MOLECULAR AND SUBCELLULAR CARDIOLOGY Effects of Structure and Function ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Editorial Board: NATHAN BACK, State University of New York at Buffalo IRUN R. COHEN, The Weizmann Institute of Science DAVID KRITCHEVSKY, Wistar Institute ABEL LAJTHA, N. S. Kline Institute for Psychiatric Research RODOLFO PAOLETTl, University of Milan Recent Volumes in this Series Volume 375 DIET AND CANCER: Molecular Mechanisms of Interactions Edited under the auspices of the American Institute for Cancer Research Volume 376 GLYCOIMMUNOLOGY Edited by Azita Alavi and John S. Axford Volume 377 TISSUE RENIN-ANGIOTENSIN SYSTEMS: Current Concepts of Local Regulators in Reproductive and Endocrine Organs Edited by Amal K. Mukhopadhyay and Mohan K. Raizada Volume 378 DENDRITIC CELLS IN FUNDAMENTAL AND CLINICAL IMMUNOLOGY, Volume 2 Edited by Jacques Banchereau and Daniel Schmitt Volume 379 SUBTILISIN ENZYMES: Practical Protein Engineering Edited by Richard Bott and Christian Betzel Volume 380 CORONA- AND RELATED VIRUSES: Current Concepts in Molecular Biology and Pathogenesis Edited by Pierre J. Talbot and Gary A. Levy Volume 381 CONTROL OF THE CARDIOVASCULAR AND RESPIRATORY SYSTEMS IN HEALTH AND DISEASE Edited by C. Tissa Kappagoda and Marc P. Kaufman Volume 382 MOLECULAR AND SUBCELLULAR CARDIOLOGY: Effects of Structure and Function Edited by Samuel Sideman and Rafael Beyar Volume 383 1MMUNOBIOLOGY OF PROTEINS AND PEPTIDES VIII: Manipulation or Modulation of the Immune Response Edited by M. Zouhair Atassi and Garvin S. Bixler, Jr. A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher. MOLECULAR AND SUBCELLULAR CARDIOLOGY Effects of Structure and Function Edited by Samuel Sideman and Rafael Beyar Technion-Israel Institute of Technology Haifa, Israel SPRINGER SCIENCE+BUSINESS MEDIA, LLC Librar y of Congress Catalog1ng-1n-PublIcatto n Data Molecular an d subcellula r cardiolog y : effect s of structur e and functio n / edite d by Samuel Sideman and Rafael Beyar. p. cm . — (Advances i n experimental medicin e and biolog y ; v. 382) Includes bibliographica l references and index . ISBN 978-1-4613-5772-8 ISBN 978-1-4615-1893-8 (eBook) DOI 10.1007/978-1-4615-1893-8 1. Heart—Molecula r aspects . I . Sideman, S. II . Beyar, Rafael . III . Series . QP114.M65M2 6199 5 612. 1'7—dc2 0 95-2512 8 CIP Proceedings of the Ninth Goldberg Workshop on Molecular and Subcellular Cardiology: Effects on Structure and Function, held December 4-8,1994, in Haifa, Israel ISBN 978-1-4613-5772-8 © 1995 Springer Science+Business Media New York Originally published by Plenum Press, New York in 1995 Softcover reprint of the hardcover 1st edition 1995 10 98765432 1 All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher To Our families-for their love and encouragement Our sponsors-for their trust and support Our colleagues-for their vision and stimulation Our students-for their enthusiasm and imagination The 9th Goldberg Workshop Molecular and Subcellular Cardiology: Effects of Structure and Function December 4-8, 1994 Haifa, Israel Organizing Committee Professor J. Bassingthwaighte Director, Center of Biomedical Engineering, University of Washington, Seattle, WA, USA Professor R. Beyar, Co-Chairman Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa Israel Professor S. Sideman, Chairman Chair, Department of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa Israel Professor E.L. Ruman Biodynamics Laboratory, Mayo Medical School, Roshester, MN, USA Scientific Advisory Committee Professor HA. Fozzard The University of Chicago, 5841 Maryland Avenue, MC 6094, Chicago, IL USA Professor M. Gotsman Director, Cardiology Department, Hadassah Medical Organization, Jerusalem, Israel Professor Eduardo Marban Department of Cardiology, Johns Hopkins University School of Medicine, 725 N. Wolf Street, Baltimore, MD USA Professor R. Reneman Department of Physiology, University of Limburg, Rijksuniv, Limburg, The Netherlands Professor S.v. Vatner Primate Research Center, 1 Pine Hill Drive, Southboro, MA USA Professor M. L. Weisfeldt, Chairman Chair, Department of Medicine, Columbia Presbyterian Medical Center, New York, NY,USA Professor W. Welkowitz Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA vii The 9th Goldberg Worksbop on MOLECULAR AND