Cardiovascular Diabetology: Clinical, Metabolic and Inflammatory Facets
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1 Cardiovascular Diabetology: Clinical, Metabolic and Inflammatory Facets
2 Advances in Cardiology Vol. 45 Series Editor Jeffrey S. Borer, New York, N.Y
3 Cardiovascular Diabetology: Clinical, Metabolic and Inflammatory Facets Volume Editors Enrique Z. Fisman Holon Alexander Tenenbaum Tel-Hashomer 23 figures and 5 tables, 2008 Basel Freiburg Paris London New York Bangalore Bangkok Singapore Tokyo Sydney
4 Prof. Enrique Z. Fisman Cardiovascular Diabetology Research Foundation Holon (Israel) Prof. Alexander Tenenbaum Cardiac Rehabilitation Institute Chaim Sheba Medical Center Tel-Hashomer (Israel) Library of Congress Cataloging-in-Publication Data Cardiovascular diabetology : clinical, metabolic, and inflammatory facets / volume editors, Enrique Z. Fisman, Alexander Tenenbaum. p. ; cm. (Advances in cardiology, ISSN ; v. 45) Includes bibliographical references and index. ISBN (hard cover : alk. paper) 1. Diabetes Complications. 2. Cardiovascular system Diseases Complications. I. Fisman, Enrique Z. II. Tenenbaum, Alexander. III. Series. [DNLM: 1. Cardiovascular Diseases complications. 2. Diabetes Complications. W1 AD53C v / WK 835 C ] RC660.C dc Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents and Index Medicus. Disclaimer. The statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 2008 by S. Karger AG, P.O. Box, CH 4009 Basel (Switzerland) Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhardt Druck, Basel ISSN ISBN
5 To my wife Elsa Meryn Fisman, our daughters Gabriela and Dana, our grandchildren Rotem, Guy, Ethan and Einav. To my parents of blessed memory. In gratitude to my beloved family, who in countless ways provides unlimited support, encourages my labor and enriches my existence. E.Z. Fisman To my wife, Helena, my best friend and colleague, to our kids, Ilan and Oren who stood by me so strong when I needed them the most. To my mother and father of blessed memory. To a loving family that exceeds my hopes and dreams. A. Tenenbaum
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7 Contents IX Contributors XI Preface Fisman, E.Z. (Holon); Tenenbaum, A. (Tel-Hashomer) 1 Hyperglycemia and the Pathobiology of Diabetic Complications Aronson, D. (Haifa) 17 Endothelial Dysfunction in Normal and Abnormal Glucose Metabolism Esper, R.J.; Vilariño, J.O.; Machado, R.A.; Paragano, A. (Buenos Aires) 44 Biomarkers in Cardiovascular Diabetology: Interleukins and Matrixins Fisman, E.Z. (Holon); Adler, Y.; Tenenbaum, A. (Tel-Hashomer) 65 Arterial Elasticity in Cardiovascular Disease: Focus on Hypertension, Metabolic Syndrome and Diabetes Cernes, R.; Zimlichman, R.; Shargorodsky, M. (Holon/Tel-Aviv) 82 Hypertension and Diabetes Grossman, E. (Tel-Hashomer); Messerli, F.H. (New York, N.Y.) 107 Impaired Glucose Metabolism and Cerebrovascular Diseases Tanne, D. (Tel-Hashomer/Tel-Aviv) VII
8 114 Impact of Metabolic Syndrome in Patients with Acute Coronary Syndrome Feinberg, M.S.; Schwartz, R.; Behar, S. (Tel-Hashomer) 127 Optimal Management of Combined Dyslipidemia: What Have We Behind Statins Monotherapy? Tenenbaum, A. (Tel-Hashomer); Fisman, E.Z. (Holon); Motro, M.; Adler, Y. (Tel-Hashomer) 154 Non-Insulin Antidiabetic Therapy in Cardiac Patients: Current Problems and Future Prospects Fisman, E.Z. (Holon); Motro, M.; Tenenbaum, A. (Tel-Hashomer) 171 Subject Index Contents VIII
9 Contributors Yehuda Adler, MD, MHA p. 44, 127 Professor of Cardiology, Sackler Faculty of Medicine, Tel-Aviv University, Israel. General Secretary, Working Group on Cardiac Rehabilitation, Israel Heart Society; Medical Director, Shfela Region, Leumit Health Fund; Physician-in-charge, field of Cardiac Rehabilitation and Assistant to the Director General, Sheba Medical Center, Tel-Hashomer, Israel. Doron Aronson, MD p. 1 Director, Cardiac Care Unit, Division of Cardiology, Rambam Medical Center, Bat Galim, Haifa, Israel. Solomon Behar, MD p. 114 Medical Director, Israel Society for Prevention of Heart Attack (ISPHA), Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Hashomer, Israel; Professor of Cardiology, Sackler Faculty of Medicine, Tel-Aviv University, Israel. Relu Cernes, MD p. 65 Department of Nephrology, Wolfson Medical Center, Holon, Israel; Brunner Institute for Cardiovascular Research, Sackler Faculty of Medicine, Tel-Aviv University, Israel. Ricardo J. Esper, MD, PhD, FACC, FAHA p. 17 Professor of Medicine and Cardiology, Universities of Buenos Aires & del Salvador, Buenos Aires, Argentina; Cardiology Consultant, Hospital Militar Central, Buenos Aires; Past-President, Argentine Society of Cardiology, Argentine Foundation of Cardiology, Interamerican Heart Foundation; InterAmerica Representative, Executive Board, World Heart Federation. Micha S. Feinberg, MD p. 114 Director of Noninvasive Cardiology Unit, Heart Institute, Sheba Medical Center, Tel- Hashomer, Israel; Professor of Cardiology, Sackler Faculty of Medicine, Tel-Aviv University, Israel. IX
