 72 ophthalmologist, 158 optics, 84 optimization, 59 oral, 127, 133, 144, 145 organ, 80, 101, 105, 106 organism, 155 orientation, 188

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Index osmolality, 95 out-of-hospital, 28 overload, 7, 79, 153 oxide, 96, 183 oxygen, xiii, 45, 46, 50, 51, 54, 55, 58, 59, 60, 65, 67, 69, 71, 72, 76, 77, 79, 84, 96, 97, 100, 101, 104, 158, 177 Oxygen, 77 oxygen saturation, xiii, 45, 46, 58, 59, 60, 71, 72, 84, 158, 177 oxygenation, 46, 47, 54, 57, 58, 59, 70, 72, 84, 100, 102, 106, 163 oxyhemoglobin, 54

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P PA, 32, 37, 67, 72, 86, 107, 108, 111, 134, 175, 182, 186, 189 pacemaker, 19, 24, 39, 132, 133, 154 pacing, 14, 19, 24, 37 pain, 198 palliative, xiii, 64, 165, 177 palpitations, 13, 15 paradoxical, 199, 201 paralysis, 4, 8, 57 parasites, 151 parasitic diseases, 150 parents, xii, 22, 24, 27, 154, 157, 158, 161, 162 Parkinson, vii, 115, 157, 162, 163 paroxysmal tachycardia, 160 passive, 54, 78, 100, 161 patent ductus arteriosus, ix, x, 75, 76, 81, 82, 86, 98, 100, 103, 104, 105, 106, 107, 108, 109, 110, 111, 193 pathogenesis, 6, 20, 45, 166, 167, 169, 174 pathogenic, 8, 9, 13, 15, 29, 174, 203 pathology, xi, 113, 133 pathophysiological, 89, 128 Pathophysiological, 38 pathophysiological mechanisms, 128 pathophysiology, x, 15, 103, 113, 115, 125, 165 pathways, xiii, 47, 56, 171, 175 patients, x, xii, xiii, 2, 5, 6, 7, 8, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 27, 32, 36, 37, 39, 40, 41, 43, 45, 51, 52, 53, 56, 57, 58, 59, 60, 61, 64, 65, 73, 98, 107, 108, 111, 137, 139, 141, 142, 143, 144, 146, 147, 148, 150, 151, 152, 153, 154, 166, 167, 171, 172, 173, 174, 177, 178, 179, 181, 183, 188, 192, 202, 203 PCR, 172

219

PD, 9, 10, 67, 157, 169 PDAs, 91, 93, 94, 95, 96 PDI, 52, 55, 56 PE, 138, 194 pediatric, 13, 22, 30, 60, 72, 163, 183 pediatric patients, 13, 60, 163 pediatrician, 163 PEEP, 94 penetrance, 11, 20 penicillin, 151, 158 peptide, x, 7, 75, 89, 107, 108, 109, 111 Peptide, 88 peptides, 88, 89, 92, 107 perforation, 95, 181, 183 perfusion, 44, 47, 49, 51, 53, 54, 55, 57, 59, 60, 69, 70, 71, 80, 82, 84, 85, 152, 154, 166, 167, 169, 178, 181 pericardial, 131 pericardial effusion, 131 pericarditis, 152 perinatal, 47, 48, 67, 98, 108, 111, 153 periodic, 4, 8, 132 periventricular, 52, 105 periventricular leukomalacia, 52 periventricular leukomalacia (PVL), 52 permeability, 167, 169 permit, x, 1 persistent pulmonary hypertension of the newborn, 107 personality, 70 PF, 111, 168, 169 PG, 38, 39, 109 pH, 54, 69, 101, 102, 154 pharmacodynamics, 137 pharmacokinetics, 137 pharmacological, 16, 38, 57, 141, 142, 143, 186 pharmacological treatment, 38 pharmacology, 127, 147 phenotype, 7, 8, 9, 11, 22, 31, 33, 35, 37, 38, 40, 41, 140, 143, 146, 179 phenotypes, 5, 7, 19, 34, 35 phenytoin, 22 Philadelphia, 135, 170 phosphate, 17, 94 photon, 152 PHTN, 173 physical activity, 20, 22, 202 physical exercise, 20, 202 physicians, 141, 155 physiological, x, 43, 67, 89, 114, 158, 179