SUBCELLULAR CARDIOLOGY: EFFEcrs OF STRUcruRE AND FuNCTION Sponsored by THE TECHNION-IsRAEL INSTITUTE OF TECHNOLOGY THE IsRAEL CARDIOLOGY SOCIETY MR. JULIUS SILVER, NEW YORK, USA MR. HENRY (DECEASED) AND VIOLA GOLDBERG, NEW YORK, USA Supported by MR. ARTHUR GoLDBERG, NEW JERSEY, USA viii PREFACE The Henry Goldberg Workshops were set up to address the following goals: (1) To foster interdisciplinary interaction between scientists and cardiologists, identify missing links, and catalyze new ideas. (2) To relate basic microscale phenomena to the global, clinically manifested cardiac function. (3) To relate conceptual modeling and quantitative analysis to experimental and clinical data. (4) To encourage international cooperation so as to disperse medical and technological knowhow and lead to better understanding of the cardiac system. The first Henry Goldberg Workshop, held in Haifa in 1984, introduced the concept of interaction between cardiac mechanics, electrical activation, perfusion, and metabolism, emphasizing imaging in the clinical environment. The second Workshop, in 1985, discussed the same parameters with a slant towards the control aspects. The third Goldberg Workshop, held in the USA at Rutgers University in 1986, highlighted the transformation of the microscale activation phenomena to macroscale activity and performance, relating electrophysiology, energy metabolism, and cardiac mechanics. The fourth Goldberg Workshop, in 1987, continued the effort to elucidate the interactions among the various parameters affecting cardiac performance, with emphasis on the ischemic heart. The fifth Workshop, held in Cambridge, UK, in 1988, dwelt on the effects of inhomogeneity of the cardiac muscle on its performance in health and disease. The sixth Workshop highlighted the role of new modem imaging techniques, that allow us to gain more insight into local and global cardiac performance in cardiac research and clinical practice. The seventh Workshop explored the electrophysiology, microcirculation, and microlevel transport phenomena that affect the cardiac system in health and disease. The eighth Workshop explored the interactive phenomena in the cardiac system. The present ninth Goldberg Workshop aims to highlight some of the basic molecular and subcellular interactions that affect the activation and performance of the heart. These gatherings of outstanding scientists from allover the world are a testimonial to international cooperation and highlight the pleasure of joining hands in the pursuit of the secrets of the cardiac system. It is with great pleasure that we acknowledge here those who have helped make these workshops a reality. Particular thanks go to our new sponsor, Mr. Arthur Goldberg, whose support provided for the continuation of these Goldberg Workshops, and to Mrs. Viola Goldberg and the late Mr. Henry Goldberg, for their generosity and kindness, which made these Goldberg Workshops significant milestones in cardiac research. Special thanks are due to Mr. Julius Silver and Ms. Dinny Winslow (Silver) of New York, for their personal support and continued friendship, which inspired and shaped our goals and made it all possible. Thanks are also due to the Women's Division of the American Society for the Technion, who encouraged us with their unshakable trust and provided the means to start the Heart System Research Center. Personal thanks go to the Scientific Advisory Committee and the Organizing Committee. Last, we acknowledge with pleasure and many thanks the secretarial and editorial work of Ms. Deborah E. Shapiro, who made this book what it is. Samuel Sideman Rafael Beyar IX WELCOME Medicine and engineering are two great ancient professions which are dedicated to the improvement of human conditions. Both are crucial in man's struggle for survival. Both originate from practice and not from theory, having preceded science by hundreds of centuries, but they were enormously enriched by the penetration and permeation of science. Medicine helps us to cope with our well being. Engineering helps us cope with the environment by providing food, shelter. and improving the standard of living. These two professions have made us the only animal that does not fit naturally into an evolutionary niche; we make our own unique physical, mental, and