Atherosclerosis, Large Arteries and Cardiovascular Risk U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U Advances in Cardiology Vol. 44 Series Editor Jeffrey S. Borer New York, N.Y. U U U U U U U U U U U U U U U U U U U U U U U U U U U Atherosclerosis, Large Arteries and Cardiovascular Risk Volume Editors Michel E. Safar Paris Edward D. Frohlich New Orleans, La. 63 figures, 1 in color, and 29 tables, 2007 Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Singapore • Tokyo • Sydney U U U U U U U U U U U U U U U U U U U U U U U U U U U Prof. Dr. Michel E. Safar Hôpital Hôtel-Dieu Centre de Diagnostic 1 place du Parvis Notre-Dame F–75181 Paris Cedex (France) Prof. Dr. Edward D. Frohlich Ochsner Clinic Foundation 1514 Jefferson Highway New Orleans, LA 70121 (USA) Library of Congress Cataloging-in-Publication Data Atherosclerosis, large arteries, and cardiovascular risk / volume editors, Michel E. Safar, Edward D. Frohlich. p. ; cm. – (Advances in cardiology ; v. 44) Includes bibliographical references and index. ISBN-13: 978-3-8055-8176-9 (hard cover : alk. paper) 1. Atherosclerosis–Pathophysiology. 2. Arteriosclerosis–Pathophysiology. 3. Coronary heart disease–Etiology. I. Safar, Michel. II. Frohlich, Edward D., 1931- . III. Series. [DNLM: 1. Atherosclerosis–physiopathology. 2. Arteries–physiopathology. 3. Atherosclerosis–complications. 4. Cardiovascular Diseases–etiology. 5. Risk Factors. W1 AD53C v.44 2007 / WG 550 A8694 2007] RC692.A6748 2007 2006030607 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 individ- ual 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 re- sulting 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 2007 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 0065–2326 ISBN-10: 3–8055–8176–9 ISBN-13: 978–3–8055–8176–9 Advances in Cardiology Contents U U U U U U U U U U U U U U U U U U U U U U U U U U U VII Preface Section I – Pathophysiology 1 Arterial Stiffness: A Simplified Overview in Vascular Medicine Safar, M.E. (Paris) 19 Aging and Arterial Structure-Function Relations Izzo, J.L. Jr. (Buffalo, N.Y.); Mitchell G.F. (Waltham, Mass.) 35 Local Elasticity Imaging of Vulnerable Atherosclerotic Coronary Plaques Baldewsing, R.A.; Schaar, J.A.; Mastik, F. (Rotterdam); van der Steen, A.F.W. (Rotterdam/Utrecht) 62 Endothelial Function, Mechanical Stress and Atherosclerosis Hayoz, D.; Mazzolai L. (Lausanne) 76 Arterial Stiffness and Extracellular Matrix Díez, J. (Pamplona) 96 Animal Models of Arterial Stiffness Atkinson, J. (Nancy) Section II – Arterial Stiffness, Atherosclerosis and End-Organ Damage 117 Blood Pressure, Large Arteries and Atherosclerosis Frohlich, E.D.; Susic, D. (New Orleans, La.) 125 Arterial Stiffness and Coronary Ischemic Disease Kingwell, B.A.; Ahimastos, A.A. (Melbourne) 139 Central Pulse Pressure and Atherosclerotic Alterations of Coronary Arteries Danchin, N. (Paris); Mourad, J.-J. (Bobigny) 150 Does Brachial Pulse Pressure Predict Coronary Events? Verdecchia, P.; Angeli, F. (Perugia) V 160 Does Arterial Stiffness Predict Atherosclerotic Coronary Events? McEniery, C.M. (Cambridge); Cockcroft, J.R. (Cardiff) 173 Carotid Atherosclerosis, Arterial Stiffness and Stroke Events Agabiti-Rosei, E.; Muiesan, M.L. (Brescia) 187 Atherosclerosis versus Arterial Stiffness in Advanced Renal Failure Guerin, A.; Pannier, B.; London, G. (Fleury Mérogis) 199 Arterial Stiffness and Peripheral Arterial Disease Safar, M.E. (Paris) Section III – Arterial Stiffness, Atherosclerosis and Cardiovascular Risk Factors 212 Cardiovascular Risk Factors, Atherosclerosis and Pulse Pressure Amar, J.; Chamontin, B. (Toulouse) 223 Pulse Pressure and Inflammatory Process in Atherosclerosis Abramson, J.L.; Vaccarino, V. (Atlanta, Ga.) 234 Calcifications, Arterial Stiffness and Atherosclerosis Mackey, R.H.; Venkitachalam, L.; Sutton-Tyrrell, K. (Pittsburgh, Pa.) 245 Diabetes and Arterial Stiffening Winer, N. (New York, N.Y.); Sowers, J.R. (Columbia, Mo.) 252 Insulin Resistance, Arterial Stiffness and Wave Reflection Yki-Järvinen, H.; Westerbacka, J. (Helsinki) 261 Cholesterol, Lipids and Arterial Stiffness Wilkinson, I. (Cambridge); Cockcroft, J.R. (Cardiff) 278 Homocysteine and Large Arteries van Guldener, C. (Breda); Stehouwer, C.D.A. (Maastricht) Section IV – Therapeutic Aspects 302 Nitrates, Arterial Function, Wave Reflections and Coronary Heart Disease Smulyan, H. (Syracuse, N.Y.) 315 Modulation of Atherosclerosis, Blood Pressure and Arterial Elasticity by Statins Sinha, A.K.; Mehta, J.L. (Little Rock, Ark.) 331 Atherosclerosis, Arterial Stiffness and Antihypertensive Drug Therapy Safar, M.E. (Paris); Smulyan, H. (Syracuse, N.Y.) 352 Author Index 353 Subject Index Contents VI In recent years, our fundamental knowledge of atherosclerosis in the hu- man being has dramatically increased, not only from a better understanding of the pathophysiological information, but also from the clinical use of new hypolipidemic agents which are so very different from the traditional thera- peutic mechanisms directed toward atherosclerotic disease. This advance was exceedingly important for all clinical investigators since their clinical ap- proach to atherosclerotic disease has changed, particularly