High-Risk Atherosclerotic Plaques: Mechanisms, Imaging, Models, and Therapy

212 Pages·2004·8.149 MB·English

by  Levon Michael Khachigian

HIGH-RISK
ATHEROSCLEROTIC
PLAQUES
Mechanisms, Imaging,
Models, and Therapy
© 2005 by CRC Press
HIGH-RISK
ATHEROSCLEROTIC
PLAQUES
Mechanisms, Imaging,
Models, and Therapy
E
DITED BY
Levon Michael Khachigian
CRC PR ESS
Boca Raton London New York Washington, D.C.
© 2005 by CRC Press
3028_C000.fm Page 4 Tuesday, October 12, 2004 8:17 AM
Library of Congress Cataloging-in-Publication Data
High-risk atherosclerotic plaques: mechanisms, imaging, models, and therapy / edited by
Levon Khachigian.
p. ; cm.
Includes bibliographical references and index.
ISBN 0-8493-3028-9 (alk. paper)
1. Atherosclerotic plaque. I. Khachigian, Levon.
[DNLM: 1. Arteriosclerosis—diagnosis. 2. Arteriosclerosis—therapy. 3. Diagnostic
Imaging. 4. Heart Diseases—etiology. WG 550 H638 2004]
RC692.H535 2004
616.1'36—dc22
2004054450
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© 2005 by CRC Press
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Preface
Instability of atherosclerotic plaques is the primary cause of acute coronary syn-
dromes comprising unstable angina, myocardial infarction, and sudden death. “Vul-
nerable” or “high-risk” plaques are associated with inflammation, apoptosis, rupture,
and thrombosis. Greater understanding of the cellular and molecular pathogenesis
of high risk plaques, together with our ability to visualize and diagnose these lesions,
will lead to the more effective management of acute coronary syndromes.
This book brings together timely, authoritative, in-depth reviews by renowned
international cardiologists and scientists covering the definition, structure, cellular
and molecular mechanisms of high-risk plaque development, animal models of
vulnerable plaque, plaque imaging, and current and future therapies.
Prediman Shah (Chapter 1) and Martin Bennett (Chapter 2) describe the cellular
and molecular mechanisms of plaque vulnerability, with emphasis on plaque size,
cellular composition, thrombosis, and the critical role of apoptosis. Harry Lowe et al.
(Chapter 3) discuss the advantages and limitations of large and small animal models
of vulnerable plaques. Johannes Schaar et al. (Chapter 4) provide an overview of
current and future imaging and diagnostic approaches including angiograms, angios-
copy, optical coherence tomography, intravascular ultrasound, palpography, ther-
mography, Raman spectroscopy, near-infrared spectroscopy, and magnetic resonance
imaging.
Paul Schoenhagen et al. (Chapter 5) focus on intravascular ultrasound. Fabian
Moselewski et al. (Chapter 6) discuss optimal coherence tomography. Stephen
Worthley and Juan Badimon (Chapter 7) describe magnetic resonance imaging. John
Davies et al. (Chapter 8) devote their work to single photon emission computed
tomography and positron emission tomography. Konstantinos Toutouzas et al.
(Chapter 9) discuss catheter-based techniques of coronary thermography. Finally,
Len Kritharides et al. (Chapter 10) review current and future local and systemic
strategies for the therapeutic management of vulnerable plaques.
I am confident this book will serve as a valuable practical and informative
resource for vascular biologists, interventionalists, cardiologists, and radiologists
alike.
Levon Khachigian
Sydney, Australia
© 2005 by CRC Press
3028_C000.fm Page 7 Tuesday, October 12, 2004 8:17 AM
About the Editor
Professor Levon Michael Khachigian (BSc(Hons), PhD, DSc)
is a Principal Research Fellow of the National Health and Med-
ical Research Council of Australia and Head of the Transcription
and Gene Targeting Laboratory at The Centre for Vascular
Research, University of New South Wales and Prince of Wales
Hospital, Sydney.
His research, encompassed in over 100 journal articles and
book chapters, has greatly increased our understanding of the
fundamental transcriptional mechanisms that led to the inappro-
priate expression of harmful genes in cells of the artery wall. It has also led to his
generation of novel DNA-based drugs that block arterial renarrowing after balloon
angioplasty in a variety of experimental models. More recently, he has been unrav-
elling the mechanisms behind tumor growth control and other neovascular pathol-
ogies by inhibiting angiogenesis.
Professor Khachigian has been a major contributor to the broader workings of
science on matters of policy, advocacy, consultancy, peer-review, mentorship, and
societal service. For example, he is National Executive Director and President-Elect
of the Australian Society for Medical Research, and Immediate-Past President of
the Australian Vascular Biology Society. He has served on numerous grant review,
fellowship, and policy formulation panels for the National Health and Medical
Research Council of Australia and the National Heart Foundation of Australia. He
sits on the editorial boards of five international journals.