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

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220 physiology, 57, 61, 64, 166, 167, 174, 183 pig, 69, 104 pigs, 69, 104, 169, 181 placebo, 95, 96, 110, 126, 147 placenta, xi, 46, 48, 76, 92, 114, 127, 131, 133 placental, 47, 48, 50, 68, 91, 127, 128 plaque, ix plasma, 101, 107, 108, 111, 132, 138, 170 plasmapheresis, 138 platelet, 98 Platelet, 170 platelet count, 98 play, 76, 78, 79, 96, 115, 125, 144, 166, 167, 169, 174 pleural, 179 pleural effusion, 179 PM, 19, 66, 68, 73, 193 pneumonia, 150, 153 polarization, 84, 106 polymerase, 152, 154, 156, 172 polymerase chain reaction, 152, 154, 156, 172 polymorphism, 35, 173 polymorphisms, 9, 173, 203 polysomnography, 162 poor, xi, 24, 44, 47, 48, 60, 89, 93, 98, 99, 103, 114, 126, 127, 131, 132, 145, 154, 165 population, x, xii, 43, 44, 45, 51, 53, 55, 56, 58, 60, 64, 65, 67, 84, 140, 149, 150, 155, 163, 165, 166, 167, 173, 174, 202 pore, 2, 6, 8, 15, 32, 39 postischemic hyperthermia, 60 postoperative, 55, 58, 59, 60, 71, 72, 167, 199 postpartum, 23, 125 postpartum period, 23 post-translational, 3 potassium, 7, 8, 9, 13, 14, 15, 30, 31, 32, 33, 34, 35, 77, 140, 144, 145, 146, 147, 148 potassium channels, 8, 9, 15, 34, 77, 146, 147 precipitation, 96 prediction, 85, 106 predictors, 126, 134 prednisone, 132 pre-existing, 72, 94 preference, 44 pregnancy, 23, 24, 41, 47, 104, 114, 120, 125, 126, 127, 129, 131, 132, 133, 138, 158 pregnant, 131, 132 pregnant women, 131, 132 premature contraction, xi, 113, 115, 129 premature delivery, 133

Index premature infant, xii, 78, 93, 95, 96, 104, 105, 109, 110, 165, 166 prematurity, xii, 76, 97, 127, 165, 166 preschool, 73 pressure, xiii, 54, 55, 79, 82, 85, 86, 88, 89, 91, 100, 101, 102, 105, 109, 171, 172 preterm infants, x, 45, 53, 75, 78, 84, 85, 87, 88, 89, 93, 94, 95, 97, 98, 99, 103, 104, 105, 106, 107, 108, 109, 110, 168 prevention, 110 preventive, 132 primary pulmonary hypertension, 175, 176 primates, 173 proarrhythmia, 35 probability, 162 proband, 13, 22, 23, 24, 25, 26 probands, 25, 27 probe, 86 production, 89, 164 prognosis, 39, 72, 126, 131, 132, 133, 136, 152, 154 program, xiii, 172, 173, 174, 183 proinflammatory, 167 pro-inflammatory, 167 prolapse, 183, 191 proliferation, 49, 181 propagation, 2 property, vi, 16 prophylactic, 14, 76, 94, 95, 96, 97, 132, 138, 141 prophylaxis, 99, 110 propranolol, xii, 22, 23, 24, 127, 139, 141, 142, 144, 146, 148 Propranolol, 141, 142, 146 prostaglandin, 76, 95, 166, 179, 183, 186 prostaglandins, 76, 78, 96, 186 prostanoids, 109 prosthesis, 185, 194 protection, 57, 72 protein, ix, xiii, 1, 2, 3, 4, 5, 6, 7, 17, 26, 32, 35, 53, 68, 92, 94, 171, 172, 173, 175, 197, 198, 202 proteinase, 110 proteins, ix, 1, 6, 23, 33, 92, 127, 140, 172, 175 prothrombin, xiii, 197, 198, 199, 202, 203 protocol, 97 protocols, 14 pseudo, 152 psychological development, 70 pulmonary arteries, 152, 179, 180, 181, 183, 185, 188, 192, 193, 194 pulmonary artery pressure, 82

