Classic Papers in Coronary Angioplasty

Transcription

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2 Classic Papers in Coronary Angioplasty

3 Clive Handler and Michael Cleman (Eds) Classic Papers in Coronary Angioplasty With 18 Figures

4 Clive Handler, MD, FACC, FESC Consultant Cardiologist and Physician The National Pulmonary Hypertension Unit The Royal Free Hospital London, UK and Consultant Cardiologist Highgate Hospital London, UK Michael Cleman, MD, FACC Professor of Medicine Director Cardiac Catheterization Laboratory and Angioplasty Services Yale University School of Medicine/Yale-New Haven Hospital New Haven, Connecticut, USA British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Control Number: ISBN-10: e-isbn: Printed on acid-free paper ISBN-13: Springer-Verlag London Limited 2006 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Whilst we have made considerable efforts to contact all holders of copyright material contained in this book, we may have failed to locate some of them. Should holders wish to contact the Publisher, we will be happy to come to some arrangement with them. Printed in the United States of America (EB) Springer Science+Business Media springer.com

5 Contents Editors Contributors Acknowledgements Preface Foreword vi vi viii ix xi Chapter 1 Vascular biology of atherosclerosis 1 Peter F. Bodary, Daniel T. Eitzman Chapter 2 Chapter 3 Quantification of coronary atherosclerosis for cardiovascular risk assessment: the hole in the doughnut? 21 Paul Schoenhagen, Steven E. Nissen Primary angioplasty (PPCI) in ST-elevation myocardial infarction 39 Iqbal Saeed Malik, Rodney Foale Chapter 4 Coronary angioplasty for acute coronary syndromes 65 Steven Pfau Chapter 5 High-risk coronary intervention: a selective literature review of high-risk subsets 89 Jeffrey J. Popma, Hung Ly Chapter 6 Stenting in coronary angioplasty 115 Jeptha P. Curtis, John F. Setaro Chapter 7 Ancillary techniques in interventional cardiology 141 John M. Lasala, George Chrysant, Adrian Messerli Chapter 8 Anti-thrombotic management in interventional cardiology 163 James Tcheng, Steve Kindsvater Chapter 9 Coronary artery bypass grafts in the era of percutaneous coronary angioplasty 191 Thanos Athanasiou, Brian Glenville Chapter 10 Epilogue 217 Gerry Coghlan Frequently cited papers in coronary angioplasty 229 Index 231

6 Editors Clive Handler MD, FACC, FESC Consultant Cardiologist and Physician, The National Pulmonary Hypertension Unit, The Royal Free Hospital, London, UK and Consultant Cardiologist, Highgate Hospital, London, UK Michael Cleman MD, FACC Professor of Medicine, Director, Cardiac Catheterization Laboratory and Angioplasty Services, Yale University School of Medicine/Yale-New Haven Hospital, New Haven, Connecticut, USA Contributors Thanos Athanasiou MD, PhD, FETCS Consultant Cardiothoracic Surgeon, St. Mary s Hospital, London, UK Peter F. Bodary PhD Research Investigator of Internal Medicine/Cardiology, University of Michigan, Ann Arbor, Michigan, USA George Steven Chrysant MD Director, Advanced Cardiac Imaging, Integris Heart Hospital, Oklahoma City, Oklahoma, USA Gerry Coghlan MD, FRCP Consultant Cardiologist, The Royal Free Hospital, London, UK Jeptha P. Curtis MD Instructor of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA Daniel T. Eitzman MD, FACC Associate Professor of Internal Medicine/Cardiology, University of Michigan, Ann Arbor, Michigan, USA Rodney Foale MBBS, FRCP, FACC, FESC, FCSANZ Consultant Cardiologist and Clinical Director of Surgery, Cardiovascular Science and Critical Care, Waller Department of Cardiology, St. Mary s Hospital, London, UK Brian Glenville BSc(Hons), MS Professor and Head of Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel Steven Michael Kindsvater MD Keesler Medical Center, Keesler AFB, Mississippi, USA John M. Lasala MD, PhD Associate Professor of Cardiology, Washington University School of Medicine, St Louis, Missouri, USA Hung Ly MD Interventional Cardiology Fellow, Cardiology Division, Brigham and Women s Hospital, Boston, Massachusetts, USA vi

7 Iqbal Saeed Malik MA, MRCP, PhD Consultant Interventional Cardiologist, Waller Department of Cardiology, St. Mary s Hospital, London, UK Adrian W. Messerli MD Cardiology Associates of Kentucky, Lexington, Kentucky, USA Steven E. Nissen MD, FACC Medical Director, Cleveland Clinic Cardiovascular Research Coordinating Center, The Cleveland Clinic Foundation, Cleveland, Ohio, USA Steven Pfau MD Associate Professor of Medicine, Yale University School of Medicine, Cardiology Section, New Haven, Connecticut, USA Jeffrey J. Popma MD Director, Interventional Cardiology, Brigham and Women s Hospital, Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts, USA Paul Schoenhagen MD, FAHA Cardiovascular Imaging, Departments of Radiology and Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA John F. Setaro MD Associate Professor of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA James E. Tcheng MD, FACC, FBCAI, FESC Associate Professor of Medicine; Associate Professor of Community & Family Medicine, Duke Clinical Research Institute, Duke University Medical Center Durham, North Carolina, USA vii

8 Acknowledgements Both Clive Handler and Michael Cleman would like to thank Professor Lawrence Cohen for writing the foreword to this book and for arranging the transatlantic link between London and New Haven, which was essential for this project, and for his encouragement and wise counsel. Clive Handler would like to acknowledge the support of his wife, Caroline, and their three children, Charlotte, Sophie and Julius, during the production of this book. The idea for this book came from his colleague from school, Dr Neil Soni, who co-edited the first book in this series, Classic Papers in Critical Care. He is also grateful to his colleague from the Royal Free Hospital, Dr Gerry Coghlan, who not only contributed the final chapter but also proof read the book. Michael Cleman would like to acknowledge his wife Marilyn, and his children, Jake and Katie for their patience and support in this project. The support and expertise of his interventional colleagues at Yale has been invaluable in collating the material. viii

