(Fundamental and Clinical Cardiology ) Robert Shaddy, Gil Wernovsky-Pediatric Heart Failure (Fundamental and Clinical Cardiology)-Informa Healthcare (2005)

DK3035_FM 1/14/05 1:14 PM Page A

Fundamental and Clinical Cardiology

Editor-in-ChiefSamuel Z. Goldhaber, M.D.

Harvard Medical Schooland Brigham and Womens Hospital

Boston, Massachusetts

1. Drug Treatment of Hyperlipidemia, edited by Basil M. Rifkind2. Cardiotonic Drugs: A Clinical Review, Second Edition, Revised and

Expanded, edited by Carl V. Leier3. Complications of Coronary Angioplasty, edited by Alexander J. R. Black,

H. Vernon Anderson, and Stephen G. Ellis4. Unstable Angina, edited by John D. Rutherford5. Beta-Blockers and Cardiac Arrhythmias, edited by Prakash C. Deedwania 6. Exercise and the Heart in Health and Disease, edited by Roy J. Shephard

and Henry S. Miller, Jr.7. Cardiopulmonary Physiology in Critical Care, edited by Steven M. Scharf 8. Atherosclerotic Cardiovascular Disease, Hemostasis,

and Endothelial Function, edited by Robert Boyer Francis, Jr.9. Coronary Heart Disease Prevention, edited by Frank G. Yanowitz10. Thrombolysis and Adjunctive Therapy for Acute Myocardial Infarction,

edited by Eric R. Bates11. Stunned Myocardium: Properties, Mechanisms, and Clinical

Manifestations, edited by Robert A. Kloner and Karin Przyklenk12. Prevention of Venous Thromboembolism, edited by Samuel Z. Goldhaber 13. Silent Myocardial Ischemia and Infarction: Third Edition, Peter F. Cohn 14. Congestive Cardiac Failure: Pathophysiology and Treatment,

edited by David B. Barnett, Hubert Pouleur and Gary S. Francis15. Heart Failure: Basic Science and Clinical Aspects, edited by Judith K.

Gwathmey, G. Maurice Briggs, and Paul D. Allen16. Coronary Thrombolysis in Perspective: Principles Underlying Conjunctive

and Adjunctive Therapy, edited by Burton E. Sobel and Desire Collen17. Cardiovascular Disease in the Elderly Patient, edited by Donald D. Tresch

and Wilbert S. Aronow18. Systemic Cardiac Embolism, edited by Michael D. Ezekowitz 19. Low-Molecular-Weight Heparins in Prophylaxis and Therapy of

Thromboembolic Diseases, edited by Henri Bounameaux20. Valvular Heart Diseases, edited by Muayed Al Zaibag and

Carlos M. G. Duran 21. Implantable Cardioverter-Defibrillators: A Comprehensive Textbook,

edited by N. A. Mark Estes, Antonis S. Manolis, and Paul J. Wang

DK3035_FM 1/14/05 1:14 PM Page B

22. Individualized Therapy of Hypertension, edited by Norman M. Kaplan and C. Venkata S. Ram

23. Atlas of Coronary Balloon Angioplasty, Bernhard Meier and Vivek K. Mehan

24. Lowering Cholesterol in High-Risk Individuals and Populations, edited by Basil M. Rifkind

25. Interventional Cardiology: New Techniques and Strategies for Diagnosis and Treatment, edited by Christopher J. White and Stephen Ramee

26. Molecular Genetics and Gene Therapy of Cardiovascular Diseases, edited by Stephen C. Mockrin

27. The Pericardium: A Comprehensive Textbook, David H. Spodick28. Coronary Restenosis: From Genetics to Therapeutics, edited by

Giora Z. Feuerstein29. The Endothelium in Clinical Practice: Source and Target of Novel

Therapies, edited by Gabor M. Rubanyi and Victor J. Dzau30. Molecular Biology of Cardiovascular Disease, edited by Andrew R. Marks

and Mark B. Taubman31. Practical Critical Care in Cardiology, edited by Zab Mohsenifar

and P. K. Shah 32. Intravascular Ultrasound Imaging in Coronary Artery Disease,

edited by Robert J. Siegel33. Saphenous Vein Bypass Graft Disease, edited by Eric R. Bates

and David R. Holmes, Jr.34. Exercise and the Heart in Health and Disease: Second Edition, Revised

and Expanded, edited by Roy J. Shephard and Henry S. Miller, Jr35. Cardiovascular Drug Development: Protocol Design and Methodology,

edited by Jeffrey S. Borer and John C. Somberg36. Cardiovascular Disease in the Elderly Patient: Second Edition, Revised

and Expanded, edited by Donald D. Tresch and Wilbert S. Aronow37. Clinical Neurocardiology, Louis R. Caplan, J. Willis Hurst,

and Mark Chimowitz38. Cardiac Rehabilitation: A Guide to Practice in the 21st Century,

edited by Nanette K. Wenger, L. Kent Smith, Erika Sivarajan Froelicher, and Patricia McCall Comoss

39. Heparin-Induced Thrombocytopenia, edited by Theodore E. Warkentin and Andreas Greinacher

40. Silent Myocardial Ischemia and Infarction: Fourth Edition, Peter F. Cohn 41. Foundations of Cardiac Arrhythmias: Basic Concepts and Clinical

Approaches, edited by Peter M. Spooner and Michael R. Rosen42. Interpreting Electrocardiograms: Using Basic Principles and Vector

Concepts, J. Willis Hurst43. Heparin-Induced Thrombocytopenia: Second Edition, edited by

Theodore E. Warkentin and Andreas Greinacher44. Thrombosis and Thromboembolism, edited by Samuel Z. Goldhaber

and Paul M. Ridker

DK3035_FM 1/14/05 1:14 PM Page C

45. Cardiovascular Plaque Rupture, edited by David L. Brown46. New Therapeutic Agents in Thrombosis and Thrombolysis: Second Edition,

Revised and Expanded, edited by Arthur A. Sasahara and Joseph Loscalzo 47. Heparin-Induced Thrombocytopenia: Third Edition, edited by

Theodore E. Warkentin and Andreas Greinacher48. Cardiovascular Disease in the Elderly, Third Edition, edited by Wilbert

Aronow and Jerome Fleg49. Atrial Fibrillation, edited by Peter Kowey and Gerald Naccarelli50. Heart Failure: A Comprehensive Guide to Diagnosis and Treatment,

edited by G. William Dec51. Phamacoinvasive Therapy in Acute Myocardial Infarction, edited by

Harold L. Dauerman and Burton E. Sobel52. Clinical, Interventional, and Investigational Thrombocardiology, edited by

Richard Becker and Robert A. Harrington53. Pediatric Heart Failure, edited by Robert Shaddy and Gil Wernovsky

DK3035_FM 1/14/05 1:14 PM Page D

edited by

Robert E. ShaddyUniversity of Utah School of Medicine, Salt Lake City, U.S.A.

Gil WernovskyUniversity of Pennsylvania School of Medicine, Philadelphia, U.S.A.

The Cardiac Center at The Childrens Hospital of Philadelphia, Pennsylvania, U.S.A.

DK3035_FM 1/14/05 1:14 PM Page i

Published in 2005 byTaylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300Boca Raton, FL 33487-2742

2005 by Taylor & Francis Group, LLC

No claim to original U.S. Government worksPrinted in the United States of America on acid-free paper10 9 8 7 6 5 4 3 2 1

International Standard Book Number-10: 0-8247-5929-X (Hardcover) International Standard Book Number-13: 978-0-8247-5929-2 (Hardcover)

This book contains information obtained from authentic and highly regarded sources. Reprinted material isquoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable effortshave been made to publish reliable data and information, but the author and the publisher cannot assumeresponsibility for the validity of all materials or for the consequences of their use.

No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic,mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, andrecording, or in any information storage or retrieval system, without written permission from the publishers.

For permission to photocopy or use material electronically from this work, please access www.copyright.com(http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive,Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registrationfor a variety of users. For organizations that have been granted a photocopy license by the CCC, a separatesystem of payment has been arranged.

Trademark Notice:

Product or corporate names may be trademarks or registered trademarks, and are used onlyfor identification and explanation without intent to infringe.

Library of Congress Cataloging-in-Publication Data

Catalog record is available from the Library of Congress

Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com

Taylor & Francis Group is the Academic Division of T&F Informa plc.

DK3035_Discl Page 1 Monday, January 24, 2005 10:03 AM

Although great care has been taken to provide accurate and current information,neither the author(s) nor the publisher, nor anyone else associated with this publica-tion, shall be liable for any loss, damage, or liability directly or indirectly caused oralleged to be caused by this book. The material contained herein is not intended toprovide specific advice or recommendations for any specific situation.

Trademark notice: Product or corporate names may be trademarks or registered tra-demarks and are used only for identification and explanation without intent toinfringe.

Library of Congress Cataloging-in-Publication DataA catalog record for this book is available from the Library of Congress.

ISBN: 0-8247-5929-X

This book is printed on acid-free paper.

HeadquartersMarcel Dekker, 270 Madison Avenue, New York, NY 10016, U.S.A.tel: 212-696-9000; fax: 212-685-4540

World Wide Webhttp:==www.dekker.com

Copyright # 2005 by Marcel Dekker. All Rights Reserved.Neither this book nor any part may be reproduced or transmitted in any form or byany means, electronic or mechanical, including photocopying, microfilming, andrecording, or by any information storage and retrieval system, without permissionin writing from the publisher.

Current printing (last digit):

10 9 8 7 6 5 4 3 2 1

PRINTED IN THE UNITED STATES OF AMERICA

Series Introduction

The Taylor & Francis Group has focused on the developmentof various series of beautifully produced books in differentbranches of medicine. These series have facilitated the inte-gration of rapidly advancing information for both the clinicalspecialist and the researcher.

My goal as editor-in-chief of the Fundamental and Clin-ical Cardiology Series is to assemble the talents of world-renowned authorities to discuss virtually every area of cardi-ovascular medicine. In the current monograph, tric HeartFailure, Robert E. Shaddy and Gil Wernovsky have edited amuch-needed and timely book. Future contributions to thisseries will include books on molecular biology, interventionalcardiology, and clinical management of such problems as cor-onary artery disease and ventricular arrhythmias.