10 Enrique Z. Fisman, MD.... p. 44, 127, 154 Professor of Cardiology, Sackler Faculty of Medicine, Tel-Aviv University, Israel; Honorary Professor of Cardiology, University del Salvador, Buenos Aires, Argentina; Editor-In-Chief, Cardiovascular Diabetology, BioMed Central, London, United Kingdom. Ehud Grossman, MD p. 82 Professor of Medicine, Vice Dean for Academic Promotions, Sackler Faculty of Medicine, Tel-Aviv University, Israel; Head of Internal Medicine D and Hypertension Unit, Sheba Medical Center, Tel-Hashomer, Israel. Rogelio A. Machado, MD p. 17 Professor of Cardiology and Biostatistics, University del Salvador, Buenos Aires, Argentina; Staff member, Cardiology Service, Hospital Militar Central, Buenos Aires; Chief, Echocardiography Laboratory, Hospital Fancés, Buenos Aires; Member of the Argentine Society of Cardiology. Franz H. Messerli, MD, FACC, FACP p. 82 Professor of Medicine, Director, Hypertension Program, Division of Cardiology, St.Luke s-roosevelt Hospital, Columbia University, New York, N.Y., USA Michael Motro, MD, FACC.... p. 127, 154 Full Professor of Cardiology, Sackler Faculty of Medicine, Tel-Aviv University, Israel. Antonio Paragano, MD p. 17 Staff member, Cardiology Service, Hospital Militar Central, Buenos Aires, Argentina; Professor of Cardiology, University del Salvador, Buenos Aires, Argentina. Roseline Schwartz, MS p. 114 Israel Society for Prevention of Heart Attack (ISPHA), Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Hashomer, Israel. Marina Shargorodsky, MD p. 65 Department of Endocrinology and Diabetes, Wolfson Medical Center, Holon, Israel; Brunner Institute for Cardiovascular Research, Sackler Faculty of Medicine, Tel-Aviv University, Israel. David Tanne, MD p. 107 Director, Stroke Center, Department of Neurology and Sagol Neuroscience Center, Sheba Medical Center, Tel-Hashomer, Israel; Professor of Neurology, Sackler Faculty of Medicine, Tel-Aviv University, Israel. Alexander Tenenbaum, MD, PhD p. 44, 127, 154 Director of Research, Cardiac Rehabilitation Institute, Sheba Medical Center, Tel-Hashomer, Israel. Professor of Cardiology, Sackler Faculty of Medicine, Tel-Aviv University, Israel; Editor-In-Chief, Cardiovascular Diabetology, BioMed Central, London, United Kingdom. Jorge O. Vilariño, MD, FACC, FAHA p. 17 Chief, Cardiology Service, Hospital R. Gutiérrez, Venado Tuerto, Argentina; Professor of Cardiology, University del Salvador, Buenos Aires, Argentina. Reuven Zimlichman, MD p. 65 Chief of Medicine, Wolfson Medical Center, Holon, Israel; Brunner Institute for Cardiovascular Research, Sackler Faculty of Medicine, Tel-Aviv University, Israel; Professor of Medicine, Sackler Faculty of Medicine, Tel-Aviv University, Israel. Contributors X
11 Preface The prevalence of obesity, metabolic syndrome and diabetes, which we previously defined as the atherothrombotic chain, has reached pandemic proportions worldwide. Consequences of diseases related to this atherothrombotic chain such as hypertension, coronary heart disease, peripheral artery disease and stroke account for much of the morbidity in these patients. As a result, our civilization is currently at war against the threatening enemy of cardio-diabetes. The growing understanding of the inter-relationship between diabetes and cardiovascular disease has been reflected by recent guidelines for diabetes and cardiovascular disease to enhance the diagnosis and management of cardio-diabetes. Indeed, effective cardiovascular prevention in patients with obesity, metabolic syndrome and diabetes needs a global strategy, based on knowledge of the importance of different risk factors, both conventional and newly described. In fact, we are currently witnesses and participants of the emergence of a new scientific discipline Cardiovascular diabetology. Several independent physiological processes underlie the clustering that defines cardio-diabetes, including insulin resistance, central obesity, dyslipidemia, impaired glucose tolerance, and hypertension. Diabetic arteriopathy, which encompasses endothelial dysfunction, inflammation, hypercoagulability, changes in blood flow, and platelet abnormalities, contributes to the early evolution of these events. Chronic complications of diabetes affecting the cardiovascular system are characterized by a dysfunction of the viscoelastic properties of the arterial vessels and, in particular, of arterial distensibility and compliance. Other nonclassical risk factors such as abnormal oxidized low-density XI