9 Preface Percutaneous coronary intervention (PCI) is one of the most commonly performed cardiac procedures. Physicians, all healthcare professionals and healthcare managers, as well as patients and their families, the world over, are aware that it is a very useful and powerful tool to help improve the lives of patients with coronary heart disease. But how did we get here? Cardiologists of our generation were in training when PCI was in its infancy. There was no evidence base to guide us and we witnessed and practiced with comparatively primitive equipment. We all had to learn from our own successes and failures as well as from the experiences of colleagues. The residents and trainees of today may not fully appreciate the anxieties of interventionists during procedures during those early years. Inherent problems included imaging and evaluating the significance of a coronary artery lesion; lack of data on what constituted high risk lesions and patients which made case selection difficult (this, in turn added uncertainty when discussing and quantifying the procedural risks to patients); arterial access problems and bleeding (particularly during the anticoagulation era); primitive and traumatic hardware complicating target lesion access; the sinking feeling of dealing with abrupt vessel closure, dissection and haemodynamic collapse before the availability of stents; and the disappointment felt by patients and interventionists with a comparatively high incidence of restenosis. Subacute thrombosis was an infrequent but worrying and unpredictable complication. On-site backup coronary artery surgery was generally considered mandatory and this had a knock-on effect on the work and finances of hospitals and providers. Memories of those early days when our expectations of the procedure, performed mainly for accessible, proximal, comparatively simple lesions in patients with single vessel disease, were that plain old balloon angioplasty would keep our patients away from the surgeons for a little while longer, and that it could be used as a salvage procedure for inoperable patients, have faded and have been replaced with a different, more confident, evidence-based practice. The frontiers have been pushed back; PCI incorporating drug-eluting stents and modern antiplatelet treatments is a routine, low-risk, day-case procedure performed in patients of all ages and co-morbidity, with high patient and clinician expectations for both acute and chronic coronary artery disease, without the necessity of on-site surgery. PCI has changed the way we approach clinical problems. Physicians managing patients with known or suspected coronary heart disease, whether in their office, in the emergency room or in the coronary care unit, understand that prompt diagnosis and treatment are now available. We continually search for improvements and refinements in equipment and pharmacological therapies. We collaborate with our basic science colleagues to find answers to molecular and cellular biological obstacles. Our imaging and vascular colleagues are key members of the multidisciplinary approach to develop and expand the use of the technique and enhance the quality of service we provide our patients. These rapid developments in the management of coronary heart disease, which will eventually affect nearly all of us, have been possible only through the vision, persistence, intellectual curiosity, skill and discipline of our predecessors. Interventionists today have been handed the baton and continue the quest. The aim of this book is not intended to be a birthday party for PCI, although its publication coincides with the 25th anniversary of Grüntzig s paper. We wanted to pause, take breath and try to produce a small, useful and enjoyable book that would remind all those involved in PCI, of some of the major contributions to the literature. Looking back often helps in seeing what may lie ahead. ix

10 Preface We have invited some of the world s leading interventionists to help us and they have done a fine job. They were given a difficult task. We asked them to provide us with their personal choice of the papers that have most influenced their practice and understanding of PCI in a number of its components. As busy clinicians, we are not often (if ever) forced to identify the papers that have been the most influential in shaping our practice. It may be considered a somewhat artificial approach, but reading an expert s personal, restricted choice of papers that he would take on a desert island (without internet or library access), is of interest. Dr Mitchell Fink MD, in his preface to Classic Papers in Critical Care, excused the personal choices of the contributors by likening them to the views of a San Francisco restaurant critic. We have also included citation indices for each paper so that our readers have the additional views of the wider PCI community. You may have your own personal choices and may disagree with the choice of our contributors. We would beg your tolerance with this, an inherent weakness of this book. But it is also a strength, because the very nature and enjoyment of this series is that leading world experts allow readers to peep at their academic proclivities and personal perspectives of papers they think are scientifically and clinically useful. We feel that it provides a useful reference for others and has educational and historical value. Our friend and teacher, the eminent Professor Lawrence Cohen, confessed in his foreword, that he got it wrong at his first attempt to 25 years ago. Even he could not have anticipated how things were to turn out. This collection of Classic Papers in Coronary Angioplasty, 25 years down the road, is an opportunity to look behind us as we enter an early lap of a long distance race. Together with our contributors, we hope that you will enjoy this coned-in snapshot of PCI in We have no doubt that the next quarter of a century will bring us more surprises and improved care for our patients. Clive Handler MD, FACC, FESC Michael Cleman MD, FACC x

11 Foreword I am particularly pleased to get a second chance. I refer to the fact that at the time of my first chance, I got it all wrong. The year was 1979 and Dr Andreas Grüntzig had recently published an article in The New England Journal of Medicine entitled Nonoperative Dilation of Coronary Artery Stenosis: Percutaneous Transluminal Coronary Angioplasty. I took the opportunity to write a Letter to the Editor in which I stated: A method for relief of coronary obstructions that did not involve operations would obviously have a major impact on medical, surgical, economic and psychologic aspects of this disease... Although this report is of great interest, it would be wise for cardiologists to maintain a healthy skepticism... This operation is clearly not the answer for most patients with obstructive coronary lesions. It is appropriate for only a fraction of patients with coronary artery disease perhaps between 3 and 10 per cent. It may be successful in some patients with intrinsic coronary lesions and even in some who have previously undergone bypass grafting with subsequent occlusion of the graft. I further went on to say: Even when the obstructive lesion can be reached by the catheter, in how many patients will the dilatation be successful and free from complications such as intimal dissection? Further, if a lesion can be dilated, will the obstruction remain open for an extended period or will it return in days, weeks or months? Perhaps you can understand my relief at being given a second chance to visit the topic of coronary angioplasty. This excellent book explores the growth in our knowledge gleaned over a quarter of a century. It explores the field from perspectives ranging from that of the vascular biologist to that of the surgeon who must thoughtfully reassess the diminishing role of coronary artery bypass surgery now that a non-operative approach is not only possible but in many instances preferable. It would not be a stretch to say that coronary angioplasty is to cardiology as the Rosetta Stone was to Egyptian hieroglyphics, allowing the language to be translated. The opening chapter on Vascular Biology of Atherosclerosis begins with the seminal work of Ross which was the first to identify the vascular smooth muscle cell as playing a critical role in the development of the atherosclerotic plaque. In collaboration with L. Harker, Ross went on to point to the role of hyperlipidemia in causing endothelial injury. The chapter by Schoenhagen and Nissen chronicles our ability to quantify the extent of coronary plaquing and also estimate the composition of coronary plaques. Proudfit s paper of 40 years ago reports on the correlation between clinical findings and selective cine coronary arteriography in 1000 patients. For the first time, a patient s clinical symptoms could be evaluated alongside a picture of the coronary arterial tree. This chapter also contains the 1990 article by Nissen et al. describing the development of intravascular ultrasound (IVUS), a technique that is able not only to quantify the extent of plaque but also its morphology. As experience with coronary angioplasty grew in patients with stable angina, it is not surprising that clinicians would extend this technique to the patient who is in the midst of a myocardial infarction. This approach is compared to the previous gold standard, thrombolytic therapy. It is now generally agreed that although both procedures have their respective roles, primary xi