Samuel Z. Goldhaber

iii

Preface

Heart failure is a major cause of morbidity and mortality inchildren. Although there are many similarities between heartfailure in children and adults, the etiologies, pathophysiology,and physiologic consequences of heart failure in children areoften very different than in adults. We are publishing thisbook because it is the first book of its kind to specifically focuson heart failure in children and a comprehensive text of thiskind is lacking. This text provides a single reference sourcefor pediatric heart failure and is a must-read for all healthcare professional who care for children with heart disease sothey will be able to recognize and treat heart failure inchildren. The overall objectives of this book are to define theetiologies, pathophysiology, and treatment of heart failurein children from fetal life, childhood, adolesence, and throughadult life with congenital heart disease. This book willaddress both chronic and acute decompensated heart failure,thus providing insights into the diagnosis and management ofchildren from the womb, to the nursery, the intensive careunit, and the outpatient clinic. The target audience for thisbook includes pediatric cardiologists, pediatric cardiothoracic

v

surgeons, pediatric intensivists, pediatricians, anesthesiolo-gists, nurses, and all health care providers who deal withchildren with heart failure. This book will have specialemphasis on the mechanisms, diagnosis, and managementof heart failure that are unique to childern.

Robert E. ShaddyGil Wernovsky

vi Preface

Contents

Contributors . . . . xv

1. Heart FailureA Historical Perspective . . . . . . 1Abraham M. RudolphDefining Heart Failure . . . . 1Heart Failure Syndromes . . . . 4Mechanisms of Cardiac Failure . . . . 9Treatment . . . . 19Future Directions . . . . 22

2. Developmental Aspects of CardiacPerformance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31David F. TeitelIntroduction . . . . 31Fetal Cardiovascular Performance . . . . 40Postnatal Cardiovascular Performance . . . . 49

vii

3. Cellular and Molecular Aspects of MyocardialDysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65Steven M. SchwartzCellular and Molecular Basis of Cardiac

Contractility . . . . 66Acute Myocardial Dysfunction . . . . 74Myocardial Compensation and Chronic Heart

Failure . . . . 80Summary . . . . 91

4. Neurohormonal and Immunologic Aspectsof Pediatric Heart Failure . . . . . . . . . . . . . . . . . 105Reiner BuchhornIntroduction . . . . 105Clinical Aspects of Neurohormonal Activation in

Pediatric Heart Failure . . . . 107Methodological Aspects of Neurohormonal Activation in

Pediatric Heart Failure . . . . 114Pathophysiology of Neurohormonal Activation in

Pediatric Heart Failure . . . . 116Immunologic Aspects of Pediatric

Heart Failure . . . . 123

5. Genetics of Pediatric Heart Failure . . . . . . . . . 137Timothy M. OlsonIntroduction . . . . 137Dilated Cardiomyopathy, A Heritable Form of Heart

Failure . . . . 138Identifying Genes for Dilated Cardiomyopathy . . . . 141X-Linked DCM and Duchenne Muscular DystrophyA

Common Etiology . . . . 144Autosomal Dominant DCMA Genetically Heterogeneous

Disorder . . . . 149Inherited Defects in ActinDCM Gene Discovery Using a

Candidate Gene Approach . . . . 151Mutations in Genes Encoding Cytoskeletal ProteinsA

Unifying Etiology for DCM . . . . 153

viii Contents

DCM with Conduction DiseaseNovel Disease GeneDiscovery by Linkage Analysis . . . . 157

DCM and HCMShared Disease Genes, DivergentCardiac Remodeling Pathways . . . . 159

A New Mechanism for Familial DCMDefectiveMyocellular Calcium Regulation . . . . 161

Conclusions . . . . 162

6. Heart Failure in the Fetus . . . . . . . . . . . . . . . . . 171Lisa K. Hornberger and Masaki NiiBackground . . . . 171Clinical Findings Associated with Fetal CHF . . . . 175Etiologies Associated with Fetal Heart Failure . . . . 181Treatment Strategies and Outcome . . . . 194

7. Heart Failure in the Neonate . . . . . . . . . . . . . . . 209Dana Connolly, Marcelo Auslender, and Michael ArtmanIntroduction . . . . 209Pathophysiology . . . . 210Etiologies of Neonatal Heart Failure . . . . 217General Guidelines for Medical Therapy . . . . 226Appendix A . . . . 235

8. Metabolic Causes of Pediatric Heart Failure . . 241Brian D. HannaIntroduction . . . . 241Clinical Presentation . . . . 243Investigations . . . . 245Initial Treatment . . . . 248Mitochondrial Cardiomyopathies . . . . 249Storage Diseases Associated with Cardiac

Failure . . . . 261

9. Cardiomyopathy and Myocarditis . . . . . . . . . . . 273J.A. Towbin, Matteo Vatta, and N.E. BowlesOverview . . . . 273Introduction . . . . 274

Contents ix

Normal Cardiac Structure . . . . 276Z-Disc Organization . . . . 280Disorders of Ventricular Systolic Dysfunction . . . . 282Arrhythmias and Conduction System Disease in Dilated

Cardiomyopathy . . . . 285Heart Failure with Preserved Systolic

Function . . . . 286Syndrome of Heart Failure . . . . 287Clinical Genetics of Dilated Cardiomyopathy . . . . 288Molecular Genetics of Dilated Cardiomyopathy . . . . 289X-Linked Cardiomyopathies . . . . 290Barth Syndrome . . . . 292Autosomal Dominant Dilated Cardiomyopathy . . . . 293Lamin A=C . . . . 297Muscle Is Muscle: Cardiomyopathy and Skeletal Myopathy

Genes Overlap . . . . 298Myocarditis . . . . 300Arrhythmogenic Right Ventricular Dysplasia=

Cardiomyopathy (ARVD=ARVC) . . . . 316Diseases of Ventricular Diastolic Function . . . . 322Therapy in Hypertrophic Cardiomyopathy . . . . 333Restrictive Cardiomyopathy . . . . 334Overlap Disorders . . . . 337Final Common Pathway Hypothesis . . . . 341Relevance of the Final Common Pathway

Hypothesis . . . . 342

10. Inflammatory Causes of Pediatric Heart Failure:Rheumatic Fever, Rheumatic Heart Disease, andKawasaki Disease . . . . . . . . . . . . . . . . . . . . . . . 371Lloyd Y. Tani and Robert E. ShaddyRheumatic Fever . . . . 371Rheumatic Heart Disease . . . . 380Treatment of Rheumatic Heart Disease . . . . 392Kawasaki Disease . . . . 400Treatment of Heart Failure in Patients

with KD . . . . 407

x Contents

11. Arrhythmias and Sudden Cardiac Death inPediatric Heart Failure . . . . . . . . . . . . . . . . . . 433Michael J. Silka and Jacqueline R. SzmuszkoviczIntroduction . . . . 433Pathophysiology of Arrhythmias and Sudden Death in

Heart Failure . . . . 435Arrhythmias in Specific Conditions Associated with

Pediatric Heart Failure . . . . 438Treatment of Arrhythmias in Pediatric Heart

Failure . . . . 459Conclusions . . . . 468

12. Single Ventricle Lesions . . . . . . . . . . . . . . . . . . 481Charles E. CanterHeart Failure in the Newborn Period . . . . 482Establishment of a Series Connection of the Systemic and

Pulmonary Circuit in the Single VentriclePatientFontan Physiology . . . . 487

Optimization of Cardiac FunctionThe Timing andMechanism of Ventricular VolumeUnloading . . . . 493

Aortopulmonary Collaterals . . . . 496Atrioventricular Valve Regurgitation . . . . 496Optimization of Cardiac FunctionThe Manipulation of

Ventricular Preload . . . . 497Optimization of Cardiac FunctionThe Influence of

Afterload . . . . 500Pulmonary Vascular Resistance . . . . 502Optimization of Cardiac FunctionThe Design of the

Pathway of Systemic Venous Return to the PulmonaryArteries . . . . 504

Optimization of Cardiac Function-AssociatedDisturbances of Cardiac Rhythm . . . . 507

Sinus Node Dysfunction . . . . 508Intra-atrial Reentrant Tachycardia (IART)=Atrial

Flutter . . . . 509Optimization of Cardiac FunctionMyocardial

Issues . . . . 510

Contents xi

Treatment of Cardiac Failure in the Single VentriclePatient . . . . 512

Cardiac Transplantation . . . . 513

13. Right-Sided Heart Failure . . . . . . . . . . . . . . . . 533Erika Berman Rosenzweig and Robyn J. BarstEtiology . . . . 534Pathophysiology . . . . 536Diagnosis . . . . 544Medical Management . . . . 555Interventional=Surgical Treatment . . . . 559Summary . . . . 561

14. Chronic Heart Failure in Congenital HeartDisease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567Daphne T. HsuIntroduction . . . . 567Etiologies of Heart Failure in Congenital Heart

Disease . . . . 568Manifestations of Heart Failure in Children with

Congenital Heart Disease . . . . 571Evaluation of Heart Failure . . . . 577Therapy . . . . 579

15. Medical Management of Chronic Systolic LeftVentricular Dysfunction in Children . . . . . . . 589Robert E. ShaddyEtiologies . . . . 590

16. Nutritional Aspects of Pediatric HeartFailure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621Catherine A. LeitchEnergy Expenditure . . . . 624Energy Intake . . . . 631Nutritional Support . . . . 633Summary . . . . 634

17. Heart Failure Postpediatric HeartTransplantation . . . . . . . . . . . . . . . . . . . . . . . . . 641Mark BoucekBackground . . . . 641

xii Contents

Mechanisms . . . . 643Early Graft Failure . . . . 648Diagnosis of Acute Rejection . . . . 650Clinical Presentation of Acute Rejection . . . . 651Late Heart Failure Post Transplantation . . . . 652Adolescent Recipients . . . . 654Late Allograft Rejection . . . . 655Nonimmune Causes of Late Heart Failure . . . . 658

18. Cancer Treatment-Related Cardiotoxicities . . 665Svjetlana Tisma-Dupanovic, William G. Harmon,M. Jacob Adams, Gul H. Dadlani, Amy Kozlowski,Sarah Duffy, Larissa Herbowy, Karolina Zareba,Carol French, Katharine McLaughlin, andSteven E. LipshultzIntroduction . . . . 665The Pathophysiology of Cardiotoxicity . . . . 666Types of Anticancer Therapies . . . . 668Management of Treatment-Related

