MOLECULAR CARDIOLOGY IN CLINICAL PRACTICE BASIC SCIENCE FOR THE CARDIOLOGIST 1. B. Levy, A. Tedgui (eds.): Biology of the Arterial Wall. 1999 ISBN 0-7923-8458-X 2. M.R. Sanders, J.B. Kostis (eds): Molecular Cardiology in Clinical Practice. 1999. ISBN 0-7923-8602-7 3. B. Swynghedauw (ed.): Molecular Cardiology for the Cardiologist. Second Edition. 1998. ISBN: 0-7923-8323-0 MOLECULAR CARDIOLOGY IN CLINICAL PRACTICE edited by Michael R. Sanders John B. Kostis Department of Medicine University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School KLUWER ACADEMIC PUBLISHERS Boston 1 Dordrecht 1 London Distributors for North, Central and South America: Kluwer Academic Publishers 101 Philip Drive Assinippi Park Norwell, Massachusetts 0206 1 USA Telephone (78 1) 87 1-6600 Fax (781) 871-6528 E-Mail <kluwer @ wkap.com> Distributors for all other countries: Kluwer Academic Publishers Group Distribution Centre Post Office Box 322 3300 AH Dsrdrecht, THE NETHERLANDS Telephone 31 78 6392 392 Fax 31 78 6546 474 E-Mail Corderdept @ wkap.nl> 46 Electronic Services <http:Nw%vw.wkap,nb Library of Congress Cataloging-in-PublieationD ata Molecular cardiology in clinical practiceledited by Michael R. Sanders, John B. Kostis. P. Cm. -- (Basic science for the cardiologist : 2) Includes index. ISBN 0-7923-8602-7 . 1. Heart--Diseases-Molecular aspects. I. Sanders, Michael, 1943- 11. Kostis, John B. 111. Series. [DNLM: 1. Cardiovascular Diseases--physiopathology. 2. Cardiovascular Diseases--genetics. WG 120 M7 177 19991 RC682.9.M645 1999 6 16.1'207--dc2 1 DNLMJDLC for Library of Congress 99-37334 CIP Copyright 0 1999 by Kluwer Academic Publishers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photo- copying, recording, or otherwise, without the prior written permission of the publisher, Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, Massachusetts 02061 Printed on acid-free paper. Printed in the United States of America TABLE OF CONTENTS .................................................................... List of Contributors vii ................................................................................ Foreword.. xi ................................................................................... Preface.. xv 1. Introduction to Molecular Medicine: A Contemporary View of Heart Failure ......................................................... Michael R. Sanders, M. D.. 1 2. Molecular Mechanisms of Myocardial Remodeling ....................................................... Wilson S. Colucci, M. D.. ..29 3. Pathophysiology of Heart Failure in Regurgitant Valvular Diseases: Relation to Ventricular Dysfunction and Clinical Debility Jeffrey S. Borer, M. D., Edmund McM. Herrold, M. D., Ph. D., Clare A. Hoclzreiter, M.D., Sharada L. Truter, Ph.D., John N. Carter, Ph. D., ...................................................... Steven M. Goldfine, Ph. D.. 43 4. Coronary Atherothrombosis: Pathophysiology and Clinical Implications Avi Fisclzer, M.D., David E. Gutstein, M.D., Zahi A. Fayad, Ph.D., ................................................. Valentin Fuster, M. D., Ph. D.. ..57 5. Prevention of Atherosclerosis: Endothelial Function, Cholesterol And Antioxidants ............................................................. RobertA. Vogel, M.D 77 6. Physiologic and Pathophysiologic Effects of Angiotensin in the Heart and Vessel Wall ....................................................... Riclzard E. Pratt, Ph. D.. 107 7. Regulation of Inflammation by FAS Ligand Expression on the Vascular Endothelium ........................ Kennetlz Walslz, Plz. D. and Masataka Sata, M. D.. .I25 8. Molecular Mechanisms of Platelet Activation and Inhibition ............................................................ A. Koneti Rao, M. D.. 143 9. Molecular Determinants of the T Wave ....................................................... Miclzael R.. Rosen, M. D .I69 10. Sexual Dimorphism in Cardiovascular Disease .............................. Stephen Bakir, M.D., Suzanne Oparil, M.D.. 187 .................................................................................. Index.. 219 LIST OF CONTRIBUTORS Michael R. Sanders, M.D. Clinical Professor of Medicine Director of Molecular Medicine Department of Medicine University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School New Brunswick, N.J. 08903 John B. Kostis, M.D. John G. Detwiler Professor of Cardiology Professor of Medicine and Pharmacology Chairman, Department of Medicine University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School New Brunswick, N.J. 08903 Wilson S. Colucci, M.D. Chief, Cardiovascular Medicine Professor of Medicine and Physiology Boston University School of Medicine Boston, Massachusetts 02 1 18 Jeffrey S.Borer, M.D. Chief, Division of Cardiovascular Pathophysiology New York Presbyterian Hospital-Weill Cornell University Medical