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Index pulmonary circulation, x, xiii, 75, 79, 80, 82, 85, 86, 177, 178, 181, 183, 193, 195 pulmonary edema, 152, 153 pulmonary hypertension, 94, 96, 107, 153, 173, 175, 176 pulmonary stenosis, 188, 193 pulmonary vascular resistance, xiii, 92, 96, 166, 177 pulse, 86, 116 pulses, 85, 86 Purkinje, 129 PVL, 53, 95, 96

Q QRS complex, 115, 160 QT interval, 2, 3, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 22, 38, 120, 137, 140, 142, 143, 145, 148 QT prolongation, 7, 8, 144 quality of life, x, 43 quinidine, 127

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R RA, 66, 69, 70, 71, 72, 110, 136, 168, 169 radio, 183 rain, 51, 52, 72, 98 range, 58, 61, 64, 65, 83, 91, 92, 93, 94, 95, 114, 126, 131, 181 rat, 98, 104, 148 rats, 76 RB, 35, 107, 168 RC, 34, 68, 109, 147 reactants, 152 reactive oxygen, 77 reactivity, 47, 58 Receiver Operating Characteristics, 103 receptor agonist, 104 receptors, 40, 76, 89, 104, 111, 151, 172, 179 recognition, xi, 113 recovery, 56, 114 recurrence, 14, 131, 133, 138 red blood cell, 51, 152, 199 red blood cell count, 51 red blood cells, 152, 199 redistribution, 46, 67 redox, 104 refining, 53, 60 refractoriness, 128 refractory, 15, 96, 120, 128, 129, 137

221

Registry, xii, 36, 139, 140, 141, 146 regression, 98, 132 regression analysis, 98 regular, xi, 12, 87, 113, 114, 118, 123, 129, 130, 201 regulation, 9, 44, 76, 89, 104 rejection, 151 relationship, xi, 7, 39, 49, 56, 70, 71, 72, 82, 87, 89, 108, 111, 112, 113, 114, 115, 117, 118, 123, 124, 126, 129, 148, 166 relationships, 41 relatives, 15, 30 relaxation, 100, 170 relaxation time, 100 relevance, xi, 113, 115 reliability, 162 remission, 153 remodeling, 30, 104, 179 remodelling, 78 renal, x, 75, 77, 80, 85, 95, 101, 102, 104, 109, 144, 154, 199 renal dysfunction, x, 75, 77, 80 renal failure, 102, 104 renal function, 95, 144, 199 renin, 89 renin-angiotensin system, 89 repair, x, xiii, 43, 44, 52, 55, 56, 57, 58, 59, 61, 64, 66, 73, 74, 177, 178, 184 reperfusion, 55, 59, 167 replication, 20, 151 repolarization, xi, 7, 9, 15, 35, 37, 38, 135, 139, 143, 144, 146, 147, 148 reserves, 151 resistance, xiii, 47, 48, 49, 50, 92, 96, 177 resolution, 84, 117, 125, 126, 133, 136, 203 respiration, 158 respiratory, 95, 96, 100, 105, 106, 108, 111, 112, 161, 164 respiratory distress syndrome, 95, 105, 106, 108, 111, 112 response time, 88 resuscitation, 24, 158, 162 retardation, 4, 8, 46, 47, 48, 52, 64, 67 retention, 95 reticulum, 20 retinopathy, 97 retinopathy of prematurity, 97 retinopathy of prematurity (ROP), 97 returns, 82, 84 Reynolds, 106, 107 RF, 110, 170

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Index

222 rheumatoid arthritis, 151 rhythm, ix, x, xi, 2, 12, 15, 23, 24, 27, 113, 114, 115, 116, 120, 121, 124, 126, 127, 128, 133, 135, 136, 163, 198 rhythms, 24 right atrium, 122 right ventricle, 46, 76, 86, 121, 122, 128, 172, 174 rings, 77 risk factors, ix, xii, xiii, 65, 73, 98, 105, 111, 126, 139, 140, 158, 161, 165, 166, 168, 197, 198, 202, 203 risk profile, 66, 183 risks, 56, 98 RNA, 77, 89, 152 ROP, 95, 97, 98 RP, 136 runoff, 85