12 lipoprotein-cholesterol, adiponectin, interleukins, matrixins and C-reactive protein levels are highly correlated with cardio-diabetes. Although therapeutic improvements and public health policies for risk factor control have brought about a dramatic reduction in cardiovascular mortality among the general population during the last two decades, this success has not been extended to diabetic patients. The presence of diabetes mellitus increases all-cause mortality and, in particular, cardiovascular mortality by 2- to 4-fold. Furthermore, mortality is dramatically increased in the presence of clinical features such as diabetic nephropathy. Although part of this increase can be explained by interaction with other risk factors and by the clustering of diabetes with other risk elements of the metabolic syndrome, increased cardiovascular mortality and morbidity are essentially conferred by the presence of diabetes per se. Atherosclerotic coronary plaques tend to develop earlier and be more advanced and more diffuse in diabetic patients. Unfortunately, the reperfusion strategies have proven less efficacious in those patients. Percutaneous coronary interventions seem to have a worse outcome in these patients, who are affected by a high incidence of re-occlusion. Due to the frequent coexistence of silent ischemia, this diagnosis is often found too late. Furthermore, a complex of different adverse characteristics of diabetes, including endothelial dysfunction and a prothrombotic state, augments the probability of plaque instability and occlusion. Diabetes renders patients especially prone to heart failure, resulting from both diffuse coronary heart disease and direct microvascular and myocardial damage. Heart failure is the main cause of death during acute myocardial infarction, the global risk of failure being almost three times higher in the presence of diabetes. The risk of developing significant coronary artery disease is also high in diabetic patients because of the increased frequency of dyslipidemia, which is linked to central obesity and insulin resistance. The complex and intimate relationship between cardiovascular disease and diabetes is discussed in the following chapters of Cardiovascular Diabetology: Clinical, Metabolic and Inflammatory Facets in a crescendo style from basic science to clinical and therapeutic concerns. Beginning with molecular, biochemical, inflammatory and cellular aspects, the book continues with histological and pathophysiologic issues, details particular problems in specific metabolic and clinical settings, and finally analyzes several aspects of clinical pharmacology. The book is made up of nine chapters. In the first, Aronson delineates the biochemical mechanisms by which hyperglycemia induces a large number of alterations in vascular tissue that potentially promote accelerated atherosclerosis. Next, Esper and coworkers clarify how the endothelium is the favorite common target of diabetes and other risk factors, showing that its functional impairment in response to injury occurs long before the development of Preface XII
13 visible atherosclerosis. Subsequently, Fisman s group describes the main features of interleukins and matrixins, features that suggest a common inflammatory basis for both diabetes and coronary disease. Cernes and coworkers discuss the factors influencing the viscoelastic properties of the arterial wall, Grossman and Messerli analyze the several epidemiological and clinical aspects linking diabetes and hypertension, Tanne analyzes impaired glucose metabolism as a predictor of cerebrovascular disease, and Feinberg s group discuss the impact of metabolic syndrome in patients with acute coronary syndrome. The last two chapters are dedicated to therapeutic issues. Tenenbaum and coworkers talk about the optimal management of combined dyslipidemia, detailing both the classical and modern therapeutic options, and Fisman and coworkers describe the current problems and future prospects of non-insulin antidiabetic therapy in cardiac diabetic patients. We would like to pay tribute and express our appreciation to the distinguished and internationally renowned co-authors of this book for their outstanding contribution. Despite their many commitments and busy time schedules, these colleagues in Israel, Argentina and the United States enthusiastically stated their acquiescence to cooperate. This book could not have become a reality were it not for their dedicated efforts. Enrique Z. Fisman Alexander Tenenbaum Preface XIII
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