College Gladys and Roland Harriman Professor of Cardiovascular Medicine Professor of Cardiovascular Medicine in Radiology and Cardiothoracic Surgery Weill Medical College of Cornell University New York, N.Y. 10021 Edmund McM. Herrold, M.D., Ph.D. Director, Section of Biomechanics and Biophysics Division of Cardiovascular Pathophysiology New York Presbyterian Hospital-Weill Cornell University Medical College Associate Professor of Medicine and Cardiovascular Medicine in Cardiothoracic Surgery Weill Medical College of Cornell University New York, N.Y. 1002 1 Clare A. Hochreiter, M.D. Director, Section of Clinical Epidemiology and Clinical Trials Division of Cardiovascular Pathophysiology New York Presbyterian Hospital-Weill Cornell University Medical College Associate Professor of Medicine and Cardiovascular Medicine in Cardiothoracic Surgery Weill Medical College of Cornell University New York, N.Y. 10021 Sharada L. Truter, Ph.D. Division of Cardiovascular Pathophysiology New York Hospital-Weill Cornell University Medical College Assistant Professor of Cell Biology in Medicine and Cell Biology and Anatomy Well Medical College of Cornell University New Yrok, N.Y. 10021 John N. Carter, Ph.D. Division of Cardiovascular Pathophysiology Research Associate in Cardiovascular Surgery Weill Medical College of Cornell University Adjunct Assistant Professor of Chemical Engineering Cornell University Ithaca, N.Y. 14850 Steven M. Goldfine, Ph.D. Senior Scientist, Department of Physiology and Biophysics Health Sciences Center at SUNY Stony Brook Stony Brook, N.Y. 11 794 Avi Fischer, M.D. Fellow in Cardiology Zena and Michael A. Weiner Cardiovascular Institute Mt. Sinai Medical Center New York, N.Y. 10029 David E. Gutstein, M.D. Fellow in Cardiology Zena and Michael A. Weiner Cardiovascular Institute Mt. Sinai Medical Center New York, N.Y. 10029 Zahi A. Fayad, Ph.D. Director, Cardiovascular Imaging Physics and Research Assistant Professor Zena and Michael A. Weiner Cardiovascular Institute and Department of Radiology Mt. Sinai Medical Center New York, N.Y. 10029 Valentin Fuster, M.D., Ph.D. Director, The Zena and Michael A. Weiner Cardiovascular Institute Richard Gorlin, MD 1 Heart Research Foundation Professor of Cardiology Dean of Academic Affairs Mount Sinai Medical Center New York, N.Y. 10029 Robert A. Vogel, M.D. Herbert Berger Professor of Medicine Head, Division of Cardiology University of Maryland School of Medicine Baltimore, Maryland 2 120 1 Richard E. Pratt, Ph.D. Associate Professor of Medicine Harvard Medical School Director, Laboratory of Genetic Physiology Brigham and Women's Hospital Boston, Massachusetts 02 11 5 Kenneth Walsh, Ph.D. Associate Professor of Medicine Tufts University School of Medicine Boston, Massachusetts 02 11 1 Masataka Sata, M.D. Senior Physician Department of Cardiovascular Medicine Graduate School of Medicine University of Tokyo Tokyo, Japan A.Koneti Rao, M.D. Professor of Medicine and Thrombosis Research Director, Thromboembolic Diseases Temple University School of Medicine Philadelphia, Pennsylvania 19 140 Michael R. Rosen, M.D. Gustavus A. Pfeiffer Professor of Pharmacology Professor of Pediatrics College of Physicians and Surgeons of Columbia University New York, N.Y. 10032 Stephen Bakir, M.D. Associate in Cardiology Department of Medicine University of Alabama at Birmingham Birmingham, Alabama 35294 Suzanne Oparil, M.D. Director, Vascular Biology and Hypertension of the Division of Cardiovascular Diseases Professor of Medicine University of Alabama at Birmingham Birmingham, Alabama 35294 It had been several years since I had attended a national meeting of the American Heart Association Scientific Sessions. While the sessions on clinical cardiology had the same feel and tone I was long accustomed to, I was struck by the immense changes which had occurred within the basic scientific sessions. Not only were the topics foreign to what I had come to expect, but its very essence had undergone a profound metamorphosis; I found myself inside a molecular biologist's world! Instead of force-velocity curves or action potentials, the projection screen flourished Northern blots, PCR gels and supershift assays. Sarcomeres were replaced by phosphorylation cascades and contractility by apoptosis. Even the style and demeanor of the speakers had altered, exemplified by the custom of recognizing laboratory co-workers at the end of each presentation. I supposed that I should not have been surprised since I had recently noticed the changing format of some standard cardiology publications to make them look more like basic science journals. It was true; cardiology had entered the world of molecular biology on a large scale. But it was also true that the practicing cardiologists and internists at this meeting seemed essentially unaware or disinterested in what appeared to me as a major