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S safety, 158, 161, 169 Salmonella, 151 sample, 118, 172, 174 sampling, 116, 128 saturated fat, ix saturated fatty acids, ix saturation, xiii, 45, 46, 58, 59, 60, 71, 72, 84, 158, 177, 181 Saudi Arabia, 1 SCD, ix, 1, 7, 13, 14, 20, 22, 140 school, 22, 61, 65, 66, 73, 74, 158 school performance, 74 scintigraphy, 152 scleroderma, 151 scores, 50, 52, 55, 56, 59, 64, 65 SD, 62, 63 SE, 66, 158, 169, 181, 183, 193 secretion, 92 sedation, 57, 59, 178, 187 seizure, 22, 23, 45, 58, 59, 61 seizures, 20, 22, 23, 44, 55, 56, 58, 60, 71, 72 semilunar valve, 172 sensing, 77, 104 sensitivity, 5, 31, 90 sensors, 67, 120, 164 separation, 146, 172 sepsis, 78, 95, 97, 153 septum, 46, 51, 178, 183 sequelae, 59, 68 sequencing, xiii, 171

serology, 154 serum, 13, 23, 34, 53, 89, 108, 111, 144 services, vi, 65 severity, x, 7, 8, 19, 75, 152 sex, 36, 175 SH, 34, 108, 138 shock, xiii, 24, 151, 153, 154, 166, 197, 199 shock therapy, 153 shocks, 24, 140 short period, 114, 179 short run, 24 short-term, x, 43, 44, 87, 178, 181, 183, 192, 194 shunts, 179, 195 siblings, 56, 161 sick sinus syndrome, 39 sickle cell, 201 side effects, 95, 141, 142, 143, 181 SIDS, 13, 20, 40, 158, 161, 162, 163 sign, 38, 79, 126, 131, 162 signal quality, 120 signaling, 175 signaling pathway, 175 signaling pathways, 175 signals, 117, 120, 134, 175 signs, xiii, 24, 85, 87, 92, 97, 99, 100, 115, 127, 150, 153, 158, 160, 166, 197, 199 similarity, 45 sine, 13 single nucleotide polymorphism, 173 sinus, xi, xiii, 2, 7, 12, 17, 19, 20, 21, 23, 27, 32, 39, 113, 114, 121, 123, 124, 126, 127, 128, 129, 133, 152, 197, 198, 199, 200, 201, 202, 203 sinus rhythm, 12, 23, 124, 126, 127, 128, 133, 198 sites, 16, 98, 170 Sjogren, 131 skeletal muscle, 4, 8, 92 skills, 56, 64, 65, 155 skin, 84, 120, 161 sleep, 3, 5, 6, 7, 13 SMA, 89, 166 smokers, 161 smoking, 161 smooth muscle, 77, 78, 104, 170, 179, 181, 193 smooth muscle cells, 77, 78, 104, 179, 181 SND, 19 SNP, 9, 10, 173, 174 SNPs, 10 SNS, 9 soccer, 29

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

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Index sodium, xi, 3, 4, 7, 8, 9, 13, 16, 17, 30, 34, 35, 36, 39, 95, 139, 140, 143, 146, 148 software, 172 solubility, 142 somatosensory, 58 South America, 151 Southeast Asia, 16 SP, 37, 66, 136, 148 spatial, 56 species, 26, 151, 173 specificity, 90, 106 spectrophotometry, 106 spectroscopy, 53, 57, 58, 71, 84, 106 spectrum, xiii, 35, 39, 44, 106, 177, 178 speech, 56, 59, 64, 65 speed, 159 sporadic, 156 SR, 28, 104, 107, 111, 168, 169 SSB, 131 SSS, 17, 19 stability, 3 stabilization, 178, 179, 181, 184, 185, 192 stabilize, 190 stages, 6, 19 standard deviation, 52, 55 standardization, 92 statistics, 155 status of children, 70 stenosis, 52, 180, 181, 185, 188, 193 stent, xiii, 57, 177, 178, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 193, 194 steroid, 60, 72, 132, 133, 138 Steroid, 72 steroids, 60, 132, 133 stimulus, 3, 8, 167 storage, 89, 153 storms, 14 strain, 117 strategies, x, xii, 19, 43, 44, 54, 56, 57, 60, 65, 69, 115, 149, 155 stratification, xii, 139 stress, 3, 5, 13, 20, 21, 37, 40, 47, 89, 141 stressors, 14 stroke, 53, 79, 99, 111, 131, 203 stroke volume, 79, 131 structural defect, x, 2 structural defects, x, 2 structural protein, 92 subacute, 148 subgroups, 99