Cardiotoxicities . . . . 704

19. Coronary Artery Abnormalities . . . . . . . . . . . . 739Elfriede Pahl and Stephen G. PophalIntroduction . . . . 739Normal Coronary Anatomy . . . . 740Congenital AnomaliesIsolated . . . . 742Myocardial Bridge . . . . 751Congenital Coronary AnomalyWith Intracardiac

Defect . . . . 754Kawasaki Disease . . . . 756Coronary Stenosis=Iatrogenic . . . . 759Heart Transplant Coronary Artery Disease . . . . 761Miscellaneous Causes of Premature Coronary

Disease . . . . 763Conclusions . . . . 765

20. Heart Failure in the Postoperative Patient . . 773Chitra Ravishankar and Gil WernovskyFrequency and Risk Factors . . . . 774Etiology . . . . 775

Contents xiii

Diagnosis=Detection of LCOS . . . . 776Treatment of Postoperative LCOS . . . . 778Rule Out Residual Lesions . . . . 779Preload . . . . 780Pharmacological Support . . . . 780Management of Pulmonary Hypertension . . . . 785Arrhythmia after CPB . . . . 787Fluid Overload after CPB . . . . 788Creation of a Right-to-Left Shunt . . . . 789Mechanical Support . . . . 790Other Strategies . . . . 791Conclusion . . . . 791

21. Ventricular Assist Devices . . . . . . . . . . . . . . . . 801Pedro J. del NidoTypes of Pumps . . . . 802Types of Circulatory Support Systems . . . . 806Indications for Support . . . . 810Patient Management on Circulatory Support . . . . 818Results with VAD Systems . . . . 825Future Directions . . . . 827

22. Psychosocial Aspects of Acuteand Chronic Heart Failure in Children . . . . . 833Kathy MussattoMeasurement Issues . . . . 836Health-Related Quality of Life . . . . 837Neurocognitive Impact . . . . 844Psychological and Behavioral Functioning . . . . 846Impact on the Family . . . . 852Transplantation . . . . 853Implications for Research and Practice . . . . 858

23. Heart Failure in the Adult with Congenital HeartDisease (ACHD) . . . . . . . . . . . . . . . . . . . . . . . . . 869Michael J. Landzberg

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889

xiv Contents

Contributors

M. Jacob Adams Division of Pediatric Cardiology, University ofRochester Medical Center and Golisano Childrens Hospital atStrong, University of Rochester School of Medicine and Dentistry,Rochester, New York, U.S.A.

Michael Artman Department of Pediatrics, New YorkUniversity School of Medicine, New York, New York, U.S.A.

Marcelo Auslender Department of Pediatrics, New YorkUniversity School of Medicine, New York, New York, U.S.A.

Robyn J. Barst Columbia University, College of Physicians andSurgeons, New York, New York, U.S.A.

Mark Boucek Department of Pediatric Cardiology,The Childrens Hospital/UCHSC, Denver, Colorado, U.S.A.

N.E. Bowles Department of Pediatrics (Cardiology),Baylor College of Medicine, Houston, Texas, U.S.A.

xv

Reiner Buchhorn Department of Pediatric Cardiology,Georg-August-University Gottingen, Gottingen, Germany

Charles E. Canter Washington University School of Medicine,St. Louis, Missouri, U.S.A.

Dana Connolly Department of Pediatrics, New York UniversitySchool of Medicine, New York, New York, U.S.A.

Gul H. Dadlani Division of Pediatric Cardiology, University ofRochester Medical Center and Golisano Childrens Hospital atStrong, University of Rochester School of Medicine and Dentistry,Rochester, New York, U.S.A.

Pedro J. del Nido Department of Cardiac Surgery, ChildrensHospital, Harvard Medical School, Boston, Massachusetts, U.S.A.

Sarah Duffy Division of Pediatric Cardiology, University ofRochester Medical Center and Golisano Childrens Hospital atStrong, University of Rochester School of Medicine and Dentistry,Rochester, New York, U.S.A.

Carol French Division of Pediatric Cardiology, University ofRochester Medical Center and Golisano Childrens Hospital atStrong, University of Rochester School of Medicine and Dentistry,Rochester, New York, U.S.A.

Brian D. Hanna Department of Pediatrics, Divisionof Cardiology, Childrens Hospital of Philadelphia,University of Pennsylvania School of Medicine, Philadelphia,Pennsylvania, U.S.A.

William G. Harmon Division of Pediatric Cardiology, Universityof Rochester Medical Center and Golisano Childrens Hospital atStrong, University of Rochester School of Medicine and Dentistry,Rochester, New York, U.S.A.

Larissa Herbowy Division of Pediatric Cardiology, University ofRochester Medical Center and Golisano Childrens Hospital atStrong, University of Rochester School of Medicine and Dentistry,Rochester, New York, U.S.A.

xvi Contributors

Lisa K. Hornberger Fetal Cardiovascular Program, Departmentof Pediatrics, Division of Cardiology, University of California,San Francisco, California, U.S.A.

Daphne T. Hsu Columbia University Medical Center, College ofPhysicians and Surgeons, Childrens Hospital of New York,New York, New York, U.S.A.

Amy Kozlowski Division of Pediatric Cardiology, University ofRochester Medical Center and Golisano Childrens Hospital atStrong, University of Rochester School of Medicine and Dentistry,Rochester, New York, U.S.A.

Michael J. Landzberg Brigham and Womens Hospital, Boston,Massachusetts, U.S.A..

Catherine A. Leitch Section of NeonatalPerinatal Medicine,Department of Pediatrics, Indiana University Medical Center,Indianapolis, Indiana, U.S.A.

Steven E. Lipshultz Department of Pediatrics, University ofMiami School fof Medicine and Holtz Children Hospital, Miami,Florida, U.S.A.

Katharine McLaughlin Division of Pediatric Cardiology,University of Rochester Medical Center and Golisano ChildrensHospital at Strong, University of Rochester School of Medicine andDentistry, Rochester, New York, U.S.A.

Kathy Mussatto Herma Heart Center, Childrens Hospital andHealth System, Milwaukee, Wisconsin, U.S.A.

Masaki Nii Department of Pediatrics, Division of Cardiology,The Hospital for Sick Children, Toronto, Canada

Timothy M. Olson Associate Professor of Medicine andPediatrics, Mayo Clinic College of Medicine, Rochester, Minnesota,U.S.A.

Elfriede Pahl Department of Pediatrics, Childrens MemorialHospital, Northwestern University, Feinberg School of Medicine,Chicago, Illinois, U.S.A.

Contributors xvii

Stephen G. Pophal Department of Pediatrics, ChildrensMemorial Hospital, Northwestern University, Feinberg School ofMedicine, Chicago, Illinois, U.S.A.

Chitra Ravishankar Department of Pediatrics, Division ofPediatric Cardiology, Childrens Hospital of Philadelphia,University of Pennsylvania School of Medicine, Philadelphia,Pennsylvania, U.S.A.

Erika Berman Rosenzweig Columbia University, College ofPhysicians and Surgeons, New York, New York, U.S.A.

Abraham M. Rudolph Emeritus Professor of Pediatrics andSenior Staff, Cardiovascular Research Institute, University ofCalifornia, San Francisco, California, U.S.A.

Steven M. Schwartz Division of Cardiology, Childrens HospitalMedical Center, Cincinnati, Ohio, U.S.A.

Robert E. Shaddy Division of Pediatric Cardiology, PrimaryChildrens Medical Center, University of Utah School of Medicine,Salt Lake City, Utah, U.S.A.

Michael J. Silka Division of Cardiology, Childrens HospitalLosAngeles, The Keck School of Medicine, University of SouthernCalifornia, Los Angeles, California, U.S.A.

Jacqueline R. Szmuszkovicz Division of Cardiology, ChildrensHospitalLos Angeles, The Keck School of Medicine, University ofSouthern Los Angeles, California, U.S.A.

Lloyd Y. Tani Division of Pediatric Cardiology, PrimaryChildrens Medical Center, University of Utah School of Medicine,Salt Lake City, Utah, U.S.A.

David F. Teitel Professor of Pediatrics, Division of PediatricCardiology, University of California, San Francisco, California, U.S.A.

Svjetlana Tisma-Dupanovic Division of Pediatric Cardiology,University of Rochester Medical Center and Golisano Childrens

xviii Contributors

Hospital at Strong, University of Rochester School of Medicine andDentistry, Rochester, New York, U.S.A.

J.A. Towbin Molecular and Human Genetics, and CardiovascularSciences, Baylor College of Medicine, Houston, Texas, U.S.A.

Matteo Vatta Department of Pediatrics (Cardiology), BaylorCollege of Medicine, Houston, Texas, U.S.A.

Gil Wernovsky Department of Pediatrics, Division of PediatricCardiology, Childrens Hospital of Philadelphia, University ofPennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.

Karolina Zareba Division of Pediatric Cardiology, University ofRochester Medical Center and Golisano Childrens Hospital atStrong, University of Rochester School of Medicine and Dentistry,Rochester, New York, U.S.A.

Contributors xix

1Heart FailureA HistoricalPerspective

ABRAHAM M. RUDOLPH

Emeritus Professor of Pediatrics and Senior Staff,Cardiovascular Research Institute,

University of California, San Francisco,California, U.S.A.

DEFINING HEART FAILURE

Heart failure (HF) is recognized as a leading cause of deathin the adult population. Recently, it has been claimed thatHF is occurring in adults in epidemic proportions (1,2). The pre-valence of HF has been reported to be 3 per 1000 personyears (3). In 1913, MacKenzie (4) defined HF as the condi-tion in which the heart is unable tomaintain an efficient circula-tion when called upon to meet the efforts necessary to thedaily life of the individual, whereas Lewis (5) regarded itas inability of the heart to discharge its contents adequately.Surprisingly, there is still no unanimity of opinion regarding

1

what constitutesHF and a variety of definitions are encounteredin current texts.

Based on the experimental and clinical observations ofcardiac ventricular function, the concept generally acceptedby adult cardiologists is that the term cardiac failure impliesstructural heart disease (6) and that chronic HF is asyndrome that evolves from damage to the myocardium,resulting in significant reduction in left ventricularfunction (7). The definition has, however, been modified totake into consideration the relationship of cardiac functionand body requirements. Braunwald (8) states Heartfailure is the pathophysiological state in which an abnormal-ity of cardiac function is responsible for the failure ofthe heart to pump blood at a rate commensurate with therequirements of the metabolizing tissues and=or allows it todo so only from an elevated diastolic volume. The HF isfrequently, but not always, caused by a defect in myocardialcontraction, and then the term myocardial failure isappropriate.