12 Foreword percutaneous coronary intervention (PPCI) is the preferable method if the patient can be brought to the catheterization laboratory in a timely manner. Coronary angioplasty has spawned a wealth of research directed at prevention of thrombosis. The work on platelet glycoprotein IIb/IIIa receptor inhibition was stimulated by the need to prevent thrombosis at the site of angioplasty. It is unlikely that this field of research would have been advanced as far as it is today had it not been for the needs brought about by angioplasty. Once balloon angioplasty became an established therapeutic procedure, the addition of coronary stenting was a natural sequence. It was hoped that stenting would help prevent restenosis, a complication that plagued up to 20 per cent of patients undergoing balloon angioplasty. Starting slowly 15 years ago, coronary stents are now placed in 80 per cent of patients undergoing balloon angioplasty. The latest improvement is the development of drug-eluting stents to further prevent smooth muscle proliferation leading to restenosis. Chapter 9 of this important book is a reflective commentary on the respective roles of angioplasty and coronary artery bypass surgery. From its slow beginnings in 1980 where there were about 1000 angioplasties performed, there are currently 900,000 angioplasties performed annually. Most of these angioplasties are performed in patients who could not have been considered candidates when the procedure was first introduced over 25 years ago. It has already become the primary treatment of patients with coronary artery disease. Finally, I want to commend the two editors Drs Clive Handler and Michael Cleman. I first met Dr Handler when I was a Visiting Professor at the Brompton Hospital in He was a member of the Junior Cardiac Club. We became colleagues and friends, a relationship that has been a mutual pleasure for the past 20 years. Dr Cleman is my respected colleague at Yale. I have watched him grow from the time he came to Yale as a Cardiology Fellow 25 years ago, to his becoming a Professor and Head of our Interventional Cardiology Team. As I indicated in the beginning of this piece, I am grateful to both of them for the opportunity of having a second chance to visit coronary angioplasty. This time I believe I got it right. Professor Lawrence S. Cohen The Ebenezer K. Hunt Professor of Medicine Yale University School of Medicine New Haven, CT USA Fellow, British Cardiac Society xii

13 Chapter 1 Vascular biology of atherosclerosis Peter F. Bodary, Daniel T. Eitzman Introduction The pathogenesis of atherosclerosis has been the subject of thousands of articles published over the past several decades. Currently over 5000 papers per year are being published related to atherosclerosis. To identify only eight articles from this vast literature that have had great impact on our understanding of the biology of atherosclerosis is a difficult task. It will be impossible to do justice to the hundreds of investigators that have shaped the field as it is currently viewed. Most of the fundamental concepts shaping the field of atherosclerosis were generated by pathologists through observational studies. The current view of atherosclerosis probably began with the work of Rudolph Carl Virchow, a professor of pathology, who published Cellular Pathology in Virchow put forth the novel notion that cells were affected by outside stimuli and that diseased cells arose from other diseased cells. Virchow suggested that the atherosclerotic lesion resulted from lipid accumulation and cellular proliferation in the arterial wall. During the same time period (1852), von Rokitansky suggested that atherosclerotic lesion development was preceded by fibrin deposition and that persistence of fibrin deposits might contribute to the formation of an atherosclerotic lesion. Many other pathologists preceding and during this time period had made similar observations and it is difficult to determine who should be credited with the original observations. Suffice it to say, many pathologists have described atheromatous changes in the vasculature but experimental data to support specific hypotheses were lacking during this time period. This review will therefore focus on papers from the more modern era of vascular biology. The modern biology of atherosclerosis arguably began with a series of seminal primate studies described by Russell Ross. In 1973, Ross and Glomset described the cellular composition of atherosclerotic lesions and proposed a critical role for the vascular smooth muscle cell in atherogenesis. Ross and Harker went on to propose the response to injury hypothesis to explain the development of atherosclerotic plaques and establish the critical role of hyperlipidemia in the initiation and progression of atherosclerosis. In 1981, Ross Gerrity established the role of the monocyte in atherogenesis using a hypercholesterolaemic swine model. This work de-emphasized the contribution of the vascular smooth muscle cell in the growing atherosclerotic lesion and stressed the importance of foam cells derived from monocytes. In 1983, Erling Falk studied human autopsy specimens and demonstrated that coronary thrombosis developed when plaque rupture occurred at a site of pre-existing coronary stenosis. Further characterization of the vulnerable plaque composition was provided by Michael Davies from an autopsy series of patients who died suddenly of ischaemic coronary disease. Seymour Glagov and co-workers introduced the concept of vascular remodelling when he demonstrated that the vascular wall could actually enlarge to accommodate atherosclerotic lesion growth. Further elucidation of the complexity of atherosclerotic lesions was provided by Herbert Stary when he published results of an autopsy series that included infants through young adults. These studies demonstrated that growth of the atherosclerotic plaque begins very early in life and progresses through various stages of complexity. Following the establishment of the contribution of lipids to atherosclerosis by several investigators, Brown and Goldstein elucidated the major pathway responsible for cholesterol homoeostasis. This work would earn them the Nobel prize and lead to therapeutical breakthroughs towards the battle against atherosclerotic vascular disease.