Professor Khachigian has won many highly competitive awards for innovative
research including the Commonwealth Health Minister’s Award for Excellence in
Health and Medical Research, the Gottschalk Award from the Australian Academy
of Science, Eureka Prize for Scientific Research from the Australian Museum, RT
Hall Prize from the Cardiac Society of Australia and New Zealand, AMGEN Medical
Researcher Award, Eppendorf Award for the Young Australian Researcher, Quantum
Scientific Research Award, Young Tall Poppy Award, and numerous named research
awards for research excellence from the Heart Foundation of Australia.
Professor Khachigian received his BSc with first-class honors in biochemistry,
and PhD in cell and molecular biology from the University of New South Wales,
then studied transcriptional control in the Department of Pathology, Brigham and
Women’s Hospital, Harvard Medical School. In 2004, he was awarded a DSc in
vascular pathobiology and translational research from the University of New South
Wales.
© 2005 by CRC Press
3028_C000.fm Page 9 Tuesday, October 12, 2004 8:17 AM
Contributors
Stephan Achenbach, MD Tim Fryer, PhD
Massachusetts General Hospital and Addenbrooke’s Hospital
Harvard Medical School Cambridge University
Boston, Massachusetts Cambridge, United Kingdom
Chourmouzios A. Arampatzis, MD, Frank J. Gijsen, PhD
PhD Erasmus Medical Center
Erasmus Medical Center Rotterdam, The Netherlands
Rotterdam, The Netherlands
Jonathan Gillard, MD, FRCP
Addenbrooke’s Hospital
Juan J. Badimon, PhD, FACC
Cambridge University
Mount Sinai School of Medicine
Cambridge, United Kingdom
New York, New York
Ik-Kyung Jang, MD, PhD
Martin R. Bennett, BCh, PhD, Massachusetts General Hospital and
FRCP Harvard Medical School
Addenbrooke’s Hospital Boston, Massachusetts
Cambridge University
Cambridge, United Kingdon Jason L. Johnson, MSc
Bristol Heart Institute
David Brieger, PhD, FRACP University of Bristol
Concord Hospital Bristol, United Kingdom
University of Sydney
Sydney, Australia Levon M. Khachigian, PhD, DSc
Centre for Vascular Research
John Davies, MBBS, MRCP University of New South Wales
Addenbrooke’s Hospital Sydney, Australia
Cambridge University
Leonard Kritharides, PhD, FRACP,
Cambridge, United Kingdom
FAHA
Concord Hospital
Pim J. de Feyter, MD, PhD
University of Sydney and
Erasmus Medical Center
Centre for Vascular Research
Rotterdam, The Netherlands
University of New South Wales
Sydney, Australia
S. Benedict Freedman, PhD, FRACP,
FACC Harry C. Lowe, FRACP, PhD, FACC
Concord Hospital Centre for Vascular Research
University of Sydney University of New South Wales
Sydney, Australia Sydney, Australia
© 2005 by CRC Press
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Fabian Moselewski, MD Christodoulos Stefanadis, MD,
Massachusetts General Hospital and PhD
Harvard Medical School Hippokration Hospital and
Boston, Massachusetts Athens Medical School
Athens, Greece
Steven E. Nissen, MD, FACC
The Cleveland Clinic Foundation Konstantinos Toutouzas, MD
Cleveland, Ohio Hippokration Hospital and
Athens Medical School
Evelyn Regar, MD, PhD Athens, Greece
Erasmus Medical Center
Rotterdam, The Netherlands Sophia Vaina, MD
Hippokration Hospital and
James Rudd, PhD, MRCP Athens Medical School
Addenbrooke’s Hospital Athens, Greece
Cambridge University
Cambridge, United Kingdom A.F.W. van der Steen, PhD
Erasmus Medical Center
Johannes A. Schaar, MD, PhD Rotterdam, The Netherlands
Erasmus Medical Center
Rotterdam, The Netherlands Arjen R.A. van der Ven, MD
Erasmus Medical Center
Paul Schoenhagen, MD, FAHA Rotterdam, The Netherlands
The Cleveland Clinic Foundation
Cleveland, Ohio Peter Weissberg, MD, FRCP,
FMedSci
Patrick W. Serruys, MD, PhD Addenbrooke’s Hospital
Erasmus Medical Center Cambridge University
Rotterdam, The Netherlands Cambridge, United Kingdom
Prediman K. Shah, MD Jolanda J. Wentzel, PhD
Cedars Sinai Medical Center and Erasmus Medical Center
UCLA School of Medicine Rotterdam, The Netherlands
Los Angeles, California
Richard D. White, MD, FACC,
Cornelis J. Slager, PhD FAHA
Erasmus Medical Center The Cleveland Clinic Foundation
Rotterdam, The Netherlands Cleveland, Ohio
Stephen G. Worthley, MBBS, PhD, FRACP
Wakefield Hospital
Adelaide, South Australia
© 2005 by CRC Press
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About the Senior Authors
Juan J. Badimon is a professor of medicine and director of the Cardiovascular
Biology Research Laboratory at the Cardiovascular Institute of the Mount Sinai
School of Medicine in New York City. He earned a specialty degree in pharmacology
from the School of Medicine of the University of Barcelona and the High Council
for Scientific Research of Spain and a Ph.D. also from the University of Barcelona.