Inherent in most definitions is the assumption that myo-cardial function is disturbed, so that the heart does not ade-quately eject blood. Based on the clinical features, the termleft-sided congestive failure was used to denote the presenceof dyspnea, orthopnea, and pulmonary rales, whereas right-sided failure was characterized by hepatomegaly, increasedsystemic venous pressure, and peripheral edema. To explainthese manifestations, the concept of forward and backwardHF was proposed. The forward failure hypothesis suggestedthat impaired left ventricular function reduces cardiac out-put. Blood flow to the kidneys is decreased, resulting in poorurinary output and fluid retention. The fall in systemic bloodflow interferes with tissue oxygen supply that causesincreased capillary permeability with edema. The backwardfailure theory proposed that inadequate output by the leftventricle causes accumulation of blood in the pulmonary veinsand left atrium, resulting in an increase in pressure, progres-sing to pulmonary venous congestion and edema. Reducedejection by the right ventricle explains the increase in sys-temic venous pressure, with hepatomegaly and pulmonary

2 Rudolph

edema. A marked increase in systemic venous pressureresulting from back-up of blood by reduced right ventricularejection was difficult to sustain in view of the largecapacitance of the systemic venous system. An increase incirculating blood volume was also proposed, but its originwas not apparent. The concept of forward and backwardfailure has also been discarded because it was appreciatedthat reduced cardiac output, pulmonary venous congestionand systemic venous congestion and hepatomegaly arefrequently concurrent.

It was not until the mid-1950s that it was appreciatedthat sodium excretion by the kidneys was impaired withHF. Barger et al. (9,10) showed that urinary excretion of anadministered load of sodium was markedly delayed in dogswith experimental congestive cardiac failure. Also, Farberand Soberman (11) demonstrated that total body water andsodium were increased in patients with edema and cardiacdisease. The importance of and mechanisms responsible forsodium retention in heart disease are discussed below.

Congestive HF in children was described in associationwith rheumatic fever and rheumatic heart disease in earlytexts on pediatrics (12). However, in this text, published in1897, no mention is made of the occurrence of HF in infantsand children with congenital heart disease. In 1936, Abbott(13), in the Atlas of Congenital Cardiac Disease, mentionedcardiac insufficiency as one of the causes of death, but didnot allude to congestive cardiac failure in the clinical featuresof the various lesions described. Although, during this era,the development of cardiac failure in association with conge-nital heart disease was beginning to be recognized, the occur-rence of congestive failure in infants was rarely appreciated.The vast majority of infants with respiratory distress, whosubsequently were found to have cardiac lesions, were firstdiagnosed by pediatricians as having respiratory infection.In 1957, Nadas described the occurrence of congestive HF ininfants with coarctation of the aorta several months afterbirth, as well as in babies with large ventricular septal defect.Of interest is the fact that he did not acknowledge the occur-rence of cardiac failure in infants with patent ductus

Heart FailureA Historical Perspective 3

arteriosus and mentions that congestive failure does notappear in patients with this lesion until the age of 2030years (14).

It is difficult to explain why the presence of congestiveHF was for so long either not recognized or not acknowl-edged in infants. A possible reason is that, as mentionedabove, HF was equated with myocardial disease and reducedejection, especially by the left ventricle. The concept washeld that, in infants with congenital heart disease, althoughcommunications between the chambers, or inflow or outflowobstructions were present, the heart muscle was normal. Infact, it was recognized that rather than having a reducedoutput, the left ventricle was capable of ejecting volumesthree times or more greater than normal in the presenceof a large left-to-right shunt. Although it was recognizedthat the manifestations of pulmonary congestion and edema(left-sided failure) and systemic venous pressure elevationand hepatomegaly (right-sided failure) were similar inadults and children, the definitions of HF used for adultswere not applicable.

In 1957 Nadas, in discussing congestive failure, statedthat since, at present, no precise physiological definition isavailable, it might well be to regard congestive failure simplyas a clinical syndrome associated with heart disease (14).Despite the current recognition that a complex interplay ofmechanical factors influencing the heart and neurohormonalmechanisms are responsible for the manifestations, it stillseems appropriate to define HF as a clinical syndrome asso-ciated with a multitude of cardiac disorders. Recently, thereis a trend for adult cardiologists to apply similar definitions.In a review of HF, Jessup and Brozena state The clinicalsyndrome of HF is the final pathway for myriad diseasesthat affect the heart (15).

HEART FAILURE SYNDROMES

Recognizing that HF is a clinical syndrome, it is not surpris-ing that noncardiac conditions may present with manifesta-

4 Rudolph

tions of cardiac failure. This also explains the fact that pedia-tricians frequently failed to recognize cardiac disease as thecause of a variety of clinical presentations.

Cardiac Failure in the Fetus

Heart failure presents in the fetus as generalized edema orhydrops fetalis. Hydrops is associated with many disordersnot related to circulatory involvement, including erythroblas-tosis fetalis, hepatic dysfunction, severe anemia, and geneticconditions such as Turner syndrome. Cardiac lesions as thecause of hydrops had been unusual, because immune hydropsassociated with Rh blood incompatibility was by far the com-monest etiology. Since the incidence of immune hydrops hasdecreased dramatically in the United States of America, therelative incidence of cardiac causes of hydrops has increasedsignificantly.

Fetal hydrops is unusual with most congenital cardiacanomalies. The cardiovascular disturbances resulting inthe development of hydrops include arrhythmias, decreasedmyocardial function associated with cardiomyopathy, atrio-ventricular valve insufficiency, obstructed foramen ovale orductus arteriosus and high cardiac output states such assacrococcygeal teratoma and twin-to-twin transfusion syn-drome.

The underlying mechanism common to all cardiovascularcauses of hydrops is elevated venous pressure. Even smallincreases of venous pressure in the fetus may induce edemabecause several factors contribute to tissue fluid accumula-tion. These are presented in Table 1 (16).

The role of neurohormonal factors in cardiac failure inthe fetus has not been evaluated. A fall in arterial pressureinduces a rise in arginine vasopressin (AVP) and angiotensinII (A II) concentrations. The AVP decreases urinary output.Angiotensin increases fetal body fluid accumulation. It islikely that these hormones do have a role in affecting extracel-lular fluid volume in the fetus in cardiac failure.

Fluid accumulation in the lungs resulting frompulmonary venous congestion is commonly associated with


many cardiac lesions, but it is most unusual prenatally. Thewell-developed smooth muscle layer in the medial layer ofpulmonary arterioles restricts blood flow into the lungs andprevents transmission of the high pulmonary arterial pres-sure to the pulmonary capillaries and veins. In addition, thepresence of the foramen ovale limits the rise in left atrialand thus pulmonary venous pressure associated with left-sided obstructive lesions. Furthermore, the hydrostatic pres-sure difference between the pulmonary capillaries and thealveoli is less in the fetus, because the positive intra-amnioticpressure is transmitted to the alveoli, whereas postnatallyalveolar pressure is negative and thus the capillaryalveolarpressure is greater, thus facilitating fluid movement into thealveoli.

Acute Postnatal Cardiac Failure

Acute cardiac failure after birth is a result of inability of theheart to maintain a cardiac output necessary for providingnormal oxygen supply to the tissues. The inadequate left ven-tricular output is associated with elevation of left atrial andpulmonary venous pressure, leading to pulmonary venouscongestion and edema. In most circumstances, cardiac outputand systemic blood flow are reduced. Occasionally, cardiacoutput is normal or increased, whereas peripheral flow isreduced, because a large proportion of the cardiac output is

Table 1 Factors Contributing to Tissue Fluid Accumulation in theFetus

Large capillary filtration coefficientallows water to pass readilyinto tissues from capillaries

High capillary permeability to proteinreduces the concentrationdifference between blood and tissue and reduces fluid movementinto the capillary

Low plasma colloidal osmotic pressurereduces fluid movement fromtissue space to capillary

High compliance of interstitial spaceallows accumulation ofa large amount of fluid in tissues at low pressure

6 Rudolph

diverted away from the tissues. This association has beentermed high output failure and occurs with large arteriove-nous shunts to the great vein of Galen, in the liver, or in othersites. Similarly, a large proportion of the cardiac output maybe directed to a vascular tumor, such as sacrococcygealteratoma.

Inadequate Systemic Oxygen Delivery

This is usually associated with cardiomyopathy or perinatalmyocarditis, left ventricular outflow obstruction due to severeaortic stenosis or coarctation, or with atrial or ventriculartachyarrhythmias. The clinical presentation is similar to thatof shock, i.e., pallor, cool extremities, weak pulses, and poorperfusion. Metabolic acidemia due to lactic acid accumulationis the result of increased anaerobic glycolysis and PCO2 isnormal or reduced because CO2 production is inhibited. Itmay be difficult to differentiate between acute cardiac failureand other causes of shock, such as severe infection.

Reduced oxygen delivery may be associated with severalcongenital cardiac anomalies in which myocardial function isconsidered to be normal. Thus, in infants with aortic atresiaor interrupted aortic arch, blood flow to the systemic circula-tion is derived through a patent ductus arteriosus. Constric-tion of the ductus will limit systemic blood flow and resultin a clinical picture of shock, which cannot be designated ascardiac failure.

Pulmonary Edema

Pulmonary edema, manifesting as increased respiratory effortand tachypnea, results from elevated left atrial and pulmonaryvenous pressure ventricular pressure. Left ventricular failuremay be associated with increased pressure loading, as occurswith severe aortic stenosis or aortic coarctation, myocardialdysfunction, or with volume loading, such as with large left-to-right shunts or high cardiac output states. Pulmonaryedema may occur with some congenital cardiac lesions in theabsence of left ventricular dysfunction, as with total anomalous


pulmonary venous connection with obstruction to pulmonaryvenous drainage and with cor triatriatum.

Neurohormonal Responses

The neuroendocrine responses to reduced cardiac output andelevated ventricular diastolic and left atrial pressure havebeen studied extensively in chronic cardiac failure, but littleinformation is available in acute failure in infants and chil-dren. The reduced cardiac output is likely to influence aorticand carotid mechanoreceptors to induce sympathetico-adrenalactivity and increase vasopressin secretion. Decreased arterialpressure probably increases renin=angiotensin=aldosteroneactivity, and elevated atrial and ventricular pressures inducerelease of atrial and brain natriuretic peptide (BNP). Theseresponses are discussed below.