14 Vascular biology of atherosclerosis Title 1 Author Reference Abstract Summary Atherosclerosis and the arterial smooth muscle cell Ross R, Glomset J Science 1973; 180: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. In this paper, Russell Ross reviews the current data regarding the vascular smooth muscle cell in atherosclerosis. Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. At the time this paper was written, little was known about the genesis of atherosclerosis. Previous studies had demonstrated that blood pressure, smoking and plasma lipid concentrations could influence the development of clinical symptoms of atherosclerotic vascular disease but the sequence of pathological events at the cellular level was largely unknown. Focal accumulation of intimal smooth muscle cells was argued to be critical to the early stages of atherosclerosis. Ross argued that the accumulation of smooth muscle cells necessarily precedes or accompanies both the deposition of lipid and the accumulation of extracellular connective matrix, because the lipid deposits occur either within smooth muscle cells or outside them in association with connective tissue matrix components which are secretory products of smooth muscle cells. Ross stated that smooth muscle cell proliferation began when a breach of endothelial integrity occurred that would allow substances present in the plasma to stimulate cellular proliferation. Studies supporting these observations included the tendency of vascular smooth muscle cells to accumulate in the intima at arterial branch points, where endothelial permeability appeared to be increased. Stemerman and Ross had also demonstrated experimentally using macaques that vascular lesions could be induced by denuding the femoral artery vascular endothelium with balloon catheters. Three months after injury, the lesion contained as many as 15 layers of smooth muscle cells surrounded by collagen and immature elastic fibers. These lesions were described as identical in appearance to the fibromusculoelastic lesions seen in man. Ross also reviews evidence (in vitro and in vivo) that lipids appear to influence proliferation of vascular smooth muscle cells and that vascular smooth muscle cells are responsible for production of extracellular matrix. Citation Count 986 Key message Strengths Vascular smooth muscle cell proliferation plays a critical role in the development and growth of atherosclerotic lesions. The identification of vascular smooth muscle cells and the time course of proliferation and matrix production following vascular injury greatly enhanced the understanding of vascular lesion 2

15 Classic Papers in Coronary Angioplasty (a) (b) Figure 1 Light micrographs demonstrating (a) a normal primate iliac artery (Mecaca nemestrina) ( 550); (b) an iliac artery 3 months after de-endothelialization, showing a marked increase in intimal thickness due to accumulation of smooth muscle cells and extracellular matrix ( 500); and (c) an iliac artery 6 months after de-endothelialization, by which time the intimal thickness had returned to one to two layers ( 500). This sequence demonstrated the relative reversibility of an experimentally induced lesion in a monkey on a normal diet with normal concentration of plasma lipid. (c) formation. This work also identified the smooth muscle cell as a therapeutical target towards the prevention of vascular disease. Weaknesses Conclusion regarding cell types and cellular proliferation in atherosclerosis were based on studies of femoral artery injury in primates. The lesions that develop following arterial injury with balloon catheters (neointima) are fibrous and are not the same as those that occur in naturally occurring atherosclerosis. In addition, accurate means of identifying cell types in atherosclerotic plaques were not available at the time of this paper. 3

16 Vascular biology of atherosclerosis Title 2 Author Reference Abstract Hyperlipidemia and atherosclerosis Ross R, Harker L Science 1976; 193: Chronic hyperlipidemia initiates and maintains lesions by endothelial cell desquamation and lipid accumulation. Summary In this paper, Ross and Harker describe the effect of hyperlipidemia on the growth of vascular lesions, with and without mechanical injury, in primates. The article begins with an overview of the response to injury hypothesis to explain atherosclerosis development. According to this hypothesis (in 1976), everyone is susceptible to various forms of endothelial injury including mechanical, chemical, immunological and toxic sources. If the injury is a single event, the lesions would be reversible but continuous exposure to a toxic stimulus would lead to lesion progression which may be irreversible. Upon disruption of endothelial integrity, the vascular smooth muscle cells would be exposed to elements from the plasma that would stimulate proliferation. At the time of this paper, the principle mitogen present in blood serum responsible for the stimulation of smooth muscle cell growth was thought to be platelet-derived. In studies examining the effect of hyperlipidemia on vascular lesion formation, a group of monkeys were fed a hypercholesterolaemic diet and followed for up to 18 months after aorto-iliac balloon injury. At 6 weeks to 3 months following arterial injury, hypercholesterolaemic monkeys displayed thickened intima filled with lipidladen cells which were presumptively identified as vascular smooth muscle cells. The number of cells comprising the intima in a control group of normolipidemic monkeys following injury was similar but the amorphous lipid inclusions were lacking. Long-term follow-up revealed that the lesions in the hyperlipidemic group had progressed while those in the normolipidemic group had regressed. Thus, hyperlipidemia promoted intimal growth after injury. Critical observations were then made in the non-injured iliac artery. By 10 months following initiation of hyperlipidemia, there were no differences between the injured and non-injured iliac arteries. Both arteries (injured and non-injured) contained layers of lipid-laden smooth muscle cells surrounded by extracellular lipid and large quantities of newly formed connective tissue matrix. To search for evidence that hyperlipidemia was causing endothelial injury, Ross examined endothelial integrity in the hyperlipidemic animals using special staining techniques. In all of the hyperlipidemic animals, there was focal loss of endothelial cells accounting for approximately 5% of the aorto-iliac endothelial surface. In some areas, the longitudinal shape of the endothelial cells had changed to a polyhedral or round configuration, indicating abnormal endothelial regeneration. Since platelet-derived factors were believed to be critical to the growth of vascular lesions following endothelial injury, measures of platelet activity were performed. Ross and Harker found that platelet survival was reduced from 8 days to 5.8 days in animals that were hyperlipidemic for more than 6 months. To determine whether the reduced platelet survival was due to increased platelet consumption at exposed endothelial surfaces or secondary to a direct effect of hyperlipidemia, labelled platelets were transfused from a normolipidemic animal into a hyperlipidemic 4