cultural environment. Dissecting medicine and engineering by scientific tools of analysis uncovers the simplicity behind the complexity. The greater the decomposition down to the cell, the molecular, the atomic level, the greater the potential for reassembling, creating, synthesizing novel and important healing solutions and products. It is Science that weaves medicine and engineering together. This is why you find them both on the Technion campus. This is what the Julius Silver Institute of Biomedical Engineering is doing on our campus: fusing together medicine and engineering, both permeated by science, creating a synergystic amalgam of enormous potential to the improvement of the human condition. In this spirit of scientific progress, I wish you all successful deliberations. Prof Z Tadmor President, Technion-lIT xi INTRODUCTORY RE~s I come here as Chairman of the Israel Cardiac Society, as well as one of the original members of a group of physicians and scientists who have been meeting at the Hemy Goldberg Workshop for the last 10 years. The present meeting is a natural outcome of our 1992 meeting at the National Institutes of Health in Washington and represents a move into the field of molecular cardiology. Macrophysical forces and their interactions require a clear understanding of the subcellular milieu. Cardiology has changed in the last 50 years. In the 40s diagnosis and management were made by the stethoscope and <:ardiac catheterization. Open heart surgery was introduced in the 50s, followed by noninvasive imaging techniques (echo-doppler, nuclear scanning, fast cr, and MRI), coronary artery bypass grafting, percutaneous revascularization of narrowed and obstructed coronary arteries, and now invasive electrophysiology and ablation of arrhythmias. In parallel there has been the development of modem molecular biology, which help us to understand the autocrine and paracrine functions of the cells. Cardiac research covers a wide range of topics. Biomedical engineering looks at quantitative aspects of cardiac physiology and its building-blocks of molecular biology. It varies from the examination of stress, strain, pressures, work, and functions of the ventricle and the great arteries, to the dynamics of the biochemistry of the cell. It will deal with receptors, transmembrane signaling, internal vesicles and their function, the activation of DNA, manufacture of RNA, and the functions of the endosome and the sarcoplasmic retic ulum. Quantitative biochemistry of protein synthesis and turnover will be studied. We will then understand the quantitative dynamics of receptors, the density of the Golgi apparatus, manufacture of smooth and coarse endoplasmic reticulum, and cell multiplication. There is need to create a balance between the clinician on the one hand, who will deliver services to patients, and the molecular biologist on the other, who will have to investigate the profound micromolecular changes in disease. In addition, mathematicians and biophysicists will develop models of interactions between the different subcellular events in the cells. Claude !.enfant, the Director of the new National Heart Lung and Blood Institute (NHLBI) in the USA, has described two major directions of research in the clinical area that require solutions by well-controlled double-blind trials: one is thrombolysis and acute myocardial infarction and the other involves lipid lowering in atherosclerotic disease. Both have great impact on large populations and on the practice of medicine. NHLBI funds these large, controlled epidemiological research trials. On the other hand, the modem technological explosion has opened new avenues of research in molecular biology. Scientists can now manipulate receptors, turn on DNA and RNA, and understand embryogenesis. New knowledge requires rapid peer review and quick dissemination. Small special research seminars like the Hemy Goldberg Workshop create a dialogue between the scien tist and the physician, and are excellent vehicles for the transfer of up-to-date wisdom. My own field of interest is atherosclerosis. Its pathogenesis is gradually being uncovered. Our knowledge of low-density lipoprotein metabolism has undergone a quantum transformation. How do LDLs enter the subendothelium and what controls their xiii