Subacute and Chronic Cardiac Failure

This clinical presentation may follow improvement fromacute cardiac failure, or may have an insidious onset due toprogressive cardiac dysfunction or changes in loadingconditions. The clinical features of chronic cardiac failureinclude diaphoresis, failure to thrive or actual weight loss,tiring during feeding, and increased respiratory rate andeffort. Peripheral edema may occur, but is an unusual featurein early infancy and childhood. The development of cardiacfailure is influenced by factors other than the cardiac lesion.

Thus, an increase in cardiac output associated with infec-tion, or with the postnatal decrease in hemoglobin concentra-tion may increase demand on the heart and precipitate theonset of failure. Many of the clinical features of cardiac failurecould be explained as direct consequences of disturbed cardiacfunction. Thus, impaired left ventricular function could resultin pulmonary venous congestion and respiratory distress andelevated systemic venous pressure could explain hepatic con-gestion and enlargement, but the mechanisms for tachycar-dia, diaphoresis and poor weight gain or weight loss werenot apparent until relatively recently, when the importantrole of neurohormonal responses was recognized.

8 Rudolph

MECHANISMS OF CARDIAC FAILURE

Mechanical Factors

The ability of heart muscle to increase contraction in responseto stretching of its fibers was demonstrated in intact heartpreparations by Frank in 1895 (17) and by Starling in 1918(21). They first described the relationship between ventriculardiastolic volume and pressure and stroke output. Subse-quently, the concept of the ventricular function curve wasdeveloped to define cardiac function (19) and the importantrole of sympathetic nerve stimulation in increasing cardiaccontractility was demonstrated by showing an upward shiftof the function curve (20).

When myocardial damage or disease occurs and inotropyis impaired, increasing ventricular filling provides only alimited increase in cardiac output and at relatively highend-diastolic pressure, no further increase in output isachieved. The high end-diastolic pressure results in anincrease of atrial and venous pressures. An increase in after-load on the normal ventricle reduces stroke volume, but in thepresence of myocardial dysfunction, the reduction of strokevolume with elevation of afterload is greatly exaggerated (21).

In congenital cardiac lesions with left-to-right shunts, anexcessive volume load is placed on the ventricle. Dependingon the lesion, the output of the left or right or both ventriclesis increased. To achieve this increased output, ventricularend-diastolic volume and pressure are increased, based onthe FrankStarling mechanism. Although myocardial perfor-mance may be normal, the elevated diastolic pressure mayresult in pulmonary or systemic venous congestion and mayinduce neurohormonal responses (see below).

Lesions that obstruct ventricular outflow impose a pres-sure load on the ventricle. The increased afterload producedby the obstruction reduces ventricular stroke volume. In anattempt to maintain systemic blood flow, based on theFrankStarling mechanism, ventricular end-diastolic pres-sure is raised to increase stroke volume.

Although not as common in infants and children as inadults, diastolic filling of the ventricle may be impaired. This


altered lusitropy may result from myocardial fibrosis ormarked hypertrophy, and from restraint on the ventricle fromexternal factors. Systolic function may be normal, but inter-ference with filling of the ventricle restricts stroke volume.Ventricular diastolic volume enhancement is achieved onlyby very large increases in diastolic pressure, resulting inatrial distension and venous congestion.

Circulatory Changes at Birth Influencing the Onsetof Failure

Many congenital heart lesions do not significantly affect cir-culatory function during fetal life, but are associated withcardiac failure after birth. The development of failure hasgenerally been explained by alteration in flow patterns, butother postnatal circulatory and metabolic changes may contri-bute. Fetal and neonatal myocardium develops less tensionthan adult myocardium with stretch (22) and the relativeincrease of stroke volume with elevation of ventricular diasto-lic pressure is less than in the adult heart (23). The strokevolume of the left ventricle is smaller than that of the rightventricle during fetal life, but after birth, associated withthe dramatic rise in pulmonary blood flow, left ventricularoutput increases (24). In the fetus, the afterload on the ventri-cles is relatively low, because the placental circulation, whichhas a low vascular resistance, accommodating about 40% ofthe combined ventricular output, is derived from the aortavia the umbilical arteries. Removal of the placental circula-tion results in a marked increase in afterload on the left ven-tricle, particularly after the ductus arteriosus closes. The fetaland neonatal ventricle is very sensitive to the increasingafterload as shown by the marked fall in stroke volume withincreases of arterial pressure at the same end-diastolic fillingpressure (25,26). This prominent effect of restriction of leftventricular output with increasing afterload is a strikingfeature of cardiac failure in the adult (21).

In addition to these changes after birth, additional fac-tors may increase demands on the circulation. Oxygen con-sumption increases after birth in association with the

10 Rudolph

increased metabolism required to maintain body tempera-ture. This stimulates an increase in cardiac output. Thepresence of a large percentage of fetal hemoglobin in theneonate also tends to maintain cardiac output at highlevels, because oxygen extraction from blood in the tissuesis limited by the low P50 of fetal blood (27).

The possibility that disturbances in myocardial metabo-lism during the perinatal period may contribute to the devel-opment or acceleration of HF should also be considered.During fetal life, glucose is the primary substrate for the myo-cardium (28) and unlike in the adult, free fatty acids arepoorly utilized.

The heart has a high glycogen content at the time ofbirth, which can provide the substrate for energy if glucosesupply is limited (29). However, glycogen is rapidly depletedwith stress or hypoxia and energy supply may be limited inthe face of increased demand and result in myocardialdysfunction.

The considerable rise in stroke volume and increase inafterload result in a significant increase in the demand onthe left ventricle in the normal infant and thus developmentof failure is likely with additional volume or pressure loading.As mentioned above, unlike in the adult, significant periph-eral edema is unusual in infants with HF. The clinical fea-tures are predominantly those of left-sided congestion. Thisdifference in presentation can be explained by the relative dif-ferences in liver size. In the adult, liver weight averages12001500 g, about 2% of body weight, whereas in the new-born infant, the liver weighs 140150g, constituting about5% of body weight. In the infant, the compliant liver canaccommodate a considerably larger proportion of bloodvolume in the systemic venous reservoir and the venous pres-sure is thus elevated to a lesser degree than in the adult.

Neurohormonal Responses

Sympathetico-adrenal Responses

The presence of tachycardia, diaphoresis, and peripheralvasoconstriction have suggested that sympathetic nervous


activity is increased in individuals with cardiac failure. Thiswas proposed by Starling in 1897 (30), and in the early1960s, it was demonstrated that plasma norepinephrinelevels were increased in adults with HF (31). The conceptwas held that the increased sympathetic nervous and norepi-nephrine response was primarily a compensatory attempt toincrease myocardial contractility. In 1965, the failure tothrive in some infants with congenital cardiac disease wasascribed to hypermetabolism (32), suggesting there wasincreased sympathetic activity. This was subsequently con-firmed by finding increased urinary excretion of products ofcatecholamine metabolism in infants with HF (33), as wellas increased plasma levels of norepinephrine (34). Themechanisms responsible for the increased sympathetic activ-ity have not yet been fully resolved. It was first explainedon the basis of a decrease in cardiac output with a fall inarterial pressure and pulse pressure that modifies aorticand carotid baroreceptor discharge and results in reflexsympathetic stimulation. In patients with cardiac muscle dys-function or severe ventricular outflow obstruction, thereduced systemic blood flow could stimulate sympatheticactivity by modifying peripheral baroreceptor activity. How-ever, in many patients with congenital heart lesions withlarge left-to-right shunts, there does not appear to be adecrease in cardiac output or in arterial pressure. Recently,studies in adults have shown that the cardiac sympatheticactivity may increase before there is any evidence of general-ized stimulation of the sympathetic nervous system (35). Anextensive sympathetic nervous network is demonstrable inheart muscle in the adult, both in the atria and the ventricles,and norepinephrine is present in high concentrations. Largeamounts of norepinephrine are produced by cardiac muscle;some of the hormones are liberated into the general circula-tion (36). The concept is now proposed that distension of theventricle, particularly the left ventricle, induces increasedlocal sympathetic activity and norepinephrine release andpossibly also generalized sympathetic stimulation.

The role of sympathetico-adrenal stimulation in cardiacfailure during the fetal and neonatal period has not been

12 Rudolph

defined. Studies in fetal sheep have shown that the arterialbaroreceptor function increases over gestation, but is welldeveloped at birth (37). However, the responsesmay be bluntedin preterm infants. The degree of sympathetic innervation andthe concentration of norepinephrine in the myocardium alsoincrease progressively during fetal development (38). Thematuration of the process at the time of birth varies greatlyin different species (39), but appears to parallel the state ofdevelopment of the central nervous system. It is not knownwhat the state of maturation of sympathetic innervation ofthe human heart is at birth, but it can be assumed that it is lessprominent in the adult. It is thus quite likely that in thenewborn, and certainly in the premature infant, the heartis not capable of mounting the same magnitude ofcompensatory response as in the adult.

The general sympathetic stimulation causes peripheralvasoconstriction and diaphoresis, increases metabolism,affects renal function, and activates the reninangiotensinsystem, resulting in sodium retention and increased extracel-lular fluid volume. This compensatory mechanism, in theshort term, improves myocardial contractility, but this effectmay be lessened by subsequent changes in the cardiac muscle.Studies of cardiac muscle obtained from adult hearts duringcardiac transplant procedures showed that the failing heartshad about 50% reduction in beta-adrenergic receptor activity,50% reduction in adenylate cyclase stimulation by isoprotere-nol and about 50% decrease in contractility as compared withnormal cardiac muscle (40). This downregulation of beta-adrenergic receptor activity has been explained by the contin-ued stimulation of the sympathetic nerve endings and thehigh circulating plasma norepinephrine concentrations.Cardiac muscle concentrations of norepinephrine are, how-ever, reduced in failing hearts. It was generally believed thatthe beta-adrenergic blockers were contraindicated in HFpatients, because they could interfere with contractility, butthese studies prompted trial of beta-adrenergic blockers inadults with chronic cardiac failure. They have consistentlyshown that chronic administration of the beta-adrenergicblockers bisoprolol, metoprolol, or carvedilol did not depress


myocardial performance but greatly improved symptomatol-ogy, decreased incidence of hospitalization, and prolongedsurvival (41). The experience with use of beta-blockers ininfants and children is limited.