17 Classic Papers in Coronary Angioplasty animal and from a hyperlipidemic animal to a normolipidemic animal. Platelets from the hyperlipidemic animals survived normally in the normolipidemic animals while survival of platelets from the normolipidemic animals was reduced in the hyperlipidemic animals. The authors concluded that reduced platelet survival was due to increased platelet consumption on exposed subendothelium and they went on to demonstrate a correlation between the amount of endothelium removed and platelet survival. Citation Count 543 Key message Hyperlipidemia is sufficient to cause endothelial injury, initiation, and growth of atherosclerotic plaques. This study also demonstrated the effect of the hyperlipidemic environment on the progression of vascular lesions following mechanical injury. 5

18 Vascular biology of atherosclerosis Strengths In a primate model, the authors clearly demonstrated a critical direct role for a hypercholesterolaemic diet in the initiation and progression of atherosclerosis. The implications of these studies were that understanding and targeting factors involved in lipid metabolism could lead to therapeutic breakthroughs. Weaknesses The hypothesis that platelets or platelet products were essential to growth of the atherosclerotic plaque was not adequately tested. Thus the role of platelets in atherosclerotic lesion growth, based on in vitro vascular smooth muscle cell culture experiments and the transfusion experiments, was probably overemphasized. 6

19 Classic Papers in Coronary Angioplasty Title 3 The role of the monocyte in atherogenesis: I. Transition of blood-borne monocytes into foam cells in fatty lesions II. Migration of foam cells from atherosclerotic lesions Author Gerrity RG Reference Am J Pathol 1981; 103: , Abstract Paper I: In a previous publication the author and his co-workers demonstrated that atherosclerotic lesion development in the aorta of hypercholesterolemic pigs was preceded by intimal penetration of blood-borne mononuclear cells, and that medial smooth muscle cells were not involved in the formation of early fatty lesions in this model. The current study shows that aortic arch lesions do not progress beyond the fatty cell lesion stage for up to 30 weeks of a moderate cholesterol/lard diet, although they become more extensive in area. Mononuclear cells were found adherent to the endothelium, in endothelial junctions, and in the intima during this period, and were ultrastructurally identified as monocytes by the presence of peroxidase-positive granules (peroxisomes) in their cytoplasm. In addition, lesion areas with nonspecific esterase activity correlated well with Sudan IV staining. Intimal monocytes and altered intimal monocytes with an enlarged cytoplasm and containing a few lipid droplets were both shown to be phagocytic by their uptake of ferritin, which had penetrated the intima after intravenous injection. Circulating monocytes and those adherent to the endothelial surface did not contain ferritin in these animals. The results indicate that blood mononuclear cells associated with lesion formation in this model are, in fact, monocytes, which subsequently undergo transformation into macrophage foam cells in fatty streak lesions. The absence of medial cell involvement indicates that monocytes are the major foam cell precursor in these lesions. Paper II: A defined role in the atherogenic sequence is proposed for the circulating monocyte. The author has been able to demonstrate a monocyte clearance system in which large numbers of circulating monocytes invade the intima of lesion-prone areas in arteries, become phagocytic, and accumulate lipid. A fatty cell lesion results. Once lipid-laden, foam cells migrate back into the bloodstream by crossing the arterial endothelium. The ratio of penetrating monocytes to emerging foam cells decreases as fatty cell lesions develop until a one-to-one ratio is achieved in late fatty cell lesions, which do not progress further. Advanced fibroatherosclerotic plaques in the same animals do not show the same characteristics and have smooth muscle cell involvement. It would appear that advancement of the lesion is at least partially a result of failure of the monocyte clearance system to remove sufficient lipid. The invasion of monocytes and endothelial damage caused by foam cell clearance may, in late fatty lesions, contribute to plaque evolution by introducing growth factors from macrophages and platelets and allowing greater lipid influx. Elucidation of this system was facilitated by the examination of vessels from diet initiation onwards and by the observation of late nonprogressing fatty cell lesions. It is possible that this 7

20 Vascular biology of atherosclerosis (a) (b) (c) (d) Figure 1 (a) TEM of monocyte (M) trapped in junction of endothelium (E) from arch area of 12-week pig. Main body and nucleus of cell are in the lumen (Lu), with cellular extensions (arrows) spread below endothelium (uranyl acetate, lead citrate, 12,400). (b) Monocyte (M) beneath endothelium (E) in a 15-week arch lesion from a pig injected with ferritin 15 min before death. Ferritin can be seen in phagocytotic vacuoles (arrows), one of which is open to the intimal space. Inset shows ferritin in vacuole in squared area (unstained, 15,500; inset, 61,000). (c) SEM of monocyte (M) adherent to endothelium (E). Cytoplasmic extensions from monocyte can be seen to indent endothelial plasma membrane (arrows); (d) TEM of hypertrophied monocyte (HM) beneath endothelium (E) in 30-week abdominal lesion. Peroxidase-positive granules (arrows) can be seen in the cytoplasm (uranly acetate, lead citrate; peroxidase-reacted, 12,500). Summary system exists in other models but has been overlooked by a predilection for the study of advanced lesions that prevails in the literature. In this paper, parts I and II, Ross Gerrity described the progression of atherosclerotic lesions in a hypercholesterolaemic pig model. At the time of these studies the predominant cell type in growing 8