He completed a postdoctoral research fellowship at the Atherosclerosis Research
Unit of the Mayo Clinic and Foundation in Rochester, Minnesota. In 1983, he moved
to Mount Sinai. From 1991 through 1995, he worked at the Cardiac Unit of Mas-
sachusetts General Hospital in Boston, after which he returned to Mount Sinai. Dr.
Badimon’s research focuses on atherothrombotic disease, cardiovascular diseases,
restenosis, the use of MRI for plaque characterization, and assessing the effectiveness
of hypolipidemic regimens. A more recent interest is the role of tissue factor in
atherothrombosis and its potential role as new therapeutic target in antithrombotic
therapy. Dr. Badimon was designated Professor Honoris Causa by the Catholic
University of Buenos Aires, Argentina in 2001. He is a fellow of the American
College of Cardiology and the American Heart Association and an associate editor
of Vessels and Thrombosis and Haemostasis. He sits on the editorial board of the
Journal of the American College of Cardiology and the scientific board of the Spanish
Familial Hypercholesterolemia Foundation. Dr. Badimon is an ad hoc reviewer for
several major publications.
Martin R. Bennett trained in cardiology in Birmingham and Cambridge in the
United Kingdom. His research training included working with Gerard Evan and
earning a Ph.D. at the Imperial Cancer Research Fund Laboratories, London, fol-
lowed by a postdoctoral position in Seattle, Washington, working with Steve
Schwartz. He currently holds the British Heart Foundation Chair of Cardiovascular
Sciences at the University of Cambridge, and is a consultant cardiologist. His major
research interests are the vascular biology of atherosclerosis, with focus on the
regulation of vascular smooth muscle cell apoptosis and cell proliferation. Dr. Ben-
nett is currently on the editorial boards of Circulation Research, Heart, and Arte-
riosclerosis, Thrombosis, and Vascular Biology.
John Davies graduated in Medicine in 1997 from Guy’s Hospital, London. He
completed his general medical training in hospitals around London, including Guy’s
and St George’s. He then pursued training in cardiology as a specialist registrar at
Middlesex Hospital. After 2 years of clinical cardiology training, Dr. Davies moved
to Cambridge University to undertake a Ph.D. program as a British Heart Foundation
Research Fellow. Dr Davies’ research interest focuses on the biology of athero-
sclerosis, in particular the imaging and quantification of inflammation within athero-
sclerotic plaques using positron emission tomography.
© 2005 by CRC Press
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Ik-Kyung Jang is an interventional cardiologist at Massachusetts General Hos-
pital and associate professor of medicine at Harvard Medical School. He currently
serves as a director of the Center for Cardiovascular Clinical Research and co-
director of Cardiology Laboratory of Integrative Physiology and Imaging at the
Massachusetts General Hospital.
Leonard Kritharides is a consultant cardiologist at Concord Hospital, an asso-
ciate professor of medicine at the University of Sydney, and co-leader of the Mac-
rophage Biology Group at the Centre for Vascular Research, University of New
South Wales, Australia. He graduated from the University of Melbourne in 1984,
completed physician training at the Royal Melbourne Hospital in 1990, and com-
pleted a Ph.D. program and postdoctoral studies on macrophage cholesterol metab-
olism and lipoprotein oxidation at the Heart Research Institute in Sydney. His major
research interests are in clinical cardiology and in the cell biology and biochemistry
of atherosclerosis.
Harry C. Lowe is a cardiologist at Concord Hospital, a senior lecturer in
medicine at the University of Sydney. He is also a National Health and Medical
Research Council of Australia (NHMRC) C.J. Martin Research Fellow at the Centre
for Vascular Research (CVR) of the University of New South Wales, Australia.
Following cardiology training in New Zealand and at St Vincent’s Hospital in
Sydney, Dr. Lowe completed a Ph.D. program at the CVR, investigating gene
modification of the response to vascular injury. He then pursued postdoctoral studies
and interventional cardiology training at Massachusetts General Hospital and Har-
vard Medical School. His major research interests include the investigation of animal
models of cardiovascular disease and clinical cardiology.