In a group of eight infants with cardiac failure associatedwith congenital heard disease, propranolol administrationreduced plasma norepinephrine concentrations and reducedleft atrial pressure with no depression of ventricular function(42). Also, chronic administration of carvedilol to childrenawaiting cardiac transplant resulted in such symptomaticimprovement in some that they could be removed from thewaiting list (43).

This experience with beta-adrenergic blockers in adultsand limited observations in infants raises important ques-tions regarding the indications for their use in pediatricpatients. During acute cardiac failure beta-blockers arealmost certainly contraindicated, because the sympatheticnervous and norepinephrine responses represent the acuteadaptation to reduced cardiac output. The time course overwhich downregulation of beta-blockers occurs in infantsis, however, not known; it is thus necessary to evaluatewhen, after the onset of cardiac failure, beta-blockers maybe indicated.

Beta-adrenergic receptor numbers increase in fetalmyocardium with advancing gestation, but the developmentof receptors may be affected by several factors. Thus, removalof thyroid hormone activity by thyroidectomy in fetal lambsmarkedly reduces beta-receptors in myocardium anddecreases the heart rate and left ventricular output responseto isoproterenol after birth (44). Prenatal hypoxia increasesbeta-receptor responsiveness postnatally in the rat (45). Thedevelopment of myocardial beta-adrenergic receptors in thepresence of cardiac defects in fetal life has not been examined.Whether they are downregulated in response to increasedpressure or volume loading on either ventricle, or whetherbeta-receptors are increased in response to general circula-tory stress is still to be resolved, but this could be importantin influencing the development of HF after birth and theapproach to therapy.

14 Rudolph

In addition to the enhanced myocardial inotropy andeffects on metabolism, it has now been recognized that sympa-thetic stimulation has an important role in the remodeling ofthe heart following damage and associated with cardiac fail-ure (46). Transgenic overexpression of beta-adrenergic recep-tors increases myocardial contractility, but also results inprogressive loss of myocytes and subsequent fibrosis (47).Increased expression of alpha-adrenergic receptors resultsin hypertrophy of myocytes and with greater alpha-receptoractivity, apoptosis. The long-term administration of beta-adrenergic blockers may inhibit some of these progressivedeleterious effects of norepinephrine on the myocardiumand may account for the increased survival.

ReninAngiotensinAldosterone System

Renin release from the juxtaglomerular cells in the maculadensa in the renal cortex is induced by several stimuli,including decreased pressure in renal arteries, sympatheticnervous stimulation to the kidneys and reduced osmolarityof plasma perfusing the kidney. Renin is an enzyme thatacts on angiotensinogen, an alpha2-globulin synthesized inthe liver, to produce angiotensin I (AI), a decapeptide. Angio-tensin I is cleaved by angiotensin-converting enzyme (ACE)to angiotensin II (AII), an octapeptide. An ACE is presentin the vascular system in many organs, but especially inthe lung. An important effect of A II is to stimulate receptorsin the adrenal cortex to release of aldosterone. Several A IIreceptors have been identified, but stimulation of A I recep-tors is responsible for a potent peripheral vasoconstrictoreffect and also for the release of aldosterone. Aldosteroneincreases active reabsorption of sodium in the distal convo-luted tubules of the kidney. This system is stimulated toattempt to compensate for the reduced cardiac output andreduced arterial pressure by producing peripheral vasocon-striction and by retaining sodium to increase plasmavolume. The activation of this system in patients with car-diac failure has been described in adults (48,49), as well asin infants (50).


The observations indicating that cardiac output is extre-mely sensitive to the increased afterload in patients withcardiac failure, and that afterload is often markedly increasedas a result of the increased sympathetic activity and the effectof A II, introduced the concept that the reducing afterloadcould decrease loading on the ventricle and possibly improveoutput. Several vasodilators have been used, but inhibitionof production of A II by administering inhibitors of ACE hasbeen favored in recent years. Several studies in adults, usingcaptopril or enalapril, in addition to digitalis and diuretictherapy, have shown symptomatic improvement and prolon-gation of survival (51,52). The ACE inhibitors have also beenadministered to infants and children with cardiac failure withbeneficial effect (53,54).

Although the reduction of afterload may be responsiblefor the effects of ACE inhibitors, it is now evident that theymay influence the effect of A II on cardiac muscle. A II, whichis produced locally in cardiac myocytes in response to stretch,has been shown to induce hypertrophy of myocytes, unrelatedto any general hemodynamic effect, as well as apoptosis(55,56). A II directly stimulates fibroblasts and also increasesfibrosis in cardiac muscle (57). Restriction of A II productionby use of ACE inhibitors, or blockade of A I receptors withlosartan limits the development of cardiac hypertrophy, aswell as apoptosis and fibrosis.

Furthermore, inhibition of A II effects may not only limitmyocardial damage, but may reverse it by inducing regres-sion of fibrosis (58).

Plasma aldosterone concentrations are frequently mark-edly elevated in patients with cardiac failure. In addition topromoting sodium retention, aldosterone also facilitates potas-sium excretion. Spironolactone, an aldosterone receptorblocker, has been used as a mild diuretic agent, usually in con-junction with other diuretics, to attempt to limit potassiumloss in urine. Recently, however, it has become apparent that,like A II, aldosterone is synthesized in vascular cells and mayaffect endothelial function, but also induces myocardial fibro-sis (59). Administration of spironolactone to hypertensive ratsprevents the development of myocardial fibrosis (60).

16 Rudolph

Inhibition of aldactone effects with spironolactonegreatly improved exercise tolerance and ventricular functionin adults with severe HF and reduced mortality by 30%(61). Many of these patients were already being treated withACE inhibitors and it could have been anticipated that, bylowering A II concentrations, aldosterone secretion wasreduced. However, after long-term ACE inhibitor treatment,A II and especially aldosterone concentration are elevated.The spironolactone effect appears to be related to the inhibi-tion of the direct effect of aldosterone on myocardium.Recently, eplerenone, a selective aldosterone blocker, hasimproved ventricular function and reduced mortality follow-ing myocardial infarction (62). Eplerenone avoids some ofthe adverse side effects of spironolactone, because it doesnot block glucocorticoid and sex hormone receptors.

Although, as mentioned above, ACE inhibitors and spir-onolactone have been used with benefit in infants and chil-dren with HF, it is not known whether they affectventricular remodeling. Ventricular dysfunction, apparentlyrelated to myocardial damage with fibrosis, is not an uncom-mon development in patients with some types of congenitalheart disease, such as various types of single ventricle. It isinteresting to speculate whether prolonged treatment withACE inhibitors or A II receptor blockers, and aldosteronereceptor blockers should be considered for prevention of themyocardial deterioration.

Vasopressin

Plasma AVP concentrations are often increased in adults (63),as well as in infants and children with cardiac failure (64).The AVP release into blood is largely regulated by changesin osmolarity of plasma perfusing the brain. It is also releasedin response to decrease in arterial pressure through barore-ceptor mechanisms. Through its action via the V2 receptorin the kidney, it inhibits clearance of free water and thusmay contribute to the hyponatremia that is sometimes notedin adults with severe chronic cardiac failure. The AVPantagonists that affect the V2 receptor have been used in


adults and have increased plasma sodium concentrations to nor-mal and resulted in clinical improvement (65); there is no reportof their use in infants or children. Through the V1 receptors inblood vessels, constriction is induced and thus may contributeto the increased afterload in patients with cardiac failure.

Natriuretic Peptides

Cardiac natriuretic peptides are a group of compounds that aresynthesized and stored in myocardium. Atrial natriuretic pep-tide (ANP) is released from the atrial wall, whereas BNP isstored in the ventricles. Plasma concentrations of ANP, BNP,and clearance natriuretic peptide (CNP) are increased inresponse to stretch of the atria and ventricles, and have beennoted in adults with left ventricular dysfunction (66), as wellas in children with HF (67). Unlike the vasoconstrictor hor-mones described above, these peptides can be considered tobe counterregulatory, because they produce peripheral arterialand venous vasodilatation, promote natriuresis and diuresis,and inhibit the reninangiotensin system. It is difficult toexplain why the cardiac failure response should include boththe so-called compensatory stimulation of the sympathetico-adrenal and reninangiotensinaldosterone systems, and thecounterregulatory natriuretic peptide response. The possibilitythat these peptides could be beneficial in treatment of cardiacfailure has been proposed. A recombinant preparation ofBNP, nesiritide, has been administered intravenously to adultswith severe cardiac failure and poor response to inotropicagents, diuretics, and vasodilators. It has had some beneficialclinical effect and improved hemodynamic parameters, buthas not, as yet, appeared to alter mortality (68,69). Nesiritidehas not, as yet, to my knowledge, been used in infants or chil-dren with acute cardiac failure, but as BNP blood levels areincreased in children with HF, it is possible that it may be auseful therapeutic agent.

Other Circulating Factors

A number of other agents such endothelins, prostaglandinsand vasointestinal peptide, as will as cytokines, are thought

18 Rudolph

to have a role in the pathophysiology of HF. These are notdiscussed in this review.

TREATMENT

Digitalis in Adults

Detailed discussions on treatment of cardiac failure are pre-sented in ensuing chapters. In this perspective, I review onlythe use of digitalis preparations, because the concepts regardingtheir use have undergone striking changes over the years. Digi-talis, administered as foxglove, was first used by Withering (70)in the late 18th century, as treatment for edema in individualswith irregular heart rates; he ascribed its benefit to a diureticaction. It was not until about a century later that digitalis wasthought to improve cardiac contraction (71). Various digitalispreparations were subsequently widely used in adults fortreatment of cardiac failure.

Digitalis increases myocardial contractility by binding toNa, K, and ATPase in the cell membrane to inhibit thesodium pump, thus increasing intracellular sodium and sub-sequently, calcium concentration (72). Other effects of digita-lis are important in its effect in HF. It has a direct effect onrenal tubules to decrease sodium reabsorption and thusincreases sodium excretion (73). It also has autonomicnervous system effects, inhibiting sympathetic discharge(74) and decreasing plasma norepinephrine concentrationsand reninangiotensin activity.