21 Classic Papers in Coronary Angioplasty atherosclerotic plaques was controversial with much emphasis placed on the vascular smooth muscle cell. Although other authors had described monocytes in atherosclerotic lesions, this paper carefully studies the progression of atheroma at different time points and characterizes the lesion composition. Yorkshire pigs were fed a normal chow or high-fat chow and sacrificed at 6, 12, 15 and 30 weeks after the initiation of diet. At 15 weeks following high-fat chow, lesions were always of a foam cell nature, confined to the intima, with no evidence of medial cell involvement in the intima or engorgement of smooth muscle cells with lipid. Monocytes were identified using various histological criteria. At 30 weeks following high-fat diet, fibrous lesions were described as fibrous caps overlying necrotic lipid cores. Gerrity hypothesized, based on this and earlier studies from his group, that blood-derived monocytes adhere to the endothelium, which is not necessarily associated with endothelial damage, and then penetrate into the intima. He also demonstrated that intimal monocytes are phagocytic at a time that lipid droplets appear in their cytoplasm. Thus, early lesions of atherosclerosis consist of monocyte foam cells that actively accumulate lipid and may be a source of a growth factor. The author also suggests a role of the monocyte in lesion lipid efflux. Citation Count Paper I: 1132, Paper II: 354 Key message Blood-derived monocytes are the predominant cell type in early atherosclerotic lesions. This is a fundamental underpinning to our current understanding of atherosclerosis as an inflammatory disease. Strengths A detailed histological examination with elegant electron micrographs of lesions at various stages of development using a hypercholesterolaemic pig model. Weaknesses Primarily observational, descriptive data. 9

22 Vascular biology of atherosclerosis Title 4 A receptor-mediated pathway for cholesterol homoeostasis Author Brown MS, Goldstein JL Reference Abstract Science 1986; 232: Not available. Summary Animal models of hypercholesterolaemia, as described in the preceding papers, as well as humans with familial hypercholesterolaemia indicated an enormous potential for the role of cholesterol metabolism in atherosclerosis. Brown and Goldstein embarked on their studies of cholesterol homoeostasis in 1972, in an attempt to understand the human genetic disease, familial hypercholesterolaemia (FH), a disease characterized by marked hypercholesterolaemia with premature myocardial infarction. FH heterozygotes, carrying a single copy of a mutant lowdensity lipoprotein (LDL) receptor gene, are common accounting for about 1 in 500 persons. LDL levels are approximately doubled in these individuals and myocardial infarctions begin to occur in the 30 s and 40 s. The homozygous FH frequency is about 1 in a million persons and is characterized by a 6 10-fold elevation in LDL and myocardial infarctions beginning in childhood. The existence of the homozygous state facilitated the discoveries of Brown and Goldstein as they could study effects of the mutant gene without confounding effects of the normal gene. The authors demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate limiting step in cholesterol biosynthesis, was subject to negative regulation in cultured fibroblasts, i.e. activity was upregulated when lipoproteins were removed from the culture media and suppressed when they were added. This suppression only occurred with LDL, and at relatively low concentrations, suggesting the possibility of a high-affinity receptor. Homozygous FH cells had HMG CoA reductase activities that were extremely high and were not subject to regulation by LDL in the medium. This suggested that there may be a defect in the HMG CoA reductase gene that rendered it s expression resistant to LDL. However, when cholesterol was dissolved in ethanol so that it could enter cells passively, suppression of HMG CoA reductase activity was achieved. These studies supported the hypothesis of a cell surface lipid receptor. This was proven with radiolabelled LDL, which bound to normal fibroblasts and not FH-homozygous fibroblasts. The investigators and associates went on to demonstrate that cholesterol generated from LDL within the lysosome was the second messenger responsible for suppressing HMG CoA reductase activity. Cholesterol acts at several levels to influence lipid homoeostasis including suppression of transcription of the HMG CoA reductase gene and acceleration of the degradation of the enzyme protein. The LDL-derived cholesterol also activates a cholesterol-esterifying enzyme, acyl-coa: cholesterol acyltransferase (ACAT), and suppresses the synthesis of LDL receptors by lowering the concentration of LDL receptor mrna. Thus, the cells can adjust the number of LDL receptors to provide adequate cholesterol for metabolic needs without causing cholesterol overaccumulation. At least 10 different mutations in the LDL receptor were identified by structural criteria and separated into 4 classes. These included mutations that lead to the absence of LDL receptors, 10

23 Classic Papers in Coronary Angioplasty 1. HMG CoA reductase LDL receptors 2. ACAT LDL Cholesteryl linoleate Protein Cholesterol Cholesteryl linoleate 3. Amino acids LDL receptors LDL binding Internalization Lysosomal hydrolysis Regulatory actions Figure 1 Sequential steps in the LDL receptor pathway of mammalian cells. Vertical arrows indicate the direction of regulatory effects. mutations that alter receptor transport from the ER to the Golgi, mutations that lead to abnormal binding to LDL and mutations leading to failure of LDL receptors to cluster in coated pits. Citation Count 2878 Key message Cholesterol homoeostasis is under exquisite control by a complex cellular pathway initiated by a high-affinity LDL cell surface receptor. Strengths The pathways elucidated by Brown and Goldstein not only explained the cause of many cases of hyperlipidemia but have also served as the foundation for pharmaceutical discovery platforms aimed at prevention of coronary artery disease. Weaknesses None. 11

24 Vascular biology of atherosclerosis Title 5 Author Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis Falk E Reference Abstract Summary Br Heart J 1983; 50: Ruptured atheromatous plaques were identified by step-sectioning technique as responsible for 40 of 51 recent coronary artery thrombi and 63 larger intimal haemorrhages. The degree of preexisting luminal narrowing at the site of rupture was decisive for whether plaque rupture caused occlusive thrombosis or just intimal haemorrhage. If the pre-existing stenosis was greater than 90% (histologically determined) then plaque rupture nearly always caused occlusive thrombosis. Clearly indicating the primary role of plaque rupture in thrombus formation were the frequent finding of plaque fragments deeply buried in the centre of the thrombus and the nature of the thrombus at the site of rupture where it consisted predominantly of platelets. Thus, a severe chronic stenosis seems to be a prerequisite for occlusive thrombus formation, but the thrombotic process itself is triggered by an acute intimal lesion. At the time of this paper, there was general agreement that clinical complications of atherosclerotic vascular disease, such as myocardial infarction and stroke were due to thrombotic vascular occlusion. However, the underlying substrate or triggering mechanism for these thrombotic events was not well understood. In this paper, Erling Falk studied 47 patients with suspected fatal ischaemic heart disease. Postmortem angiography was performed along with detailed histological examination of the coronary arteries. Forty of 103 sites of plaque rupture identified were associated with significant recent luminal thrombosis, 95% of which were occlusive. In general, the greater the degree of underlying stenosis, the higher the risk of occlusive thrombosis. An underlying ruptured atheromatous plaque was identified in 82% of recently thrombosed coronary segments. No obstructions due to intimal haematoma (haemorrhage) were identified in this study. Citation Count 548 Key message Strengths Thrombotic complications of coronary atherosclerosis are due to plaque rupture. A combined postmortem angiographical and coronary histological study with excellent histological examples of plaque rupture and occlusive thrombosis. 12