shift in the emphasis of cardiologic science. There were, in essence, two parallel populations of attendees at the Scientific Sessions: the clinical and the scientific. On further reflection, however, it became clear to me that it was not the lack of awareness or interest that separated the practicing physicians fiom the new science. Rather, it was the lack of feeling of connectedness, which in turn, I realized, issued fiom the rapidly expanding field of "molecular cardiology'' distancing itself by the sheer speed of its growth. But deeper, at the core of the problem, was the change in the very foundation of the basic science that today's previously trained physicians had been trained in. While molecular biology is not a new field, it has not until relatively recently become an essential part of the standard medical school curriculum, an integral part of physician thinking. It was 1961 when Jacob and Monod proposed the molecular genetic basis for cellular adaptation, but Claude Bernard's 19" century model of homeostasis, rather than altered gene expression, has remained the mainstay of standard medical understanding to most of today's practicing clinicians. Even "Molecular Medicine" might not be claimed a recent innovation, recalling Garrod's description of inborn errors of metabolism in 1909, or Pauling's xii explanation of the molecular basis of sickle cell disease in 1949. Nevertheless, the subject "molecular medicine" is not found in a literature search until the 1980's when a few scant references first appear. It is not until the mid and late 1990's that this topic becomes significantly represented by a corpulent body of research publications. In truth, however, the term "molecular medicine", has taken on a modem meaning, different from just the biochemical explanation of pathophysiology. On first consideration, "molecular medicine" might be taken as: the application of the principles of molecular biology to those issues which have been traditionally of interest in the practice and science of medicine. However, experience in post-graduate education of both medical practitioners and medical scientists has led me to the realization that these are such diverse, although intersecting worlds, that even their concept of "medicine" is different. Again this duality! Its background, indeed, inhabits the very history of medicine. The practice of medicine is the ancient tradition, based on custom and folklore, in which a sufferer of a subjective feeling of being "unwell" or "sick" (a symptom) seeks aid in alleviating his distress. A medical practitioner applies some intervention which he has reason to believe may help. Only recently has medical science become one of those many different kinds of reasons to believe in the effectiveness of a medical intervention. Empiricism, that is observation or trial and error, played only a minor role until the scientific revolution, as seen in the early contributions of Morgagni, blossoming with eighteenth and nineteenth century science, as embodied by Jenner, Pasteur, Koch and Virchow. Medical science, on the other hand, is a recent tradition in which an individual's symptoms are believed to be caused by a knowable disease process which has altered normal biologic (biochemical and physiological) mechanisms, and is therefore understandable in terms of those mechanisms. Medical practice treats persons who feel unwell, whereas medical science deals with individuals who are unhealthy. In this sense, a person may feel well but be unhealthy or feel unwell (sick), yet be entirely healthy. The medical practitioner may seek to have his patient feel "normal" again - that is, the way he normally feels or feels most of the time. Medical science seeks to return the patient to "normal" as objectively compared to other people who are believed or known to be without the disease causing his symptoms. Medical science, then, has become a corpus of knowledge about the nature of the human body and its constituent parts in health and disease, based upon discoverable laws of nature; and known through proof by observation and experimentation, imitating the models of the physical sciences. This body of knowledge in which biological function (physiology) is explained in terms of observable structure has grown enormously during the past century, as technology has allowed the size of observable structures to become increasingly smaller: from organs to tissues to cells and finally to the molecular constituents of those cells. Medical science has evolved into the science of biochemical physiology, and most recently has absorbed the principles of molecular biology: hence, "Molecular Medicine", Then what are these principles of molecular biology? The eleventh century monk Gregor Mendle's observations on the inheritance of traits posed two important questions: (1) How are traits passed on