After the effect of the drug in modifying arrhythmiasbecame apparent, questions were raised about the effective-ness of digitalis in patients with HF and regular cardiacrhythm. Also, recognition of the importance of the neurohor-monal responses prompted the introduction of the newertherapies of vasodilators, beta-adrenergic receptor blockers,and ACE inhibitors. The value of digitalis in addition to thesemeasures in adults with cardiac failure became controversial.During the last decade, several studies have shown that digi-talis has a beneficial effect in adults with left ventricular fail-ure. Withdrawal of digoxin therapy from patients receiving


both ACE inhibitors and digoxin resulted in clinical deteriora-tion (75), as well as in patients with mild to moderate conges-tive cardiac failure (76). However, digoxin did not significantlyaffect mortality (77).

The dose of digoxin recommended for treatment of car-diac failure in adults has been modified recently. It was fre-quently stated that the correct dose of drug was that whichproduced clinical improvement without causing toxicity. Withthe advent of the ability to measure serum digoxin concentra-tions, it was observed that most patients manifesting clinicalresponse had concentrations of 0.82.0 ng=mL. It was there-fore tacitly assumed that this was the optimal digoxin levelto achieve. Most patients who developed toxicity had digoxinplasma concentrations above 2.0 ng=mL, although toxicity didoccur in some with lower levels. Recently the use of higherdoses of digoxin for treatment of cardiac failure has beenquestioned. When serum concentrations exceed 1.0ng=mL,there is evidence of some improvement of ventricularfunction, but not in hemodynamic parameters or clinicalmanifestations (78,79). Furthermore, in a recent study, themortality was significantly increased with digoxin concentra-tions above 1.2 ng=mL, and the authors recommend that theoptimal dose of digoxin is that which achieves a serumconcentration of 0.50.8ng=mL (80).

Digitalis in Infants and Children

Few reports on the use of digitalis in infants and children areavailable prior to the early 1920s, when McCullough andRupe (81) suggested that the dose of digitalis required for chil-dren was 1.52.0 times greater than in adults based on bodyweight. This was corroborated in a study in which digitoxinwas administered and it was stated that the younger thechild, the more digitalis per pound or per square meter of sur-face area is required, irrespective of the disease causing thecongestive HF (82). In this study, digitalis was most effectivein patients with myocardial diseases and was thought to begood in about 10% and fair in about 30% of patients with con-genital heart lesions. Despite these relatively poor results,

20 Rudolph

digitalis was routinely administered to all infants and chil-dren with congestive HF and Nadas (14) in 1957 stated Asa matter of principle, every child with obvious evidence ofHF should be digitalized. The digitalizing dose of digoxinrecommended for children was extraordinarily high as com-pared with adults80125mg=kg body weight for childrenunder 2 years of age and 4085mg=kg for older children.The recommendation for this dosage was derived from theconcept that the digitalization of every patient should bean individual experiment and digitalis dosage was increaseduntil there was clinical improvement or evidence of toxicity.The difference in estimated dosage for infants and adultscould relate to the toxic manifestations. In a study in fetaland adult sheep, the adult animals frequently developedarrhythmias at mean plasma digoxin concentrations of2.3 ng=mL, whereas the fetal lambs rarely developed arrhyth-mia at mean concentrations of 4.5ng=mL. Although atrioven-tricular conduction was prolonged in both fetal and adultanimals in relation to the increase in digoxin concentration,it was the onset of arrhythmia that prompted cessation ofdigoxin administration (83).

The high doses of digoxin were found to cause toxicity fre-quently in premature infants and lower dosages were recom-mended (84). Also, doubts were expressed regarding theefficacy of digoxin in improving clinical status in prematureinfants with patent ductus arteriosus. Arrhythmias were unu-sual in premature infants receiving digoxin, but heart blockwas the usual manifestation of toxicity. As in the fetal lambs,serum digoxin concentrations of greater than 34ng=mL couldbe tolerated, but risks of heart blockwere considerable. This risk,together with the questionable effect in relieving symptoms,promptedseveral centers toavoid theuseofdigitalis in treatmentof premature infants with patent ductus arteriosus.

The effectiveness of digoxin in treating HF in matureinfants has been examined, with conflicting results. In twostudies of infants cardiac failure associated with ventricularseptal defect, ventricular function was assessed by ultra-sound. Berman et al. (85) noted that ventricular functionimproved in only six, but clinical improvement was noted in


12 of 21 infants. Kimball et al. (86) found digoxin-enhancedventricular function in all, but provided clinical benefit innone of 19 infants.

The doses of digoxin currently recommended are consid-erably lower than those used previously; generally, the digita-lizing dose for premature infants is 25 mg=kg, for matureinfants to about 2 years it is 50mg=kg, and for older children25 mg=kg.

Although digoxin is widely used in treatment of conges-tive HF in pediatric patients, there is no reliable informationdocumenting its efficacy, nor is there any informationregarding optimal serum concentrations of digoxin. There isa crucial need to study these issues.

FUTURE DIRECTIONS

Concepts regarding the mechanisms involved in cardiac failurehave changed dramatically in recent years. There is great needto evaluate the use of therapy directed to the various neurohor-monal disturbances, such as use of beta-adrenergic receptorblockers, ACE inhibitors, angiotensin receptor blockers, andaldosterone receptor blockers, in infants and children.

Although it has been generally assumed that cardiac mus-cle development and function are normal in the presence ofcongenital cardiac lesions, there is increasing evidence thatmyocardial development may be modified. It is thus importantto understand the mechanisms involved in normal myocardialdevelopment during fetal and postnatal life and to assess theeffects of various congenital cardiac lesions andmyocardial dis-eases. Normal increase in heart weight is produced by hyper-plasia prenatally, but almost exclusively by hypertrophypostnatally (87). Abnormal increase in cardiac muscle, asoccurs with pulmonary stenosis, also results from increase incell numbers prenatally, but coronary vascular developmentmay not match myocyte growth (88). It is also important todetermine whether factors that influence the myocardiumpostnatally have similar effects prenatally. Although angioten-sin induces hypertrophy, apoptosis, and myocardial fibrosispostnatally, it appears to have different effects in the fetus.

22 Rudolph

Infusion of A II into fetal lambs did not affect myocytes (unpub-lished personal observations). Furthermore, angiotensinreceptor blockade does not influence the increase in right ven-tricular muscle mass with experimental pulmonary stenosis(89). It is apparent that the neurohormonal factors may havedifferent effects at different stages of development. Thesedifferences need to be resolved to effectively manage cardiacfailure.

Loss of myocytes is common in adults in association withmyocardial infarct, and as a result of hormonal activity withcardiac failure. Although cardiac regeneration can occur inzebrafish (90), only limited new myocytes can be generatedin the adult human. The possibility that damaged heart mus-cle can be replaced by myocytes generated from embryonicstem cells is being seriously considered (91). Determiningthe factors that induce the change in growth of cardiac muscleby means of hyperplasia prenatally to hypertophy postana-tally could provide a mechanism for replacement of damagedmyocytes and grow new cardiac muscle at all ages.

REFERENCES

1. Braunwald E. Shattuck lecturecardiovascular medicine at the turnof the millennium: triumphs, concerns and opportunities. N Engl JMed 1997; 337:13601369.

2. Redfield MM. Heart failurean epidemic of uncertain proportions. NEngl J Med 2002; 347:14421444.

3. Senni M, Tribouilloy CM, Rodeheffer RJ, Jacobsen SJ, Evans JM,Bailey KR, Redfield MM. Congestive heart failure in the community:trends in incidence and survival in a 10-year period. Arch InternMed 1999; 159:2934.

4. MacKenzie J. Diseases of the Heart. London: Oxford Medical Publica-tions, 1913.

5. Lewis T. Diseases of the Heart Described for Practitioners andStudents. 2nd ed. New York: MacMillan Co., 1937.

6. Francis GS, Gessler JP, Sonnenblick EH. In: Funster V, AlexanderRW, ORourke RA, Wellens HJ, eds. Hursts the Heart. 10th ed.New York: McGraw-Hill, 2000.

7. LeJemtel TH, Sonnenblick EH, Frishman WH. Diagnosis and man-agement of heart failure. In: ORourke RA, Funster V, AlexanderRW, Roberts R, King SB III, Wellens HJJ, eds. Hursts the HeartManual of Cardiology. New York: McGraw-Hill, 2001.


8. Braunwald E. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL,Longo DL, Jameson JL, eds. Harrisons Principle of Internal Medicine.New York: McGraw-Hill, 2001.

9. Barger AC, Ross RS, Price HL. Reduced sodium excretion in dogs withmild valvular lesions of the heart, and in dogs with congestive failure.Am J Physiol 1955; 180:249.

10. Barger AC, Yates FE, Rudolph AM. Renal hemodynamics and sodiumexcretion in dogs with graded valvular damage, and in congestivefailure. Am J Physiol 1961; 200:601608.

11. Farber SJ, Soberman RJ. Total body water and total exchangeablesodium in edematous states due to cardiac, renal or hepatic disease.Clin Invest 1956; 35:779.

12. Holt LE. The Diseases of Infancy and Childhood. New York: Appletonand Co, 1897.

13. Abbott ME. Atlas of Congenital Cardiac Disease. New York: TheAmerican Heart Association, 1936.

14. Nadas AS. Pediatric Cardiology. Philadelphia: WB Saunders Co.,1957.

15. Jessup M, Brozena S. Heart failure. N Engl J Med 2003; 348:20072018.

16. Rudolph AM. Congenital Diseases of the Heart. 2nd ed. Armonk:Futura Publishing, 2001.

17. Frank O. Zur Dynamik des Herzmuskels. Z Biol 1895; 27:370447.18. Starling EH. The Lineacre Lecture on the Law of the Heart. Delivered

at Cambridge. London: Longmans, Green, 1918.19. Sarnoff SJ, Berglund E. Ventricular function: I. Starlings law of the

heart studied by means of simultaneous right and left ventricularfunction curves in the dog. Circulation 1954; 9:706.

20. Sarnoff SJ, Brockman SK, Giimore JP, Linden RJ, Mitchell JH. Reg-ulation of ventricular contraction: influence of cardiac sympatheticand vagal nerve stimulation on atrial and ventricular dynamics. CircRes 1960; 8:1108.

21. Ross J Jr. Afterload mismatch and preload reserve: a conceptualframework for the analysis of ventricular function. Prog CardiovascDis 1976; 18:255264.

22. Friedman WF. The intrinsic properties of the developing heart. In:Sonnenblick E, Leschi M, Friedman WF, eds. Neonatal Heart Disease.New York: Grune and Stratton, 1973:2150.

23. Klopfenstein HS, Rudolph AM. Postnatal changes in the circulationand responses to volume loading in sheep. Circ Res 1978; 42:839845.