25 Classic Papers in Coronary Angioplasty (c) (a) 1 4 (d) (b) (e) Figure 1 A case clearly illustrating the primary role of plaque rupture in the pathogenesis of occlusive coronary thrombosis. (a) Postmortem angiogram showing total occlusion of the left anterior descending artery at the arrow (original magnification 0.6). (b) The thrombosed vascular segment is cut transversely at 2 3 mm intervals (white contrast medium in the non-thrombosed vascular lumen). Section no. 2 shows the disrupted fibrous cap (arrow), and it is seen that both a cap fragment and fatty atheromatous substance have been lost. The thrombotic process has started at the site of rupture (Section no. 2 4) and attains its occlusive property just distal to the rupture (Section no. 5). (c) Microscopy of Section no. 4 shows direct communication between the vascular lumen and the atheromatous gruel (big arrow) and mural thrombosis at one of the free edges of the torn fibrous cap which projects into the lumen (small arrow) (original magnification 13). (d) Microscopy of Section no. 5 shows a detached fragment of the fibrous cap (small asterisk) and atheromatous material with cholesterol clefts (big asterisk) intimately mixed with aggregated platelets in the vascular lumen (original magnification 15). (e) Histological section from the perfusion area of the left anterior descending artery showing an intramyocardial artery occluded by a platelet embolus containing atheromatous plaque material with cholesterol clefts from the ruptured plaque proximal in the artery (original magnification 33). Weaknesses A relatively small series. Thrombosis occurring at sites of less severe atherosclerotic lesions may have been less stable and more likely to be dislodged or lysed by the time histological examination was performed. Thus the conclusion that occlusive thrombosis occurs only at sites of severe underlying stenosis may have been overstated. 13

26 Vascular biology of atherosclerosis Title 6 Author Compensatory enlargement of human atherosclerotic coronary arteries Reference Abstract Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ N Engl J Med 1987; 316: Whether human coronary arteries undergo compensatory enlargement in the presence of coronary disease has not been clarified. We studied histologic sections of the left main coronary artery in 136 hearts obtained at autopsy to determine whether atherosclerotic human coronary arteries enlarge in relation to plaque (lesion) area and to assess whether such enlargement preserves the cross-sectional area of the lumen. The area circumscribed by the internal elastic lamina (internal elastic lamina area) was taken as a measure of the area of the arterial lumen if no plaque had been present. The internal elastic lamina area correlated directly with the area of the lesion (r 0.44, p less than 0.001), suggesting that coronary arteries enlarge as lesion area increases. Regression analysis yielded the following equation: Internal elastic lamina area (lesion area) (age) (heart weight). The correlation coefficient for the lesion area was significant ( p less than 0.001), whereas the correlation coefficients for age and heart weight were not. The lumen area did not decrease in relation to the percentage of Figure 1 Photograph of a cross section of a typical left main coronary artery with an advanced atherosclerotic plaque (left panel), and a corresponding contour tracing of the artery (right panel). The lumen (Lu) is clearly demarcated by the intimal surface. The internal elastic lamina (arrowheads) is readily discernible for most of the vessel circumference and almost always beneath the plaque as well, despite underlying atrophy of the media where the plaque and arterial wall tend to bulge outward (between the arrows). The area occupied by the lesion (Le) is shaded. The cross-sectional stenosis is defined as the extent to which the area encompassed by the internal elastic lamina (i.e. the potential lumen area if no plaque were present) is occupied by the lesion (percentage of stenosis, lesion area/internal elastic area 100). In this vessel, the cross-sectional stenosis is 46% (magnification, 7.4). 14

27 Classic Papers in Coronary Angioplasty Summary stenosis (lesion area/internal elastic lamina area 100) for values between zero and 40 percent but did diminish markedly and in close relation to the percentage of stenosis for values above 40 percent (r 0.73, p less than 0.001). We conclude that human coronary arteries enlarge in relation to plaque area and that functionally important lumen stenosis may be delayed until the lesion occupies 40 percent of the internal elastic lamina area. The preservation of a nearly normal lumen cross-sectional area despite the presence of a large plaque should be taken into account in evaluating atherosclerotic disease with use of coronary angiography. The purpose of this study was to determine whether human coronary arteries undergo compensatory enlargement in the presence of atherosclerosis. Histological analysis of left main coronary arteries was performed on 136 human hearts. Among the specimens there was a wide range of lumen area and lesion sizes. Comparisons between specimens revealed that lesion area increased with age at a rate of 0.08 mm 2 per year and lumen area decreased at a rate of 0.37 mm 2 for each mm 2 increase in lesion area. The internal elastic lamina area increased at a rate of 0.60 mm 2 for each mm 2 increase in lesion area. Thus, the vessel wall area increased with growth of the lesion, a relationship independent of age and heart weight. When a plot was made of lumen area vs. percentage of stenosis, there was no relationship of lumen area with stenosis up to 40% stenosis. However, as the stenosis increased above 40%, there was a marked reduction of lumen area. Thus, during early stages of plaque growth there is preservation of lumen size accomplished by expansion of the arterial wall. Citation Count 1103 Key message Strengths Arterial remodelling occurs with growth of atherosclerotic plaques. Coronary angiograms that use contrast agents to opacify the arterial lumen may markedly underestimate atherosclerotic burden. This was the first clear demonstration of vascular remodelling in humans. The implications of the concept of vascular remodelling with the accompanying necessary matrix turnover have generated an entire new field of study in vascular biology. Weaknesses This was not a longitudinal study. Thus a diverse population with varying risk factors could have affected the results. Only the left main artery was studied. Different results may occur in smaller arteries. 15