Fabian Moselewski is a research fellow at the Division of Cardiology of Mas-
sachusetts General Hospital and at CIMIT — the vulnerable plaque program of the
Department of Radiology at Massachusetts General Hospital. His research focuses
on noninvasive cardiac imaging by multidetector CT and coronary calcium screen-
ing, as well as invasive modalities such as IVUS and optical coherence tomography
with a special emphasis on the detection of vulnerable plaques.
Steven E. Nissen is medical director of The Cleveland Clinic’s Cardiovascular
Coordinating Center. Professor Nissen has authored more than 200 journal articles,
book chapters, and CD-ROMs, mostly in the field of cardiovascular imaging. He
was one of the pioneers in the development of intravascular ultrasound (IVUS), and
his research during the past decade has focused on this imaging technique. In
particular, he has examined the discrepancies between angiography and IVUS in the
assessment of coronary atherosclerosis, pointing out the limitations of radiographic
methods. Dr Nissen currently serves as the principal investigator for several large
IVUS studies of atherosclerosis regression and progression. He is also a member of
the Cardiorenal Advisory Panel of the U.S. Food and Drug Administration.
Johannes A. Schaar earned a Ph.D. (cum laude) in Wuerzburg and also studied
in St. Louis and New York. He worked at the University in Essen under the men-
torship of Professor Raimund Erbel. He currently conducts research at the Erasmus
Medical Center in Rotterdam with Professor Anton van der Steen and Professor
Patrick Serruys. His research focuses on the detection of vulnerable plaques. Dr.
Schaar has been awarded several research grants from organizations such as the
© 2005 by CRC Press
3028_C000.fm Page 13 Tuesday, October 12, 2004 8:17 AM
German Heart Foundation and the Dutch Heart Foundation. He has written several
book chapters about valve disease and vulnerable plaque detection and published in
peer review journals on the subjects of pulmonary hypertension, aortic dissection,
and vulnerable plaque detection.
Paul Schoenhagen is on staff at the Departments of Diagnostic Radiology and
Cardiovascular Medicine of The Cleveland Clinic Foundation. He earned his M.D.
from the Universitaet Tuebingen, Germany in 1992 and wrote his doctoral thesis in
medicine at the Philipps Universitaet, Marburg, Germany, in 1991. He was elected
a Fellow of the Council of Atherosclerosis, Thrombosis, and Vascular Biology of
the American Heart Association in 2001. He received the second James E. Muller
Vulnerable Plaque New Investigator Prize for clinical research in 2002. Since he
arrived at The Cleveland Clinic in 1996, his work has focused on atherosclerosis
imaging.
Patrick W. Serruys is professor of medicine and interventional cardiology and
directs the Interventional Heart Center at Erasmus Medical Center in Rotterdam.
His primary research interests are coronary artery disease and interventional cardi-
ology, for which he has received numerous awards. In the late 1980s he was among
the first researchers to apply the so-called stent — now the most commonly used
intervention procedure in cardiology. Professor Serruys is a Fellow of the European
Society of Cardiology and the American College of Cardiology. He is associate
editor of Circulation, the leading journal in the field of cardiac and cardiovascular
systems, and his scientific output exceeds 1200 papers.
Prediman K. Shah is a graduate of the University of Kashmir (India) and
received post-graduate training at Albert Einstein College of Medicine and
Montefiore Hospital in New York. Dr. Shah’s main research interests are in the area
of atherosclerosis, coronary artery disease and acute coronary syndromes. His current
major focus of research includes understanding the molecular mechanisms of athero-
sclerosis, plaque rupture, thrombosis and restenosis, and development and testing
of novel antiatherogenic and antirestenotic strategies. Dr. Shah and his colleagues
introduced recombinant apoA-I Milano, the product of a naturally occurring apoA-
I mutant gene, as a novel antiatherogenic therapy that is currently in human trials.
They have also developed a new vaccine against atherosclerosis and demonstrated
its atheroprotective effectiveness in animal models. Dr Shah’s many other important
scientific contributions have improved the understanding of the pathophysiology and
treatment of coronary syndromes. Dr. Shah has published over 250 scientific papers
and abstracts and has lectured all over the world as a visiting professor. He is a
fellow of the American College of Cardiology, member of the European Academy
of Sciences, and a member of the Editorial Boards of Circulation, American Journal
of Cardiology, International Journal of Heart Failure, Indian Heart Journal, Journal
of Preventive Cardiology, Reviews in Cardiovascular Medicine, Current Cardiology
Reports, and Journal of Cardiovascular Pharmacology and Therapeutics. Dr. Shah
has been the recipient of numerous awards including the Award of Excellence in
Teaching from the Dean of UCLA School of Medicine, the Golden Apple Award
from UCLA medical students, the Lifetime Achievement Award from the Los Ange-
les Chapter of the American Heart Association, the Gifted Teacher Award from the
© 2005 by CRC Press