24. Teitel DF, Iwamoto HS, Rudolph AM. Effects of birth-related eventson central blood flow patterns. Pediatr Res 1987; 22:557566.

25. Hawkins J, Van Hare GF, Schmidt KG, Rudolph AM. Effects ofincreasing afterload on left ventricular output in fetal lambs. CircRes 1989; 65:127134.

24 Rudolph

26. Van Hare GF, Hawkins JA, Schmidt KG, Rudolph AM. The effectsof increasing mean arterial pressure on left ventricular output innewborn lambs. Circ Res 1990; 67:7883.

27. Lister G, Walter TK, Versmold HT, Dallman PR, Rudolph AM. Oxygendelivery in lambs: cardiovascular and hematologic development. Am JPhysiol 1979; 237:H668H675.

28. Fisher DJ, Rudolph AM, Heymann MA. Myocardial oxygen andcarbohydrate consumption in fetal lambs in utero and in adult sheep.Am J Physiol 1980; 238:H399H405.

29. Shelley HJ. Glycogen reserves and their changes at birth. Brit M Bull1961; 17:137143.

30. Starling EH. Points on pathology of heart disease. Lancet 1897; 1:569572.

31. Chidsey CA, Harrison DC, Braunwald E. Augmentation of the plasmanorepinephrine response to exercise in patients with congestive heartfailure. N Engl J Med 1962; 267:650654.

32. Lees MH, Bristow JD, Griswold HE, et al. Relative hypermetabolismin infants with congenital heart disease and undernutrition. Pedia-trics 1965; 36:183..

33. Lees MH. Catecholamine metabolite excretion of infants with heartfailure. J Pediatr 1966; 69:259265.

34. Ross RD, Daniels SR, Schwartz DC, Harrison DW, Skulka R, KaplanS. Plasma norepinephrine levels in infants and children with conges-tive heart failure. Am J Cardiol 1987; 59:911914.

35. Rundqvist B, Elam M, Bergmann-Sverrisodottir Y, et al. Increasedcardiac adrenergic drive precedes generalized sympathetic activationin human heart failure. Circulation 1997; 95:169175.

36. Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI.Norepinephrine spillover to plasma in patients with congestive heartfailure: evidence of increased overall and cardiorenal sympathetic ner-vous activity. Circulation 1986; 73:615621.

37. Shinebourne EA, Vapaavuori EK, Williams RL, Heymann MA,Rudolph AM. Development of baroreflex activity in unanesthetizedfetal and neonatal lambs. Circ Res 1972; 31:710718.

38. Lebowitz EA, Novick JS, Rudolph AM. Development of myocardialsympathetic innervation in the fetal lamb. Pediatr Res 1972; 6:887893.

39. Lipp JM, Rudolph AM. Sympathetic nerve development in the rat andguinea pig heart. Biol Neonate 1972; 21:7682.

40. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS,Lurie K, Billingham ME, Harrison DC, Stinson EB. Decreased cate-cholamine sensitivity and beta-adrenergic-receptor density in failinghuman hearts. N Eng J Med 1982; 307:205211.

41. Foody MA, Farrell MH, Krumholz HM. Bete-blocker therapy in heartfailure: scientific review. JAMA 2002; 287:883889.


42. Buchhorn R, Hulpke-Wette M, Ruschewski W, Ross RD, Fielitz J,Pregla R, Hetzer R, Regitz-Zagrosek V. Effects of therapeutic betablockade on myocardial function and cardiac remodelling in congenitalcardiac disease. Cardiol Young 2003; 13:3643.

43. Azeka E, Franchini Ramires JA, Valler C, Alcides Bocchi E. Delistingof infants and children from the heart transplantation waiting listafter carvedilol treatment. J Am Coll Cardiol 2002; 40:20342038.

44. Birk E, Tyndall MR, Erickson LC, Rudolph AM, Roberts JM. Effects ofthyroid hormone on myocardial adrenergic preceptor responsivenessand function during late gestation. Pediatr Res 1992; 31:468173.

45. Roigas J, Roigas C, Heydeck D, Papies B. Prenatal hypoxia alters thepostnatal development of beta-adrenoceptors in the rat myocardium.Biol Neonate 1996; 69:383388.

46. Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophyand failure. N Engl J Med 1999; 341:12761283.

47. Dorn GW II. Adrenergic pathways and left ventricular remodeling.Card Fail 2002; 8(6 suppl):S370S373.

48. Brown JJ, Davies DL, Johnson VW, Lever AF, Robertson JL. Reninrelationships in congestive heart failure, treated and untreated. AmHeart J 1970; 80:329342.

49. Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of thereninangiotensinaidosterone system to clinical state in congestiveheart failure. Circulation 1981; 63:645651.

50. Baylen BG, Johnson G, Tsang R, Srivastava L, Kaplan S. The occur-rence of hyperaldosteronism in infants with congestive heart failure.Am J Cardiol 1980; 45:305310.

51. The Captopril Multicenter Research Group. A placebo-controlled trialof captopril in refractory chronic congestive heart failure. J Am CollCardiol 1983; 2:755763.

52. The CONSENSUS Trial Group. Effects of enalapril on mortality insevere congestive failure: results of the cooperative North Scandina-vian enalapril study group (CONSENSUS). N Eng J Med 1987; 316:14291435.

53. Friedman WF, George BL. Medical progresstreatment of congestiveheart failure by altering loading conditions of the heart. J Pediatr1985; 106:697706.

54. Artman M, Graham TP. Guidelines for vasodilator therapy of conges-tive heart failure in infants and children. Am Heart J 1987; 113:9941005.

55. Weber KT, Brilla CG, Campbell SE, Guarda E, Zhou G, Sriram KR.Myocardial fibrosis: role of angiotensin II and aldosterone. Basic ResCardiol 1993; 88(suppl 1):107124.

56. Yamazaki T, Shiojima I, Komuro I, Nagai R, Yazaki Y. Involvementof the reninangiotensin system in the development of left ventri-cular hypertrophy and dysfunction. J Hypertens (suppl) 1984: 12:S153S157.

26 Rudolph

57. Weber KT, Brilla CG. Pathological hypertrophy and cardiac intersti-tium: fibrosis and reninangiotensinaldosterone system. Circulation1991; 83:18491865.

58. Brilla CG, Matsubara L, Weber KT. Advanced hypertensive heartdisease in spontaneously hypertensive rats. Lisinopril-mediatedregression of myocardial fibrosis. Hypertension 1996; 28:269275.

59. Burlew BS, Weber KT. Cardiac fibrosis as a cause of diastolic dysfunc-tion. Herz 2002; 27:9298.

60. Brilla CG, Matsubara LS, Weber KT. Antifibrotic effects of spironolac-tone in preventing myocardial fibrosis in systemic arterial hyperten-sion. Am J Cardiol 1993; 71:12A16A.

61. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, PalenskyJ, Wittes J. The effect of spironolactone on morbidity and mortality inpatients with severe heart failure. Randomized aldactone evaluationstudy investigators. N Engl J Med 1999; 341:709717.

62. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B,Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone post-acutemyocardial infarction heart failure efficacy and survival study investi-gators. Eplerenone, a selective aldosterone blocker, in patients withleft ventricular dysfunction after myocardial infarction. N Engl JMed 2003; 348:13091323.

63. Goldsmith SR, Francis GS, Cowley AW Jr, Levine TB, Cohn JN.Increased plasma arginine vasopressin levels in patients with conges-tive heart failure. J Am Coll Cardiol 1983; 1:13851390.

64. Stewart JM, Zeballos GA, Woolf PK, Dweck HS, Gewitz MH. Variablearginine vasopressin levels in neonatal congestive heart failure. J AmColl Cardiol 1988; 11:645650.

65. Gheorghiade M, Niazi I, Ouyang J, Czerwiec F, Kambayashi J,Zampino M, Orlandi C. Vasopressin v2-receptor blockade with tolvap-tan in patients with chronic heart failure: results from a double-blind,randomized trial. Circulation 2003; 107:26902696.

66. Stoupakis G, Klapholz M. Natriuretic peptides: biochemistry, physiol-ogy, and therapeutic role in heart failure. Heart Dis 2003; 5:215223.

67. Kikuchi K, Nishioka K, Ueda T, Shiomi M, Takahashi Y, Sugawara A,Nakao K, Imura H, Mori C, Mikawa H. Relationship between plasmaatrial natriuretic polypeptide concentration and hemodynamic mea-surements in children with congenital heart diseases. J Pediatr1987; 111:335342.

68. Vichiendilokkul A, Tran A, Racine E. Nesiritide: a novel approach foracute heart failure. Ann Pharmacother 2003; 37:247258.

69. Keating GM, Goa KL. Nesiritide: a review of its use in acute decom-pensated heart failure. Drugs 2003; 63:4770.

70. Withering W. An Account of the Foxglove, and Some of Its MedicalUses: With Practical Remarks on Dropsy and Other Diseases. London:G.G.J. and J. Robinson, 1785.

71. Fothergill JM. Digitalis: Its Mode of Action. London, 1871.


72. Akera T, Brody TM. The role of Na, K, and ATPase in the inotropicaction of digitalis. Pharmacol Rev 1977; 29:187220.

73. Rudolph AM, Rokaw SN, Barger AC. Chronic catheterization of therenal artery: technic for studying direct effects of substances on kidneyfunction. Proc Soc Exp Biol Med 1956; 93:323326.

74. Ferguson DW, Berg WJ, Sanders JS, Roach PJ, Kempf JS, KienzleMG. Sympathoinhibitory responses to digitalis glycosides in heart fail-ure patients. Direct evidence from sympathetic neural recordings.Circulation 1989; 80:6577.

75. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxinfrom patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors: radiance study. N Engl J Med 1993;329:17.

76. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, JollyMK. Randomized study assessing the effect of digoxin withdrawal inpatients withmild to moderate chronic congestive heart failure: resultsof the proved trial. Proved investigative group. J Am Coll Cardiol 1993;22:955962.

77. The Digitalis Investigation Group. The effect of digoxin on mortalityand morbidity in patients with heart failure. N Engl J Med 1997;336:525533.

78. Ghe

Documents

(Fundamental and Clinical Cardiology ) Robert Shaddy, Gil Wernovsky-Pediatric Heart Failure (Fundamental and Clinical Cardiology)-Informa Healthcare (2005)