28 Vascular biology of atherosclerosis Title 7 Author Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults Stary HC Reference Arteriosclerosis 1989; 9(Supp): I-19 I-32 Abstract In an autopsy study of the evolution of atherosclerotic lesions in young people, we obtained the coronary arteries and aortas of 1160 male and female subjects who died between full-term birth and age 29 years. In this article, we report the light and electron microscopic observations of the coronary arteries of 565 of these subjects in which we fixed the coronary arteries by perfusion with glutaraldehyde under pressure. From birth, the intima was always thicker in the half of the coronary artery circumference opposite the flow-divider wall of a bifurcation (eccentric thickening). In cases where we found lipid in the intima, there was always more in eccentric thickening. Isolated macrophage foam cells in the intima of infants were the earliest sign of lipid retention. These cells occurred in 45% of infants in the first 8 months of life but decreased subsequently. At puberty, more substantial accumulations of macrophage foam cells reappeared in more children. Foam cells were now accompanied by lipid droplets in existing smooth muscle cells and by thinly scattered extracellular lipid. Sixty-five percent of children between ages 12 and 14 years had such lesions. An additional 8% of children had progressed beyond this early stage and had developed advanced preatheroma or atheroma stages. Such advanced lesions, located only in areas of eccentric thickening, were characterized by the addition of massive extracellular lipid that displaced normal cells and matrix and, thus, damaged and weakened the arterial wall. Summary This paper describes a large series of coronary histology data from 565 human subjects who died between full-term birth and 29 years of age. At the time of this study, there was controversy regarding the extent of atherosclerosis in the young and at what age dietary interventions to reduce atherosclerosis should be instituted. The left main, proximal left anterior descending and proximal circumflex arteries were analysed. Based on the findings of this series, a classification system was developed to characterize development of atherosclerotic lesions. Type 1 lesions consist of isolated macrophage foam cells in the proteoglycan layer with no extracellular lipid or vascular smooth muscle cells. These lesions were seen in some infants as early as the first week of life and appeared to be decreased after the first year. Type II lesions are fatty streaks composed of layers of cells with lipid droplet-inclusions. More macrophages are present than type I lesions. These lesions were noted beginning from late in the first decade of life. A type III lesion is a preatheroma that is intermediate between the fatty streak and the atheroma. These lesions contain all the components of a fatty streak with a marked increase in the number of extracellular lipid particles. They appear grossly as a small white elevation and are typically seen beginning in the mid second decade of life. Type IV lesions were seen in subjects beginning at the end of puberty 16

29 Classic Papers in Coronary Angioplasty (a) (b) Figure 1 (a) Outer wall at the level of the left main coronary artery just proximal to the main bifurcation. Extracellular lipid (arrows) is abundant and concentrated in the musculoelastic layer (me) of eccentric thickening and displaces some structural intimal smooth cells. Macrophage foam cells (fc) and lipid-laden smooth muscle cells are layered above the extracellular aggregates. Such lipid deposits were classified as preatheroma (type III lesion). From a 25-year-old white man who died in a motorcycle accident. (b) Outer wall at the LAD 1 level with eccentric thickening now metamorphosed into a lesion classified as atheroma (type IV lesion). Extracellular lipid now forms a confluent core in the musculoelastic layer of eccentric thickening. While this lipid deposit thickens the intima, it also weakens the wall as it displaces structural smooth muscle cells. From a 19-year-old white man who committed suicide. Pgc: proteoglycan intima; M: media; and A: adventitia. and consisted of large lipid or necrotic cores. Macrophage foam cells were seen bordering the lipid core on the luminal aspect of the lesion. A type V lesion is a fibroatheroma in which the proteoglycan layer has changed in composition with an increased number of smooth muscle cells embedded in a dense matrix of collagen and capillaries. This layer of smoothmuscle cells becomes a fibrous cap. These lesions were typically seen beginning in the mid third decade of life. Stary described the frequency of the various lesions at different ages and this data established that vascular lesions are quite common even in young children. This study raised many questions regarding the sequence of events that would lead to a fatty streak at such young ages and subsequent progression of lesion complexity. Citation Count 15 Key message Vascular lesions consistent with early atherosclerosis begin very early in life and appear to progress in complexity through a series of defined stages. 17

30 Vascular biology of atherosclerosis Strengths Detailed, extensive histological examination of very young human subjects. The idea that lesion growth occurs through predictable stages representing various cellular and molecular events set a framework for future investigations. Weaknesses Descriptive study. Although this classification system has been useful to facilitate our understanding of atherogenesis, the staging of atherosclerotic lesions may be an oversimplification of the underlying pathophysiology and not take into account the marked heterogeneity of atherogenesis between individuals. 18

31 Classic Papers in Coronary Angioplasty Title 8 Author Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J Reference Br Heart J 1993; 69: Abstract OBJECTIVE: To assess the size of the lipid pool and the number of smooth muscle cells and monocyte/macrophages in human aortic plaques that were intact and to compare the results with those in aortic plaques undergoing ulceration and thrombosis. DESIGN: The lipid pool was measured as a percentage of the total cross sectional area of the plaque. Immunohistochemistry was used to identify cell types (monocytes/macrophages (M phi) by EBM11 and HAM56, smooth muscle cells by alpha actin). The area of the tissue occupied by each cell type was measured by quantitative microscopy in the peripheral (shoulder) area of the plaque and the plaque cap. Absolute counts of each cell type were expressed as the ratio of SMC:M phi. MATERIAL: Aortas were obtained at necropsy from men aged less than 69 years who died suddenly (within 6 hours of the onset of symptoms) of ischaemic heart disease. 155 plaques from 13 aortas were studied. Four aortas showed intact plaques only (group A, n 31). Nine aortas showed both intact plaques (group B, n 79) and plaques that were undergoing thrombosis (group C, n 45). RESULTS: In 41 (91.1%) of the 45 plaques undergoing thrombosis (group C) lipid pools occupied more than 40% of the cross sectional area of the plaque. Only 12 (10.9%) of the 110 intact plaques (groups Figure 1 Contrast between an intact advanced aortic plaque (left), in which the surface is opaque and smooth, and early ulceration (right), in which thrombus has formed over the plaques. However, a large part of the plaque is not covered by thrombus. 19