regarding its links with hypertension and the aging process. Moreover, as a consequence of new epidemiological findings, we have di- vided the well-established vascular ‘diseases’ into two pedagogic categories: those related to cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidemia, obesity and smoking) and those related to specific clinical events affecting the target organ circulations (i.e., brain, kidney, heart, and lower limbs). Furthermore, because of increased longevity in recent years, a disso- ciation of atherosclerosis from the effects of aging per se has been a major effort in presenting the concept of this textbook. Another important point needed to be clarified: in understanding the different clinical and hemodynamic features of atherosclerosis, it was important to present a current means of evaluating cardiovascular risk as well as a practical rationale for developing a therapeutic strategy. Finally, in arriving at a dissociation and understanding of the mecha- nisms of hypertensive disease and of the aging process, the structural and functional changes of the vessels of each must be recognized as clearly as pos- sible with respect to how they involve the totality of the arterial and arteriolar Preface U U U U U U U U U U U U U U U U U U U U U U U U U U U VII VIII Preface system. Thus, it is necessary to comprehend both the aging phenomenon and the pathophysiology of hypertension and their respective global impacts on arterial stiffness, especially involving the aorta and its major large arterial branches. In this regard, the clinical aspects of arterial stiffness have been widely developed in hypertensive subjects over the last 10 years. In contrast, in patients with atherosclerosis, the distribution of arterial rigidity on large ves- sels is much more patchy and predominates in certain arteries – for example the coronary arteries and at the level of the arterial bifurcations. In these ves- sels, non-fibrous and non-calcified plaques do not necessarily contribute to increased vessel stiffness. Therefore, the problem of arterial rigidity in athero- sclerosis is more difficult to resolve than in hypertension. For these reasons, the principal purpose of this book was to respond to the following questions: In which conditions does the atherosclerosis process contribute to the develop- ment of vascular stiffness and to vascular calcifications since both of these fac- tors independently participate in determining cardiovascular risk and, possi- bly, in modifying therapeutic strategy? This book is composed of four sections. First, the definition and measure- ment of arterial stiffness are described with respect to the pathophysiological aspects of atherosclerosis. Second, the mechanisms underlying arterial stiff- ness are described successively in the major territories involved with athero- sclerosis, particularly the coronary arteries. Third, arterial stiffness is dis- cussed with respect to its relation with other cardiovascular factors such as diabetes mellitus or hyperlipidemia. Finally, in the fourth section the thera- peutic means of approaching arterial stiffness are analyzed in detail. We hope this approach to the effects of arterial stiffness involving hypertension, athero- sclerosis, and aging is now better understood and that it will, in turn, result in a more clearly developed concept for therapy in the future. Michel E. Safar , Paris Edward D. Frohlich , New Orleans, La. Section I – Pathophysiology Safar ME, Frohlich ED (eds): Atherosclerosis, Large Arteries and Cardiovascular Risk. Adv Cardiol. Basel, Karger, 2007, vol 44, pp 1–18 Abstract Arterial elasticity is a common index of medical semiology, easier to understand than blood pressure measurement. This chapter summarizes the most classical aspects which are important to understand in vascular medicine. Copyright © 2007 S. Karger AG, Basel In biophysics, the theory of elasticity deals with the relations between the forces applied to a body and its subsequent deformations [1–3] . The force per unit area is called the ‘stress’. The deformation, described as the ratio of the deformation to its original form, is called the ‘strain’. Because it is a ratio, strain is dimensionless. The slope of the strain-stress relationship is called ‘elastic modulus’. When forces act on a given solid body without displacing it, they will de- form it, that is, cause a movement of the various parts of the body relative to one another. If the body regains its original form exactly when the force is re- moved it is said to be ‘perfectly elastic’. If the body retains the deformation, then it is said to be ‘plastic’. A large number of substances exhibit properties appropriate to both an elastic solid and a viscous liquid, and the deformation suffered by such a material will depend on both the magnitude of the stress and on the rate at which it is applied. Such substances are called ‘visco-elastic’. It is to this large class that the arterial wall belongs. Arterial Stiffness: A Simplified Overview in Vascular Medicine Michel E. Safar Diagnosis Center, Hôtel-Dieu Hospital, Paris , France U U U U U U U U U U U U U U U U U U U U U U U U U U U