223

subjective, 88 substances, 9 substitution, 25, 26, 27, 29, 173, 174 success rate, 183 sudden infant death syndrome, 15, 33, 34, 36, 37, 38, 40, 158, 161, 163 Sudden Infant Death Syndrome, 164 suffering, 152, 154 sulfonamide, 151 sumatriptan, 202 Sun, 31 superior vena cava, 46, 105, 116, 117, 128, 137 supervision, 161 supply, 58, 78, 80, 179, 194 suppression, 8, 19, 144 supraventricular tachycardia, xi, 113, 115, 121, 123, 124, 125, 126, 127, 128, 133, 134, 135, 136, 137, 163 surfactant, 94, 105, 106 surgeons, 55 surgeries, 98 surgery, x, 19, 43, 44, 45, 51, 52, 53, 54, 55, 56, 57, 58, 60, 64, 66, 68, 69, 70, 71, 72, 73, 94, 97, 98, 99, 106, 166, 167, 169, 179, 183, 184, 193 Surgery, 60, 71, 72 surgical, x, xiii, 43, 44, 52, 53, 54, 55, 56, 57, 58, 60, 61, 64, 65, 69, 74, 76, 79, 82, 95, 96, 97, 98, 110, 165, 167, 177, 178, 179, 180, 181, 183, 184, 188, 191, 193, 194 surgical intervention, 44, 52 surveillance, 168 survival, x, xiii, 43, 44, 57, 65, 76, 131, 165, 182 survival rate, 182 surviving, 30, 44, 74, 165 survivors, x, 43, 44, 60, 61, 65, 71, 73, 97, 131, 182 susceptibility, 52, 53, 154, 174 Sweden, 155 symbols, 27 sympathetic, xii, 5, 9, 31, 37, 40, 139, 140, 146, 148 sympathetic denervation, xii, 37, 40, 139, 148 sympathetic nervous system, 9 symptom, 15, 20, 151, 166 symptomatic treatment, 96, 153 symptoms, xii, 13, 15, 18, 20, 21, 23, 131, 149, 150, 151, 152, 153, 154, 158, 161 syndrome, ix, xi, xii, xiii, 2, 6, 7, 8, 10, 11, 14, 15, 16, 17, 19, 22, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 45, 49, 50, 52, 57, 66, 68, 70, 73, 74, 95, 105, 106, 108, 111, 112, 129, 131, 139, 140, 141, 143, 144, 145, 146, 147, 148, 153, 157,

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Index

224 158, 160, 161, 162, 163, 166, 167, 169, 171, 172, 174, 175 synthesis, 39, 89 systemic circulation, 80, 84, 85, 87, 88, 98 systemic lupus erythematosus, 131, 138, 151

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T tachycardia, xi, xii, 3, 8, 13, 16, 17, 20, 21, 24, 27, 29, 39, 40, 41, 113, 114, 115, 116, 121, 123, 124, 125, 126, 127, 128, 133, 134, 135, 136, 137, 150, 151, 152, 157, 158, 159, 160, 163 TdP, 2, 11, 12 TE, 33, 36 technetium, 152 technical assistance, 175 teeth, 4, 8 telephone, 6, 23 temperature, 54, 59 temporal, 117 tension, 51, 76, 77 tetralogy, 45, 73, 174, 178, 187, 188, 194, 195 Tetralogy of Fallot, 46, 174 TF, 104, 137 TGA, 45, 48, 50, 51, 55, 56, 61, 62, 64, 65 TGF, 175, 176 thalamus, 52 therapeutic agents, 133 therapy, x, xi, xii, 10, 11, 14, 15, 19, 36, 75, 94, 98, 99, 104, 110, 113, 126, 127, 128, 132, 133, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 153, 154, 160, 162, 163, 182, 183, 188 Thomson, 176 thoracotomy, 181 threatening, 140, 141, 161 threonine, 173 throat, 152 thromboembolic, 56, 57, 151, 152, 154 thrombosis, 178, 181, 191, 198, 199, 202 thrombus, 151, 152 thyroid, 114, 128 thyrotoxicosis, 114 time consuming, 116 timing, 60, 94, 95, 97, 117, 123, 128, 162 tin, 177 tissue, 54, 59, 76, 77, 84, 89, 92, 106, 116, 117, 123, 131, 135, 178, 183, 191 tissue perfusion, 84 TJ, 30, 34, 145, 169 TM, 37, 39, 40, 108, 137, 169, 170

TMP, 10 TNF, 78, 167 TNF-α, 78, 167 tolerance, 145 tonic, 23, 24 tonic-clonic seizures, 23 toxic, 127, 151 toxic effect, 127 toxicity, 151 toxoplasmosis, 151 training, 88 trans, 88, 182 transcatheter, 181 transcranial Doppler sonography, 71 transesophageal echocardiography, 199, 203 transfer, xi, 114, 127, 128 transformation, 76 translocations, 172 transmembrane, 5 trans-membrane, 89 transmission, 114, 120 transplantation, 151 transport, 77, 97 transthoracic echocardiography, 107 travel, 78 trial, xi, 55, 69, 71, 96, 97, 110, 114, 115, 126, 127, 134, 135, 136, 147 tricuspid valve, 115, 178, 183 triggers, 22, 31, 141, 146 trisomy, 172 trisomy 21, 172 Trisomy 21, 51 TT, 39, 162 tumors, 153 tumour, 78 tumours, 116 turbulent, 151 Turbulent, 79 twins, 9, 104 two-dimensional, 100, 116

U ultrasonography, 67, 71, 116, 134 ultrasound, xi, 45, 46, 47, 50, 52, 53, 57, 59, 66, 67, 82, 86, 88, 107, 113, 116, 120, 158, 162, 169 umbilical artery, 47 umbilical cord, 111 umbilical cord blood, 111 uncertainty, 98

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook

Index uniform, 11, 141, 178, 192 United Kingdom, 150, 155 United States, 65, 161, 168, 175 unmasking, 13 urinary, 95, 109 urine, 95, 96, 97, 154

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V vagal nerve, 179 validation, 58, 92 values, 2, 45, 89, 91, 92, 111, 131, 198 variability, 60, 116, 123, 163 variables, 72, 98 variation, 11, 89, 114, 126 vascular disease, 78 vascular surgery, 70 vasculature, 48, 79, 87, 89, 96 vasodilatation, 76, 89 vasodilation, 47, 51, 54 vasodilator, 183 VC, 111 vein, 128, 135 velocity, 47, 67, 68, 79, 81, 82, 83, 85, 93, 95, 99, 100, 105, 106, 117, 125, 135 ventilation, 55, 94, 97, 100, 101, 102, 104, 106, 109, 133, 183 ventricle, 46, 64, 71, 73, 76, 86, 92, 116, 118, 119, 120, 121, 122, 123, 128, 129, 148, 152, 166, 167, 172 ventricles, 47, 51, 61, 64, 88, 89, 116, 118, 123, 124, 129, 151, 152, 162, 174 ventricular arrhythmia, xi, 6, 8, 16, 18, 20, 40, 139, 143, 144, 151, 152, 154 ventricular arrhythmias, xi, 6, 8, 16, 18, 20, 40, 139, 143, 144, 151, 154 ventricular fibrillation, 15, 19, 20, 29 ventricular septal defect, 73, 172, 178, 182, 188 ventricular septum, 51, 178, 183 ventricular tachycardia, 8, 13, 16, 17, 20, 21, 24, 29, 39, 40, 41, 123, 125, 129, 135 verapamil, 127, 128, 144, 148 Vermont, 94 vertebrates, 54 very low birth weight, 104, 110, 168 vessels, 47, 74, 116, 178, 184, 187 victims, ix, 1 viral myocarditis, 151 virus, 151, 152 viruses, 151

225

viscosity, 55 visible, 82 vision, 59 visualization, 200 VLBW, 84 vomiting, 151 VSD, 62 vulnerability, 53, 143, 155

W warfarin, xiii, 197, 199 warrants, 98, 193 water, 54, 106 water absorption, 106 weight ratio, 50 Weinberg, 66, 68 Western Europe, 158 WG, 136 wheezing, 161 white blood cells, 199 white matter, 53 wild type, 7, 26, 28, 29 wires, 181, 186 WM, 109, 148, 175 Wolff-Parkinson-White syndrome, 157, 162 women, 23, 116, 131, 132, 137 working memory, 65

X X chromosome, 52

Y yield, 30, 88 young adults, ix, 1, 16, 145, 155, 168, 202

Z zebrafish, 26

Heart Disease in Children, edited by Marius D. Oliveira, and William S. Copley, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook