Contemporary Cardiology
For other titles published in this series, go to www.springer.com/series/7677
Asymptomatic Atherosclerosis Pathophysiology, Detection and Treatment Edited by
Morteza Naghavi, MD
Society for Heart Attack Prevention and Eradication (SHAPE) Houston, Texas USA
Editor Morteza Naghavi, MD Society for Heart Attack Prevention and Eradication (SHAPE) 710 North Post Oak, Suite 400 Houston, Texas 77024
[email protected] ISBN 978-1-60327-178-3 e-ISBN 978-1-60327-179-0 DOI 10.1007/978-1-60327-179-0 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2009930357 © Springer Science+Business Media, LLC 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar or medical dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein Printed on acid-free paper Humana Press is part of Springer Science+Business Media (www.springer.com)
Dedications and Acknowledgments
They say that dedicating a book is one of the most exquisite acts of love and generosity one can perform. I would agree, and would like to dedicate my efforts in realizing this book to the following: To my father, Mohsen Naghavi, who grew up in a hardworking farmer family with 13 children who were fighting poverty and did not have the luxury of going to school. Nonetheless, he always inspired his children with stories of successful people and encouraged them to have great ambitions. He lived a difficult life as a bus driver, but brought up his 7 children to be thriving doctors, engineers, and teachers. To my mother, Khadijeh Naghavi, whose countless sacrifices and never-ending patience have kept our family warm with love. To my first mentors, Drs S. Ward Casscells and James T. Willerson, whose integrity and ingenuity taught me priceless lessons and enabled me to realize my “American Dream”. To my respectful advisors, Drs P.K. Shah and Valentin Fuster whose generous support further helped me establish my career. To my academic colleagues, Drs Erling Falk, Harvey Hecht, Mathew Budoff, Craig Hartley, Ralph Metcalfe, and Ioannis Kakadiaris for their friendship, trust and continued support. To my collaborators at SHAPE, especially Dr. Khurram Nasir for editorial assistance, Dr. Khawar Gul and Lisa Brown for management assistance, Mark Johnson for graphic illustrations and Princess Fazon for administrative support, whose work made this book possible. To my past and present associates, especially those I have not had a chance to thank and express my heartfelt appreciation. And to you who will somehow be inspired by this book and its mission to eradicate heart attacks; you will become an important link in the long causal chain of heart attack eradication. Do not doubt the cause; our mission is truly achievable. Cheers to a heart attack-free future for mankind! Houston, TX
Morteza Naghavi, MD
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Preface In the past century, preventive cardiology has been in a defensive mode. Since James Herrick first reported Clinical Features of Sudden Obstruction of the Coronary Artery Disease in JAMA 1912, and Paul Dudley White wrote the textbook of Heart Disease in 1930 and helped create cardiac care units, cardiovascular medicine for the most part has focused on the detection and treatment of symptomatic coronary artery disease. Although Dr. White recognized the importance of preventive cardiology by championing the Framingham Heart Study and establishing the American Heart Association, his dream of “mastering presenile atherosclerosis” is still unrealized. Over the past 50 years, the Framingham study defined the traditional cardiovascular risk factors of smoking, high serum cholesterol, high blood pressure, diabetes and lack of exercise, and the American Heart Association raised public awareness for early detection and treatment of these risk factors. However, atherosclerotic cardiovascular disease has remained the number one killer, diabetes and obesity have wildly increased, and out-of-hospital sudden cardiac deaths is still high and is increasing in women. New multipronged preventive strategies must be adopted to address these failures, beginning with a change in mindset from a passive defensive to an active offensive mode. The war against sudden coronary death must be shifted from hospitals to homes, and from advanced cardiac care units to primary care offices. In making such a shift, we must walk the walk, as we talk the talk. Attention must shift from the less effective and more expensive treatment of symptomatic atherosclerosis to the early detection and aggressive treatment of asymptomatic atherosclerosis. Existing risk factor based stratifications e.g., the Framingham Risk Score, have proven grossly inadequate, particularly in identifying the vulnerable patients who are at risk of a near term future event. The traditional methods must be replaced with the more accurate, yet underutilized, measures of subclinical atherosclerosis, notably coronary artery calcium scanning and carotid intima-media thickness measurement. Treatment of asymptomatic patients must be based on the severity of atherosclerosis regardless of the risk factors. The SHAPE initiative is an effort to move in this direction. In this book, leading cardiovascular physicians and investigators present the latest developments that illuminate the path to translating Dr. White’s dream into reality. We must, and I believe we can, master asymptomatic atherosclerosis to accomplish the mission of eradicating heart attacks in the twenty-first century. Houston, TX
Morteza Naghavi, MD
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Foreword
Since the landmark Framingham Heart Study introduced the concept of cardiovascular risk factors 50 years ago, the prediction and prevention of adverse cardiac events have been based primarily on the identification and treatment of these risk factors. Nonetheless, cardiovascular disease has remained the primary cause of mortality and morbidity in developed countries, and is rapidly increasing in the developing world. It is now obvious that new strategies, in addition to the traditional methods, are needed to fight the growing epidemic of atherosclerotic cardiovascular disease. In my view, early detection and treatment of high-risk asymptomatic atherosclerosis is a leading candidate to fulfill that role. I would like to congratulate Dr. Naghavi and colleagues at the Society for Heart Attack Prevention and Eradication (SHAPE) for their pioneering efforts to advance the early detection and treatment of asymptomatic atherosclerosis. Despite the many challenges ahead, this is a worthy and timely effort that goes beyond traditional risk assessment, and has the potential to transform preventive cardiology. The driving passion and commitment of the members of the SHAPE Task Force is commendable; it serves as an example to all of us who are devoted to eradicating the epidemic of atherosclerotic cardiovascular disease particularly sudden heart attacks and strokes. I am delighted to welcome “Asymptomatic Atherosclerosis” and look forward to its positive impacts on improving the knowledge and practice of preventive cardiology. Valentin Fuster, M.D., Ph.D. Director of the Cardiovascular Institute and Center for Cardiovascular Health Mount Sinai Medical Center – New York, NY President of the World Heart Federation Past President of the American Heart Association ixix
Contents Preface............................................................................................................................................
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Foreword........................................................................................................................................
ix
Contributors................................................................................................................................... xvii 1 Preventive Cardiology: The SHAPE of the Future................................................................... Morteza Naghavi
1
2 From Vulnerable Plaque to Vulnerable Patient......................................................................... 13 Morteza Naghavi and Erling Falk 3 Pathology of Vulnerability Caused by High-Risk (Vulnerable) Arteries and Plaques............. 39
Troels Thim, Mette Kallestrup Hagensen, Jacob Fog Bentzon, and Erling Falk 4 Pathophysiology of Vulnerability Caused by Thrombogenic (Vulnerable) Blood................... 53 Giovanni Cimmino, Borja Ibanez, and Juan Jose Badimon 5 Vulnerability Caused by Arrhythmogenic Vulnerable Myocardium........................................ 67 Ariel Roguin 6 Approach to Atherosclerosis as a Disease: Primary Prevention Based on the Detection and Treatment of Asymptomatic Atherosclerosis.................................................................... 77 Morteza Naghavi, Erling Falk, Khurram Nasir, Harvey S. Hecht, Matthew J. Budoff, Zahi A. Fayad, Daniel S. Berman, and Prediman K. Shah Section I Risk Factors and Circulating Markers of Asymptomatic Atherosclerotic Cardiovascular Disease 7 History of the Evolution of Cardiovascular Risk Factors and the Predictive Value of Traditional Risk-Factor-Based Risk Assessment....................................................... 89 Amit Khera 8 Comprehensive Lipid Profiling Beyond LDL.......................................................................... 107 Benoit J. Arsenault, S. Matthijs Boekholdt, John J.P. Kastelein, and Jean-Pierre Després 9 New Blood Biomarkers of Inflammation and Atherosclerosis................................................. 119 Natalie Khuseyinova and Wolfgang Koenig 10 Genomics and Proteomics: The Role of Contemporary Biomolecular Analysis
in Advancing the Knowledge of Atherosclerotic Coronary Artery Disease............................ 135 Gary P. Foster and Naser Ahmadi 11 Circulating Endothelial Progenitor Cells: Mechanisms and Measurements............................ 151
Jonathan R. Murrow and Arshed A. Quyyumi
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12 Family History: An Index of Genetic and Environmental Predisposition
to Coronary Artery Disease...................................................................................................... 169 Shivda Pandey and Khurram Nasir 13 Endothelial Activation Markers in Sub-clinical Atherosclerosis: Insights
from Mechanism-Based Paradigms.......................................................................................... 179 Victoria L.M. Herrera and Joseph A. Vita Section II Non Invasive, Non Imaging, Assessment of Asymptomatic Atherosclerotic Cardiovascular Disease 14 Exercise Stress Testing in Asymptomatic Individuals and Its Relation
to Subclinical Atherosclerotic Cardiovascular Disease............................................................ 197 Kevin S. Heffernan 15 The Ankle Brachial Index......................................................................................................... 211
Matthew A. Allison and Mary M. McDermott 16 Arterial Elasticity/Stiffness....................................................................................................... 225
Daniel A. Duprez and Jay N. Cohn 17 Assessment of Endothelial Function in Clinical Practice......................................................... 237
Jeffrey T. Kuvin 18 Digital (Fingertip) Thermal Monitoring of Vascular Function: A Novel, Noninvasive,
Nonimaging Test to Improve Traditional Cardiovascular Risk Assessment and Monitoring of Response to Treatments.............................................................................. 247 Matthew Budoff, Naser Ahmadi, Stanley Kleis, Wasy Akhtar, Gary McQuilkin, Khawar Gul, Timothy O’Brien, Craig Jamieson, Haider Hassan, David Panthagani, Albert Yen, Ralph Metcalfe, and Morteza Naghavi 19 Assessment of Macro- and Microvascular Function and Reactivity........................................ 265
Craig J. Hartley and Hirofumi Tanaka Section III Non Invasive Structural Imaging of Asymptomatic Atherosclerotic Cardiovascular Disease 20 Coronary Artery Calcium Imaging........................................................................................... 279
Harvey S. Hecht 21 Noninvasive Ultrasound Imaging of Carotid Intima Thickness............................................... 285
Tasneem Z. Naqvi 22 Carotid Intima-Media Thickness: Clinical Implementation in Individual Cardiovascular
Risk Assessment....................................................................................................................... 319 Ward A. Riley 23 Computed Tomographic Angiography..................................................................................... 323
Harvey S. Hecht 24 Role of Noninvasive Imaging using CT for Detection and Quantitation
of Coronary Atherosclerosis..................................................................................................... 335 John A. Rumberger
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25 Noninvasive Coronary Plaque Characterization: CT Versus MRI............................................ 351
John A. Rumberger 26 Magnetic Resonance Imaging.................................................................................................. 357
Zahi A. Fayad 27 The Role of MRI in Examining Subclinical Carotid Plaque.................................................... 363
Chun Yuan, Hideki Ota, Xihai Zhao, and Tom Hatsukami 28 Comprehensive Non-contrast CT Imaging of the Vulnerable Patient...................................... 375
Damini Dey, Ioannis A. Kakadiaris, Matthew J. Budoff, Morteza Naghavi, and Daniel S. Berman Section IV Non Invasive Functional Imaging of Asymptomatic Atherosclerotic Cardiovascular Disease 29 Ultrasound Assessment of Brachial Artery Reactivity............................................................. 395
A. Rauoof Malik and Iftikhar J. Kullo 30 Cardiac Imaging for Ischemia in Asymptomatic Patients: Use of Coronary Artery
Calcium Scanning to Improve Patient Selection: Lessons from the EISNER Study............... 411 Alan Rozanski, Heidi Gransar, Nathan D. Wong, Leslee J. Shaw, Michael J. Zellweger, and Daniel S. Berman 31 Targeted MRI of Molecular Components in Atherosclerotic Plaque....................................... 429
Zahi A. Fayad 32 Noninvasive Imaging of the Vulnerable Myocardium: Cardiac MRI and CT Based............... 433
Ricardo C. Cury, Anand Soni, and Ron Blankstein Section V Invasive (Intravascular) Risk Stratification for Detection of Vulnerable (High-Risk) Asymptomatic Atherosclerotic Plaques 33 Angiography for Detection of Complex and Vulnerable Atherosclerotic Plaque.................... 455
James A. Goldstein 34 Intravascular Characterization of Vulnerable Coronary Plaque............................................... 461
James A. Goldstein and James E. Muller 35 Detecting Vulnerable Plaque Using Invasive Methods............................................................. 475
Robert S. Schwartz and Arturo G. Touchard 36 Assessment of Plaque Burden and Plaque Composition Using Intravascular Ultrasound....... 483
Paul Schoenhagen, Anuja Nair, Stephen Nicholls, and Geoffrey Vince 37 Vulnerable Anatomy; The Role of Coronary Anatomy and Endothelial Shear Stress in the
Progression and Vulnerability of Coronary Artery Lesions: Is Anatomy Destiny?.................. 495 Charles L. Feldman, Yiannis S. Chatzizisis, Ahmet U. Coskun, Konstantinos C. Koskinas, Morteza Naghavi, and Peter H. Stone 38 Vasa Vasorum Imaging............................................................................................................. 507
Ioannis A. Kakadiaris, Sean O’Malley, Manolis Vavuranakis, Ralph Metcalfe, Craig J. Hartley, Erling Falk, and Morteza Naghavi
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Section VI Screening for Risk Assessment of Asymptomatic At-Risk Population and Identification of the Vulnerable Patient – The SHAPE Paradigm 39 From Vulnerable Plaque to Vulnerable Patient – Part III......................................................... 517
Morteza Naghavi, Erling Falk, Harvey S. Hecht, Michael J. Jamieson, Sanjay Kaul, Daniel S. Berman, Zahi Fayad, Matthew J. Budoff, John Rumberger, Tasneem Z. Naqvi, Leslee J. Shaw, Jay N. Cohn, Ole Faergeman, Raymond D. Bahr, Wolfgang Koenig, Jasenka Demirovic, Dan Arking, Victoria L.M. Herrera, Juan Jose Badimon, James A. Goldstein, Arturo G. Touchard, Yoram Rudy, K.E. Juhani Airaksinen, Robert S. Schwartz, Ward A. Riley, Robert A. Mendes, Pamela S. Douglas, and Prediman K. Shah 40 Cost Effectiveness of Screening Atherosclerosis..................................................................... 537
Leslee J. Shaw and Ron Blankenstein 41 Monitoring of Subclinical Atherosclerotic Disease.................................................................. 549
Daming Zhu, Allen J. Taylor, and Todd C. Villines 42 Implications of SHAPE Guideline for Improving Patient Compliance.................................... 569
Matthew J. Budoff 43 The SHAPE Guideline: Why Primary Care Physicians Should Embrace It............................ 577
Robert A. Mendes 44 Should We Treat According to the SHAPE Guidelines?.......................................................... 581
Paolo Raggi and Stamatios Lerakis 45 Duty-Bound: Rational Foundations of Clinical Strategies for Prevention
of Cardiovascular Events.......................................................................................................... 587 George A. Diamond and Sanjay Kaul 46 A Time to Live: Dynamic Changes in Risk as the Basis for Therapeutic Triage..................... 597
Sanjay Kaul and George A. Diamond Section VII Treatment of Asymptomatic Atherosclerotic Cardiovascular Disease and the Vulnerable Patients: Systemic Therapies 47 LDL Targeted Therapies........................................................................................................... 605
Raul D. Santos, Khurram Nasir, and Roger S. Blumenthal 48 Antioxidants as Targeted Therapy: A Special Protective Role for Pomegranate
and Paraoxonases (PONs)......................................................................................................... 621 Mira Rosenblat and Michael Aviram 49 The Multiconstituent Cardiovascular Pill (MCCP): Challenges and Promises
of Population Based Prophylactic Drug Therapy for Heart Attack Prevention and Eradication......................................................................................................................... 635 Michael J. Jamieson, Harvey S. Hecht, and Morteza Naghavi 50 Vaccine for Atherosclerosis: An Emerging New Paradigm..................................................... 649
Prediman K. Shah, Kuang-Yuh Chyu, Jan Nilsson, and Gunilla N. Fredrikson
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Section VIII Local and Focal Therapies for Stabilization of Vulnerable Arteries and Plaques 51 Drug-Eluting Stents: A Potential Preemptive Treatment Choice for Vulnerable
Coronary Plaques...................................................................................................................... 661 Edwin Lee, George Dangas, and Roxana Mehran 52 Intrapericardial Approach for Pancoronary Stabilization of the Vulnerable
Arteries and Myocardium......................................................................................................... 671 Venkatesan Vidi and Sergio Waxman Section IX Educations, Life Style Modifications and Non-Pharmacologic Treatments for Primary Prevention and Saving the Vulnerable 53 Dietary Management for Coronary Atherosclerosis Prevention and Treatment...................... 689
Michel de Lorgeril and Patricia Salen 54 Management of Preconditioning Physical Activity in a Vulnerable Patient:
Getting in SHAPE.................................................................................................................... 699 Sae Young Jae 55 Last Chance for Prevention (Acute Prevention): Identification
of Prodromal Symptoms and Early Heart Attack Care............................................................ 707 Raymond D. Bahr, Yasmin S. Hamirani, and Morteza Naghavi Index................................................................................................................................................ 723
Contributors Naser Ahmadi, MD Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA ●
Matthew A. Allison, MD • Department of Family and Preventive Medicine, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA Dan Arking, PhD • McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Benoit J. Arsenault, MSc • Department of Anatomy and Physiology, Université Laval, Quebec, QC, Canada Michael Aviram, DSc • Technion Institute of Technology, Rappaport Faculty of Medicine, Haifa Israel Juan Jose Badimon, PhD • Cardiovascular Biology Research Laboratory, Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY, USA Raymond D. Bahr, MD, FACC • St. Agnes Healthcare, Baltimore, MD, USA Jacob Fog Bentzon, MD, PhD • Department of Cardiology, Research Unit, Aarhus University Hospital, Aarhus, Denmark Daniel S. Berman, MD • Department of Cardiac Imaging and Nuclear Cardiology, Cedars-Sinai Medical School, Los Angeles, CA, USA Ron Blankstein, MD • Department of Radiology, Cardiac MRI-PET-CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Roger S. Blumenthal, MD • Preventive Cardiology Center, Johns Hopkins Hospital, Baltimore, MD, USA S. Matthijs Boekholdt, MD • Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands Matthew J. Budoff, MD • BioMed CT Reading Center, Harbor-UCLA Medical Center, Torrance, CA, USA Mercedes R. Carnethon, PhD • Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Yiannis S. Chatzizisis • Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115 Kuang-Yuh Chyu, MD, PhD • Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, USA Giovanni Cimmino, MD • Cardiovascular Biology Research Laboratory, Cardiovascular Institute, Mount-Sinai School of Medicine, New York, NY, USA xviixvii
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Contributors
Jay N. Cohn, MD • Division of Cardiology, Department of Medicine, University of Minnesota Medical Center, Minneapolis, MN, USA Ahmet U. Coskun • Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115 Ricardo C. Cury, MD • Department of Radiology, Cardiac MRI-PET-CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA George Dangas, MD, PhD • Center for Interventional Vascular Therapy, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA Jasenka Demirovic, MD, MSc, PhD • Division of Epidemiology, School of Public Health, The University of Texas Health Science Center, Houston, TX, USA Damini Dey, PhD • Department of Imaging, Cedars-Sinai Medical Center, Los Angeles, CA, USA Jean-Pierre Després, PhD, FAHA • Québec Heart Institute, Montreal, Quebec, QC, Canada George A. Diamond, MD • Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, USA Pamela S. Douglas, MD, FACC • Cardiovascular Imaging Center, Duke University Medical Center, Durham, NC, USA Daniel A. Duprez, MD, PhD • Division of Cardioloy, Department of Medicine, University of Minnesota Medical Center, Minneapolis, MN, USA Erling Falk, MD, PhD • Department of Cardiology Research, Aarhus University Hospital, Skejby, Aarhus, Denmark Ole Faergeman, MD, MDSc • Section of Preventive Cardiology, Department of Medicine and Cardiology, Aarhus Amtssygehu University Hospital, Aarhus, Denmark Zahi A. Fayad, PhD • Department of Radiology and Department of Cardiology, Mount-Sinai School of Medicine, New York, NY, USA Charles L. Feldman • Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115 Gary P. Foster, MD • Texas Cardiovascular Consultants, P.A., Austin, TX, USA Gunilla N. Fredrikson, PhD • Department of Medicine, University Hospital MAS, Malmo, Sweden James A. Goldstein, MD • Division of Cardiology, William Beaumont Hospital, Royal Oak, MI, USA Heidi Gransar, MS • Departments of Imaging and Medicine and the Burns and Allen Research Institute, Cedars-Sinai Medical Center and the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA Mette Kallestrup Hagensen, MSc • Department of Zoophysiology, Institute of Biological Sciences, University of Aarhus, Aarhus, Denmark Yasmin S. Hamirani, MD • St. Agnes Healthcare, Baltimore, MD, USA
Contributors
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Craig J. Hartley, PhD • Department of Medicine, Section of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX, USA Tom Hatsukami, MD • Department of Radiology, Vascular Imaging Lab, University of Washington, Seattle, WA, USA Harvey S. Hecht, MD • Department of Interventional Cardiology, Lenox Hill Hospital, New York, NY, USA Kevin S. Heffernan, PhD • Department of Kinesiology / Exercise Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA Victoria L.M. Herrera, MD • Department of Medicine, Section of Molecular Medicine, Boston University School of Medicine, Boston, MA, USA Borja Ibanez, MD • Cardiovascular Biology Research Laboratory, Cardiovascular Institute, Mount-Sinai School of Medicine, New York, NY, USA Sae Young Jae, PhD • The Health and Integrative Physiology Laboratory, Department of Sports Informatics, University of Seoul, Seoul, South Korea Craig Jamieson • Endothelix Inc., Houston, TX, USA Michael J. Jamieson, MD • Senior Director, RMRS Cardiovascular, Pfizer Inc., Houston, TX, USA K.E. Juhani Airaksinen, MD • Cardiovascular Laboratory, Department of Medicine, University of Turku, Turku, Finland Ioannis A. Kakadiaris, PhD • Department of Engineering, University of Houston, Houston, TX, USA John J.P. Kastelein, MD, PhD • Academic Medical Center, Amsterdam, The Netherlands Sanjay Kaul, MD • Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA, USA Morton Kern, MD • Division of Cardiology, Department of Medicine, University of California at Irvine, Orange, CA, USA Amit Khera, MD, MSc • Division of Cardiology, Department of Internal Medicine, University of Texas Southewestern Medical Center, Dallas, TX, USA Natalie Khuseyinova, MD • Department of Internal Medicine, Cardiology, University of Ulm Medical Center, Ulm, Germany Wolfgang Koenig, MD, PhD • Department of Internal Medicine, Cardiology, University of Ulm Medical Center, Ulm, Germany Konstantinos C. Koskinas • Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115 Iftikar J. Kullo, MD • Department of Cardiovascular Diesease, Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA Jeffrey T. Kuvin, MD • Cardiovascular Imaging and Hemodynamics Laboratory, Tufts Medical Center, Boston, MA, USA Edwin Lee, MD, PhD • Center for Interventional Vascular Therapy, Columbia University Medical Center, New York, NY, USA
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Contributors
Stamatios Lerakis, MD • Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Michel de Lorgeril, MD • Cardiovascular Stress and Associated Pathology Laboratory, Joseph Fourier University, Grenoble, France A. Rauoof Malik, MD • Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA Mary M. McDermott, MD • Division of General Internal Medicine, Northwestern Medical Faculty Foundation, Chicago, IL, USA Roxana Mehran, MD • Center for Interventional Vascular Therapy, Columbia University Medical Center, New York, NY, USA Robert A. Mendes, MD • Division of Vascular Surgery, Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Ralph Metcalfe, MD • Department of Mechanical Engineering, University of Houston, Houston, TX, USA James E. Muller, MD • Department of Medicine, Cardiac Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Jonathon R. Murrow, MD • Division of Cardiology, Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA Morteza Naghavi, MD • Society for Heart Attack Prevention and Eradication (SHAPE) 710 North Post Oak, Suite 400 Houston, Texas 77024 Anuja Nair, PhD • Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH, USA Tasneem Z. Naqvi, MD • Department of Medicine, University of Southern California, Los Angeles, CA, USA Khurram Nasir, MD • Cardiac MR-PET-CT Program, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, Boston, MA, USA Stephen Nicholls, MD, PhD • Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA Jan Nilsson, MD, PhD • Department of Medicine, University Hospital MAS, Malmo, Sweden Sean O’Malley, MD • Department of Engineering, University of Houston, Houston, TX, USA Hideki Ota, MD, PhD • Department of Radiology, Vascular Imaging Lab, University of Washington, Seattle, WA, USA Shivda Pandey, MD • Department of Radiology, Cardiac MRI-PET-CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Arshed A. Quyyumi, MD • Division of Cardiology, Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA Paolo Raggi, MD • Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
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Ward A. Riley, PhD • Department of Neurology, Wake Forest University, Winston-Salem, NC, USA Ariel Roguin, MD, PhD • Department of Cardiology, Rambam Medical Center, Haifa, Israel Mira Rosenblat, MSc • Technion Institute of Technology, Rappaport Faculty of Medicine, Haifa, Israel Alan Rozanski, MD • Department of Cardiology, St. Luke’s Roosevelt Hospital Center, New York, NY, USA Yoram Rudy, PhD • Cardiac Bioelectricity and Arrhythmia Center, Washington University in St. Louis, St. Louis, MO, USA John A. Rumberger, MD, PhD • The Princeton Longevity Center, Princeton, NJ, USA Patricia Salen, BSc • Faculté de Médecine, Domaine de la Merci, Université de Grenoble, La Tronche, France Raul D. Santos, MD • Cardiovascular Specialists, P.A., Lewisville, TX, USA Paul Schoenhagen, MD • Department of Diagnostic Radiology and Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA Robert S. Schwartz, MD • Minneapolis Heart Institute and Abbott Northwestern Hospital, Minneapolis, MN, USA Prediman K. Shah, MD • Director, Division of Cardiology and Atherosclerosis Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA Leslee J. Shaw, PhD • Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Anand Soni, MD • Department of Radiology, Cardiac MRI-PET-CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Peter H. Stone • Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115 Hirofumi Tanaka, PhD • Department of Kinesiology and Health Education, The University of Texas at Austin, Austin, TX, USA Allen J. Taylor, MD • United States Army Cardiology Service, Walter Reed Army Medical Center, Washington, DC, USA Troels Thim, MD • Atherosclerosis Research Unit, Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus, Denmark Arturo G. Touchard, MD • Minneapolis Heart Institute, Minneapolis, MN, USA Manolis Vavuranakis, MD • Department of Cardiology, Hippokration Hospital, Athens Medical School, Athens, Greece Venkatesan Vidi, MD • Department of Cardiovascular Medicine, Lahey Clinic, Burlington, MA and Tufts University School of Medicine, Boston, MA, USA Todd C. Villines, MD • United States Army Cardiology Service, Walter Reed Army Medical Center, Washington, DC, USA
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Contributors
Geoffrey Vince, PhD • Department of Biomedical Engineering, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, OH, USA Joseph A. Vita, MD • Department of Medicine, Section of Cardiovascular Medicine, Boston University School of Medicine, Boston, MA, USA Sergio Waxman, MD • Department of Cardiovascular Medicine, Lahey Clinic, Burlington, MA and Tufts University School of Medicine, Boston, MA, USA Nathan D. Wong, PhD, MPH • Heart Disease Prevention Program, University of California at Irvine, Irvine, CA, USA Albert A. Yen, MD • Endothelix Inc., Houston, TX, USA Chun Yuan, PhD • Department of Radiology, Vascular Imaging Lab, University of Washington, Seattle, WA, USA Michael J. Zellweger, MD • Department of Cardiology, University Hospital, Basel Switzerland Xihai Zhao, MD, PhD • Department of Radiology, Vascular Imaging Lab, University of Washington, Seattle, WA, USA Daming Zhu, MD • Department of Internal Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
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Preventive Cardiology: The SHAPE of the Future Morteza Naghavi Contents Introduction Traditional Preventive Cardiology Modern Preventive Cardiology The Big Picture: Health Care vs. Sick Care Preventive Cardiology, Poorly Invested Legislation for Prevention Heart Attacks Can Be Eradicated Conclusion References
Abstract In the twentieth century, atherosclerotic cardiovascular disease (ACVD) manifesting as a “heart attack,” has claimed millions of lives every year, and killed more people than all wars combined. An epidemic of this magnitude makes it very difficult to imagine a future in which heart attacks are eradicated. Nonetheless, the mission of eradicating heart attacks is no more challenging than the mission of landing humans on Mars. The vision for a heart attack-free future can become a reality in the twenty-first century and can significantly increase human life expectancy. This goal is achievable if we, including academia, industry, health-care providers, payers, and policymakers, invest in the detection and treatment of asymptomatic atherosclerotic as much as we have invested in the treatment of symptomatic atherosclerosis. Primary prevention of ACVD, through treatment of risk factors of atherosclerosis, public education, and promotion of heart-healthy life style, has been the main focus of cardiovascular organizations such as the American Heart Association. However, the continued overwhelming burden of ACVD and disappointing trends in the prevalence of ACVD risk factors, particularly obesity and diabetes, have made it clear that traditional methods are inadequate and new strategies are urgently needed. Recent discoveries have created paradigm shifts in our understanding of the underlying mechanisms of ACVD and the sequence of events that result in athero-thrombotic events. These scientific discoveries, along with new diagnostic and therapeutic developments, have opened the way to unprecedented opportunities including (1) screening for early detection and aggressive treatment of the “vulnerable patient” based on noninvasive imaging of asymptomatic atherosclerosis, (2) monitoring therapies and evaluating progression or regression of the disease based on structural, functional, and molecular markers of ACVD, (3) development of safe and From: Asymptomatic Atherosclerosis: Pathophysiology, Detection and Treatment Edited by: M. Naghavi (ed.), DOI 10.1007/978-1-60327-179-0_1 © Springer Science+Business Media, LLC 2010 1
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effective “Polypills” for preemptive population-based therapy, (4) development of safe and effective focal therapies, such as bio-absorbable drug-eluting stents, for rapid stabilization of the “vulnerable plaque,” and (5) immune modulation and vaccination strategies for prevention of atherosclerosis at an early age and halting its progression later in life. Simultaneously, the fast evolving IT and communication technologies, as well as low-cost home health-monitoring devices, will facilitate rapid dissemination of new information, empower consumers, and help shift cardiovascular care from hospitals to the home. Through the above, our modern preventive cardiology will shape the future and will lead to the eradication of heart attack in the twenty-first century. Key words: Preventive cardiology; Asymptomatic atherosclerosis; Subclinical atherosclerosis; Primary prevention; Heart attack; Stroke, Coronary artery disease; Coronary heart disease; Carotid IMT – Carotid intima media thickness; Coronary calcium score; Vulnerable plaque; Vulnerable patient; Coronary risk assessment; Cardiovascular risk assessment; Healthcare policy; Atherosclerosis vaccination; PolyPill
Introduction Atherosclerotic cardiovascular disease (ACVD), caused by ischemic complications of arterial atherosclerotic plaques manifested primarily through sudden cardiac death, acute coronary syndromes (ACS) and stroke, is the leading cause of death and disability in most developed countries, and is dramatically increasing in the developing nations. It is projected that by the year 2025 approximately 80–90% of all the cardiovascular diseases in the world will be occurring in low and middle income countries [1]. Despite many satisfactory statistical trends presented by the American Heart Association [2] and celebratory comments by opinion leaders [3] (as if we have conquered heart attacks), more Americans are dying from heart attacks now than they were 50-years ago. This statement is not true about polio and smallpox. While other areas of science and technology have witnessed incredible advances, ACVD and sudden cardiac death still kill apparently healthy people, and claim millions of lives and billions of dollars worldwide. Ironically, despite such a huge loss of lives and dollars every year, most cases of heart attacks and mortality or morbidity associated with ACVD can be prevented by early detection and aggressive treatment of asymptomatic atherosclerosis. Since 1960, a myriad of articles have been added to the medical literature offering insights into this major public health dilemma. However, a very unique opportunity to ease the dilemma, namely early detection and aggressive treatment of high-risk asymptomatic or presymptomatic atherosclerotic individuals (the vulnerable patients), has received little attention. It is well known that ACS do not occur without a preceding atherosclerotic plaque and that atherosclerosis remains hidden (asymptomatic) until too late (myocardial infarction and stroke) [4]. Nonetheless, very few efforts have focused on identification of the very high-risk (vulnerable) individuals with a high burden of asymptomatic atherosclerosis. Since 2003, this critical topic has been the focus of the SHAPE (Screening for Heart Attack Prevention and Education) Task Force and resulted in the establishment of the SHAPE organization (Society for Heart Attack Prevention and Eradication) [5–7]. The SHAPE initiative aims to advance ACVD risk assessment strategies in the asymptomatic population for saving the vulnerable patient, which current strategies have failed to accomplish.
Traditional Preventive Cardiology Prevention of ACVD is categorized into primary prevention and secondary prevention. Primary prevention can be defined as the prevention of the first heart attack or stroke, while secondary prevention deals with the prevention of the second/recurrent heart attack or stroke. Neither the concept nor
Preventive Cardiology: The Shape of the Future
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the practice of primary prevention existed for ACVD prior to the 1950s when pioneering epidemiologists such as Ancel Key, Jerry and Rose Stamler, William Kannel, Henry Blackburn and others, reported convincing epidemiologic associations between high-fat diet, high serum cholesterol, high blood pressure, smoking, physical inactivity, etc. (termed “risk factors”) and ACVD. Despite major accomplishments in reducing the age-adjusted incidence of death from coronary heart disease and stroke (which is partially because of reduced case-fatality rate), the prevalence of ACVD and its associated morbidity, e.g., heart failure, have steadily increased in the past few decades. The incidence and prevalence of most risk factors (except for smoking) have increased or not changed. With the rapidly growing epidemic of obesity, the war against ACVD-prone life style is far from won, if not already lost. It is obvious that our society is facing a serious interruption in the chain of knowledge, attitude, and practice (KAP) to maintain a heart-healthy life (Fig. 1). Over the past 50 years, great progress has been made in the early detection and management of risk factors as well as the diagnosis and treatment of symptomatic ACVD, particularly ACS. However, very little has been accomplished for asymptomatic ACVD, which accounts for the majority of sudden cardiac death, silent MI, and silent stroke. Unlike most cancers, ACVD remains asymptomatic (subclinical) for decades. Even though the majority of asymptomatic ACVD can be detected and treated, no screening test is currently approved by federal agencies and made available to physicians and patients. Current traditional risk factor-based assessment strategies have clearly proven to be insufficient. A recent report based on the Get with the Guidelines initiative of the American Heart Association which studied 136,905 patients hospitalized with the diagnosis of ACVD, has shockingly revealed the inadequecy of LDL-cholesterol, HDL-cholesterol, and triglyceride in identifying high-risk individuals. The report showed 77, 45.4, and 61.8% of the patients had normal LDL, HDL, and triglyceride, respectively (Fig. 2a–c) [8]. This study has strongly confirmed prior reports suggesting poor predictive value of traditional risk factors, in particular dislipidemia, and clearly highlighted the shortcoming of existing NCEP Guidelines (National Cholesterol Education Program) [9–12].
Fig. 1. Most people know that cardiovascular risk factors such as high-fat diet and lack of exercise increase their chance of having a future heart attack, but very few people follow a “heart-healthy” life style. Can heart attacks ever be eradicated by educational campaigns that the American Heart Association has focused on?
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In addition to the need for improving risk assessment in asymptomatic individuals, accurate monitoring of the response to therapy in treated patients is essential for success in both primary and secondary prevention of ACVD. In summary, there are two major problems in cardiology; (1) inaccurate individualized assessment of cardiovascular risk as illustrated in Fig. 3 and (2) inadequate
Fig. 1.2 (a) Of 136,905 patients hospitalized with CAD, 77% had normal LDL levels below 130 mg/dl. (b) Of 136,905 patients hospitalized with CAD, 45.4% had normal HDL levels above 40 mg/dl. (c) Of 136,905 patients hospitalized with CAD, 61.8% had normal triglyceride levels below 150 mg/dl.
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Preventive Cardiology: The Shape of the Future Who has higher cardiovascular risk based on risk factors? Sir Winston Churchill, 91
Jim Fixx, 53
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Fig. 3. This figure illustrates the inaccuracy of traditional risk factors for identification of high-risk asymptomatic individuals.
Fig. 4. The sudden death of famous journalist Tim Russert brought to light the problem of inadequate monitoring of response to treatments.
monitoring of the vascular response to treatments as illustrated in Fig. 4. The time has come to adopt new paradigms, beyond traditional ACVD risk factors, to address both these issues. In this book, leading investigators in the field of ACVD present a new strategy for risk assessment and reduction that is largely based on noninvasive screening for early detection of asymptomatic ACVD itself (subclinical atherosclerosis) rather than for its risk factors. The new strategy stratifies the asymptomatic population based on a screening pyramid in which the intensity of treatment is tailored to the severity of atherosclerosis.
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Modern Preventive Cardiology In the era of Google, remote robotic surgery, sub-millimeter noninvasive imaging, and nanotechenabled mass proteomic assays, having millions of people (many of whom are indeed health conscious) living with, but unaware of, a huge coronary plaque burden is tragic and simply unacceptable. Physicians and researchers are responsible for taking actions and for helping the medical community to take full advantage of new knowledge and technology to save lives particularly in the very productive segment of the society (90% Minor criteria Superficial calcified nodule Glistening yellow Intraplaque hemorrhage Endothelial dysfunction Outward (positive) remodeling
From Vulnerable Plaque to Vulnerable Patient19
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Pan-Coronary Vulnerability Several investigators have noted the presence of more than one vulnerable plaque in patients at risk of cardiovascular events. Mann and Davies [22] and Burke et al. [23] in cardiac autopsy specimens, Goldstein et al. [24] in angiography studies, Nissen [25] and Rioufol et al. [26] with intravascular ultrasound, and Buffon et al. [27] measuring neutrophil myeloperoxidase found multiple ruptureprone or ruptured plaques in a wide range of cardiovascular patient populations. A most recent series of publications on vulnerability reiterated the importance of going beyond a vulnerable plaque and called for evaluating the total arterial tree as a whole [28–30].
Silent-Plaque Rupture Thrombotic complications that arise from rupture or fissure (small rupture) of a vulnerable plaque may be clinically silent, yet contribute to the natural history of plaque progression and ultimately luminal stenosis [31, 32].
Beyond the Atherosclerotic Plaque It is important to identify patients in whom disruption of a vulnerable plaque is likely to result in a clinical event. In these patients, other factors beyond plaque (i.e., thrombogenic blood and electrical instability of myocardium) are responsible for the final outcome (Fig. 4). We propose that such patients be referred to as “vulnerable patients.” In fact, plaques with similar characteristics may have different clinical presentations because of blood coagulability (vulnerable blood) or myocardial susceptibility to develop fatal arrhythmia (vulnerable myocardium). The latter may depend on a current or previous ischemic condition and/or a nonischemic electrophysiological abnormality.
Fig. 4. The risk of a vulnerable patient is affected by vulnerable plaque and/or vulnerable blood and/or vulnerable myocardium. A comprehensive assessment must consider all of the above.
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Definition of a Cardiovascular Vulnerable Patient The term “cardiovascular vulnerable patient” is proposed to define subjects susceptible to an acute coronary syndrome or sudden cardiac death based on plaque, blood, or myocardial vulnerability (for example, 1-year risk ³ 5%). Extensive efforts are needed to quantify an individual’s risk of an event according to each component of vulnerability (plaque, blood, and myocardium). Such a comprehensive risk-stratification tool capable of predicting acute coronary syndromes as well as sudden cardiac death would be very useful for preventive cardiology (Fig. 4).
Diagnosis of Vulnerable Plaque/Artery A number of issues have hampered the establishment of ideal criteria for defining vulnerable plaque: (1) the current body of evidence is largely based on cross-sectional and retrospective studies of culprit plaques; (2) robust prospective outcome studies based on plaque characterization have not been done (because of the lack of a reproducible, validated diagnostic technique); and (3) a lack of a representative animal model of plaque rupture and acute coronary syndrome/sudden death. On the basis of retrospective evidence, we propose that the criteria listed in Tables 4 and 5 FX be used to define a vulnerable plaque. The sensitivity, specificity, and overall predictive value of each potential diagnostic technique need to be assessed before entering clinical practice. Table 5 Markers of vulnerability at the plaque/artery level Plaque Morphology/structure Plaque cap thickness Plaque lipid core size Plaque stenosis (luminal narrowing) Remodeling (expansive vs. constrictive remodeling) Color (yellow, glistening yellow, red, etc.) Collagen content versus lipid content, mechanical stability (stiffness and elasticity) Calcification burden and pattern (nodule vs. scattered, superficial vs. deep, etc.) Shear stress (flow pattern throughout the coronary artery) Activity/function Plaque inflammation (macrophage density, rate of monocyte infiltration and density of activated T cell) Endothelial denudation or dysfunction (local NO production, anti-/procoagulation properties of the endothelium) Plaque oxidative stress Superficial platelet aggregation and fibrin deposition (residual mural thrombus) Rate of apoptosis (apoptosis protein markers, coronary microsatellite, etc.) Angiogenesis, leaking vasa vasorum, and intraplaque hemorrhage Matrix-digesting enzyme activity in the cap (MMPs 2, 3, 9, etc.) Certain microbial antigens (e.g., HSP60, C. pneumoniae) Pan-arterial Transcoronary gradient of serum markers of vulnerability Total coronary calcium burden Total coronary vasoreactivity (endothelial function) Total arterial burden of plaque including peripheral (e.g., carotid IMT) MMP matrix metalloproteinase; NO nitric oxide; IMT intima-media thickness
From Vulnerable Plaque to Vulnerable Patient21
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Major Criteria The following are proposed as major criteria for the detection of a vulnerable plaque. The presence of one or a combination of these factors may warrant higher risk of plaque complication. Techniques for detection of vulnerable plaque based on these criteria are briefly summarized here. A detailed discussion of advantages and disadvantages are reviewed elsewhere [33]. Active Inflammation Plaques with active inflammation may be identified by extensive macrophage accumulation [13]. Possible intravascular diagnostic techniques [34, 35] include thermography (measurement of plaque temperature) [36, 37], contrast-enhanced (CE) MRI [38, 39], fluorodeoxyglucose positron emission tomography [33, 40], and immunoscintigraphy [41]. It has been shown that optical coherence tomography reflects the macrophage content of the fibrous cap [42]. Noninvasive options include MRI with superparamagnetic iron oxide [35, 36] and gadolinium fluorine compounds [43–45]. A Thin Cap With a Large Lipid Core These plaques have a cap thickness of 40% of the plaque’s total volume [8]. Possible intravascular diagnostic techniques include optical coherence tomography (OCT) [46, 47], intravascular ultrasonography (IVUS) [48], high-resolution IVUS [49], elastography (palpography) [50, 51], MRI [52], angioscopy [53], near-infrared (NIR) spectroscopy [54–56], and radiofrequency IVUS analysis [57, 58]. The only noninvasive options are presently MRI and possibly CT [34, 35, 59–62]. Endothelial Denudation with Superficial Platelet Aggregation These plaques are characterized by superficial erosion and platelet aggregation or fibrin deposition [5]. Possible intravascular diagnostic techniques include angioscopy with dye [63] and matrixtargeted/fibrin-targeted immune scintigraphy and OCT [46, 47]. Noninvasive options include fibrin/ matrix-targeted contrast enhanced MRI [64], platelet/fibrin-targeted single photon emission computed tomography [41], and MRI [52]. Fissured/Injured Plaque Plaques with a fissured cap (most of them involving a recent rupture) that did not result in occlusive thrombi may be prone to subsequent thrombosis, entailing occlusive thrombi or thromboemboli [5]. Possible intravascular diagnostic techniques include OCT [46, 47], IVUS, high-resolution IVUS [49], angioscopy, and MRI [34, 35]. A noninvasive option is fibrin-targeted CE-MRI [64, 65]. Severe Stenosis On the surface of plaques with severe stenosis, shear stress imposes a significant risk of thrombosis and sudden occlusion. Therefore, a stenotic plaque may be a vulnerable plaque regardless of ischemia. Moreover, a stenotic plaque may indicate the presence of many nonstenotic or less stenotic plaques that can be vulnerable to rupture and thrombosis [24, 66] (Fig. 5). The current standard technique is invasive x-ray angiography [32]. Noninvasive options include multislice CT [67, 68], magnetic resonance angiography with or without a contrast agent, and electron-beam tomography angiography [59, 69–71].
Minor Criteria For techniques that focus on the plaque level, minor criteria include the following features.
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Fig. 5. Plaques with nearly similar morphology in terms of lipid core and fibrous cap (middle panel) may look similar with diagnostic imaging aimed at morphology only (bottom panel). However, they might look very different using diagnostic methods capable of detecting activity and physiology of the plaques. The top left plaque is hot (as evidenced in a thermography image), whereas the top right plaque is inactive and detected relatively as a cool plaque.
Superficial Calcified Nodules These plaques have a calcified nodule within, or very close to, their cap, and this structure protrudes through and can rupture the cap. This event may or may not be associated with severe coronary calcification and a high calcium score [5]. Possible intravascular diagnostic techniques include OCT [46, 47], IVUS and elastography (palpography) [48]. Noninvasive options include electron-beam CT [72], multisection spiral CT [73], and MRI [34, 35]. Yellow Color (on Angioscopy) Yellow plaques, particularly glistening ones, may indicate a large lipid core and thin fibrous cap, suggesting a high risk of rupture. However, because plaques in different stages can be yellow and because not all lipid-laden plaques are destined to rupture or undergo thrombosis, this criterion may lack sufficient specificity [53, 74]. Possible intravascular diagnostic techniques include angioscopy [73] and transcatheter colorimetry [75]. No diagnostic method has yet been developed for noninvasive angioscopy. Intraplaque Hemorrhage Extravasation of red blood cells, or iron accumulation in plaque, may represent plaque instability [76]. Possible intravascular diagnostic techniques include NIR spectroscopy [54, 55], tissue Doppler methods [77], and intravascular MRI. A noninvasive option is MRI [34, 35, 61].
From Vulnerable Plaque to Vulnerable Patient23
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Endothelial Dysfunction Impaired endothelial vasodilator function occurs in a variety of acute and chronic disease states. Patients with cardiovascular risk factors have endothelial dysfunction. Endothelial dysfunction predicts CHD and stroke [89, 156]. Vulnerable plaques have sites of active inflammation and oxidative stress and are likely to be associated with impaired endothelial function. Possible diagnostic techniques are endothelium-dependent coronary artery dilatation (intravascular) [78] and measurement of flow-mediated dilatation by brachial artery ultrasonography and other emerging techniques (noninvasive) [79]. Expansive (Positive) Remodeling Many of the nonstenotic lesions undergo “expansive,” “positive,” or “outward” remodeling, namely compensatory enlargement before impinging significantly on the vascular lumen. This phenomenon was considered as positive remodeling because the luminal area was not affected and stenosis was the only measure of risk. However, with the emphasis on plaque rupture in nonstenotic lesions, the so-called positive remodeling may not be truly positive and beneficial. Several studies have suggested that such remodeling is a potential surrogate marker of plaque vulnerability [80, 81]. In these studies, intravascular ultrasound was used to evaluate remodeling in coronary arteries. A recent study by Kim et al. [82] introduced a noninvasive method for the detection of expansive remodeling in coronary arteries by MRI. CT might also provide a noninvasive method for studying arterial remodeling. Few of the above techniques have been tested in clinical trials showing ability to predict events. MRI and CT-based approaches are being developed. These technologies and strategies must also be evaluated with regard to their cost-effectiveness.
Functional versus Structural Assessment A growing body of evidence indicates that different types of vulnerable plaque with various histopathology and biology exist. To evaluate plaque vulnerability, it is evident that a combined approach capable of evaluating structural characteristics (morphology) as well as functional properties (activity) of plaque may be more informative and may provide higher predictive value than a single approach. For instance, a combination of IVUS or OCT with thermography [80, 83] may provide more diagnostic value than each of these techniques alone. Such an arrangement can be useful for both intravascular as well as noninvasive diagnostic methods (Fig. 6). Autopsy [84] and IVUS studies [85] have shown that atherosclerotic lesions are frequently found in young and asymptomatic individuals. It is unclear what percentage of these lesions present morphologies of rupture-prone vulnerable plaques. Moreover, chronic inflammation [86] and macrophage/foam cell formation are an intrinsic part of the natural history of atherosclerosis. These data suggest that screening only based on plaque morphology and/or chronic markers of inflammation may not provide satisfactory predictive value for detection of vulnerable patients.
Pan-Arterial Approach Diagnostic and therapeutic methods may focus on the total burden of coronary artery disease [27]. The coronary calcium score is a good example of using CT for this purpose [72]. The total burden of calcified atherosclerotic plaques in all coronary arteries is identified by ultrafast CT. Extensive efforts are underway to improve image quality, signal processing, and interpretation of detailed components of coronary arteries that lend hope of a new calcium scoring and risk stratification technique based on
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Fig. 6. Correlation between frequency of plaques, degree of stenosis, and risk of complication per plaque as a function of plaque progression. Although the average absolute risk of severely stenotic plaques may be higher than the average absolute risk of mildly stenotic plaques, there are more plaques with mild stenoses than plaques with severe stenoses.
CT information [87]. Like systemic indexes of inflammation (e.g., high sensitive CRP), endothelial dysfunction as measured by impaired flow-mediated vasodilation in the brachial artery can aid in the detection of pan-arterial vulnerability and may serve as a screening tool [88, 89]. Another emerging technique is the measurement of the transcoronary gradient (difference in concentration between coronary ostium and coronary sinus, or between proximal and distal segments of each coronary segment) of various factors, including cytokines [90], adhesion molecules [91], temperature, etc. It will be important in the future to identify plaques that are on a trajectory of evolution toward a vulnerable state, to find out how long they will stay vulnerable, and to be able to target interventions to those plaques most likely to develop thrombosis. Similarly, factors that protect plaques from becoming vulnerable also need to be identified. It is likely that local hemodynamic factors and three-dimensional morphology may provide insight regarding the temporal course of an evolving plaque. New studies are unraveling the role of the adventitia and periadventitial connective and adipose tissue in vulnerability of atherosclerotic plaques [92]. Further studies are needed to define the importance of these findings in the detection and treatment of vulnerable plaques.
From Vulnerable Plaque to Vulnerable Patient25
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Vulnerable (Thrombogenic) Blood Serum Markers of Atherosclerosis and Inflammation Serum markers may predict a patient’s risk of acute cardiovascular complications (Table 6). C-reactive protein (CRP) is an independent risk factor and a powerful predictor of future coronary events in the asymptomatic population [154, 155] and in patients with stable and unstable disease. Although CRP is a nonspecific marker of systemic inflammation, it activates endothelium and accumulates in the plaque, suggesting an important role in plaque inflammation [96, 97]. Circulating interleukin-6 levels, which are elevated in patients with acute coronary syndromes, also predict the risk of future coronary events in such patients [98]. Investigators have shown that high plasma concentrations of soluble CD40 ligand may indicate an increased vascular risk in apparently healthy women [99]. Likewise, Hwang et al. [100] showed in a large population-based sample of individuals that circulating levels of soluble intracellular adhesion molecule were predictive of future acute coronary events. Markers of systemic inflammation, such as soluble adhesion molecules, circulating bacterial endotoxin, soluble human heat-shock protein 60, and antibodies to mycobacterial heat-shock protein 65, may predict an increased risk of atherosclerosis [101]. Pregnancy-associated plasma protein A (PAPP-A) is present in unstable plaques, and its circulating levels are elevated in patients with acute coronary syndromes [102]. Increased serum levels of PAPP-A may reflect instability of atherosclerotic plaques [103]. With major advances in high-throughput genomics and proteomics research, future studies will undoubtedly identify new risk and protective factors and biomarkers that can be used for screening purposes. A recent study suggested an association between several genetic polymorphisms and clinical outcomes, some of which can be possibly related to plaque, blood, and myocardial vulnerability [104]. The tools and knowledge base, made possible by the Human Genome Project, allow the field
Table 6 Serological markers of vulnerability (reflecting metabolic and immune disorders) Abnormal lipoprotein profile (e.g., high LDL, low HDL, abnormal LDL and HDL size density, lipoprotein [a], etc.) Nonspecific markers of inflammation (e.g., hsCRP, CD40L, ICAM-1, VCAM-1, P-selectin, leukocytosis, and other serological markers related to the immune system; these markers may not be specific for atherosclerosis or plaque inflammation) Serum markers of metabolic syndrome (e.g., diabetes or hypertriglyceridemia) Specific markers of immune activation (e.g., anti-LDL antibody, anti-HSP antibody) Markers of lipid peroxidation (e.g., ox-LDL and ox-HDL) Homocysteine PAPP-A Circulating apoptosis marker(s) (e.g., Fas/Fas ligand, not specific to plaque) ADMA/DDAH Circulating nonesterified fatty acids (e.g., NEFA) hsCRP high-sensitivity CRP; CD40L CD40 ligand; ICAM intracellular adhesion molecule; VCAM vascular cell adhesion molecule; MMP matrix metalloproteinases; TIMP tissue inhibitors of MMPs; LDL low-density lipoprotein; HDL high-density lipoprotein; HSP heat shock protein; ADMA asymmetric dimethylarginine; ADMA dimethylarginine dimethylaminohydrolase; NEFA nonesterified fatty acids
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to move beyond one or a few single-nucleotide polymorphisms in a priori candidate genes. Genome-wide linkage analyses have been carried out for coronary artery calcification [105], and genome-wide association studies for myocardial infarction are already a reality [106]. Further studies are needed to address the relationship between single-nucleotide polymorphisms in components of each of the plaque, blood, and myocardial vulnerabilities and future outcomes (acute coronary syndromes and sudden cardiac death). However, ongoing proteomic research on serum samples of vulnerable patients collected from prospective studies before the onset of symptoms is most promising.
Coagulation/Anticoagulation System The importance of the coagulation system in the outcome of plaque complications was reemphasized by Karnicki et al. [107] who in a porcine model demonstrated that the role assigned to lesionbound tissue factor was not physically realistic and that blood borne factors must have a major role in thrombus propagation. A hematologic disorder is rarely the sole cause of coronary thrombosis and myocardial infarction. Inflammation promotes thrombosis and vice versa [108]. Extensive atherosclerosis may be associated with increased blood thrombogenicity, but the magnitude of thrombogenicity varies from patient to patient, and unstable plaques are much more thrombogenic than stable ones (Table 7). Some platelet polymorphisms, such as glycoprotein IIIa P1(A2) [109], Ib agene-5T/C Kozak [110], high factor V and factor VII clotting [111], have been reported as independent risk factors for myocardial infarction. Reiner et al. [112] reviewed the associations of known and potential genetic susceptibility markers for intermediate hemostatic phenotypes with arterial thrombotic disease. Other conditions that lead to a hypercoagulable state are diabetes mellitus, hypercholesterolemia, and cigarette smoking. High levels of circulating tissue factor may be the mechanism of action responsible for the increased thrombotic complications associated with the presence of these cardiovascular risk factors [113]. Acute coronary syndromes are associated with proinflammatory and prothrombotic conditions that involve a prolonged increase in the levels of fibrinogen, CRP, and plasminogen activator inhibitor [114, 115]. Table 7 Blood markers of vulnerability (reflecting hypercoagulability) Markers of blood hypercoagulability (e.g., fibrinogen, D-dimer, and factor V Leiden) Increased platelet activation and aggregation (e.g., gene polymorphisms of platelet glycoproteins IIb/IIIa, Ia/IIa, and Ib/IX) Increased coagulation factors (e.g., clotting of factors V, VII, and VIII; von Willebrand factor; and factor XIII) Decreased anticoagulation factors (e.g., proteins S and C, thrombomodulin, and antithrombin III) Decreased endogenous fibrinolysis activity (e.g., reduced t-PA, increased PAI-1, certain PAI-1 polymorphisms) Prothrombin mutation (e.g., G20210A) Other thrombogenic factors (e.g., anticardiolipin antibodies, thrombocytosis, sickle cell disease, polycythemia, diabetes mellitus, hypercholesterolemia, hyperhomocysteinemia) Increased viscosity Transient hypercoagulability (e.g., smoking, dehydration, infection, adrenergic surge, cocaine, estrogens, postprandial, etc.) t-PA tissue plasminogen activator; PAI-1 type 1 plasminogen activator inhibitor
From Vulnerable Plaque to Vulnerable Patient27
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A number of blood abnormalities, including antithrombin III deficiency, protein C or S deficiency, and resistance to activated protein C (also known as factor V Leiden), have been implicated as causes of venous thrombosis. The risk of arterial thrombosis is only modestly increased in these conditions, but these abnormalities are thought to interact with traditional risk factors for arterial thrombosis. Venous and arterial thromboses are prominent features of the antiphospholipid syndrome. The main antibodies of this syndrome are the anticardiolipin antibody, the lupus anticoagulant, and the IgG antibodies against prothrombin and b2-glycoprotein [116, 117]. In the nephrotic syndrome, proteinuria results in abnormal concentration and activity of coagulation factors. Moreover, the associated hypoalbuminemia, thrombocytosis, and hypercholesterolemia may induce arterial and venous thrombosis [118]. The importance of the coagulation/fibrinolytic system is highlighted by several autopsy studies that have shown a high prevalence of old plaque disruptions without infarctions. Therefore, an active fibrinolytic system may be able to prevent luminal thrombosis in some cases of plaque disruption [119, 120]. A transient shift in the coagulation and anticoagulation balance is likely to be an important factor in plaque–blood interaction, resulting in an acute event. “Triggers”, such as exercise and smoking, which are associated with catecholamine release, may increase the risk of plaque thrombosis [121]. Similarly, metabolic factors, such as postprandial metabolic changes, are associated with increased blood coagulability [122]. Likewise, estrogen replacement therapy can lead to a hypercoagulable state [123]. Finally, plasma viscosity, as well as fibrinogen and white blood cell counts, is positively associated with CHD events as shown by Koenig et al. [124] Furthermore, Junker et al. [125] showed a positive relationship between plasma viscosity and the severity of coronary heart disease (CHD).
Vulnerable Myocardium Ischemic Vulnerable Myocardium Without Prior Atherosclerosis-Derived Myocardial Damage Abrupt occlusion of a coronary artery is a common cause of sudden death. It often leads to acute myocardial infarction or exacerbation of chest pain [126, 127]. Extensive studies in experimental animals and increasing clinical evidence indicate that autonomic nervous activity has a significant role in modifying the clinical outcome with coronary occlusion [122, 128, 129]. Susceptibility of the myocardium to acute ischemia was reviewed by Airaksinen [130], who emphasized the key role of autonomic tone in the outcome after plaque rupture. Sympathetic hyperactivity favors the genesis of life-threatening ventricular tachyarrhythmias, whereas vagal activation exerts an antifibrillatory effect. Strong afferent stimuli from the ischemic myocardium may impair the arterial baroreflex and lead to hemodynamic instability [131]. There seems to be a wide interindividual variation in the type and severity of autonomic reactions during the early phase of abrupt coronary occlusion, a critical period for out-of-hospital cardiac arrest. The pre-existing severity of a coronary stenosis, adaptation or preconditioning to myocardial ischemia, habitual physical exercise, b-blockade, and gender seem to affect autonomic reactions and the risk of fatal ventricular arrhythmias [130, 132, 133]. Recent studies have documented a hereditary component for autonomic function, and genetic factors may also modify the clinical presentation of acute coronary occlusion [134, 135]. Table 8 depicts conditions and markers associated with myocardial vulnerability.
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With atherosclerosis-derived myocardial ischemia as shown by ECG abnormalities During rest During stress test Silent ischemia (e.g., ST changes on Holter monitoring) Perfusion and viability disorder PET scan SPECT Wall motion abnormalities Echocardiography MR imaging x-ray ventriculogram MSCT Without atherosclerosis-derived myocardial ischemia Sympathetic hyperactivity Impaired autonomic reactivity Left ventricular hypertrophy Cardiomyopathy (dilated, hypertrophic, or restrictive) Valvular disease (aortic stenosis and mitral valve prolapse) Electrophysiological disorders Long-QT syndrome, Brugada syndrome, Wolff–Parkinson–White syndrome, sinus and atrioventricular conduction disturbances, catecholaminergic polymorphic ventricular tachycardia, T-wave alternans, drug-induced torsades de pointes Commotio cordis Anomalous origination of a coronary artery Myocarditis Myocardial bridging MSCT multislice computed tomography; PET positron emission tomography; SPECT single-photon emission computed tomography
Ischemic Vulnerable Myocardium with Prior Atherosclerosis-Derived Myocardial Damage (Chronic Myocardial Damage) Any type of atherosclerosis-related myocardial injury, such as ischemia, an old or new myocardial infarction, inflammation, and/or fibrosis, potentially increases the patient’s vulnerability to arrhythmia and sudden death. In the past few decades, a number of diagnostic methods have been developed for imaging cardiac ischemia and for assessing the risk of developing a life-threatening cardiac arrhythmia. In patients with a history of ischemic heart disease, ischemic cardiomyopathy is the ultimate form of myocardial damage. With the advent of new, effective treatments for hypertension and more efficient management of acute myocardial infarction, deaths resulting from stroke and acute myocardial infarction have steadily decreased [136]. More patients are now surviving acute events, but some develop heart failure or ischemic cardiomyopathy later with the potential for fatal arrhythmias. It is also important to remember that in a significant number of patients sudden cardiac death is the first manifestation of underlying heart disease, and it is still responsible for >450,000 deaths annually in the United States.
From Vulnerable Plaque to Vulnerable Patient29
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Nonischemic Vulnerable Myocardium A smaller subset of patients experience fatal arrhythmia as a result of diseases other than coronary atherosclerosis. The various forms of cardiomyopathy (dilated, hypertrophic, restrictive, and right ventricular) account for most noncoronary cardiac deaths. Other underlying pathological processes include valvular heart disease, such as aortic stenosis and primary electrical disturbances (long-QT syndromes, Brugada syndrome, Wolff–Parkinson–White syndrome, sinus and atrioventricular conduction disturbances, catecholaminergic polymorphic ventricular tachycardia, and congenital and drug-induced long-QT syndromes with torsades de pointes), and, infrequently, commotio cordis from chest trauma. Less common pathological conditions include anomalous origin of a coronary artery, myocarditis, and myocardial bridging (Table 8). Circulating nonesterified fatty acids are another risk factor for sudden death in middle-aged men, as is elevated serum concentration of CRP; serum measurements may help screening for vulnerable myocardium [137]. The Task Force on Sudden Cardiac Death, organized by the European Society of Cardiology, issued a report that includes detailed diagnostic and therapeutic recommendations for a large number of cardiomyopathic conditions capable of causing sudden cardiac death [138]. Table 9 provides electrophysiological diagnostic criteria and techniques for the detection of myocardial vulnerability.
Risk Assessment for Vulnerable Patients Traditional Risk Assessment Strategies Despite extensive studies and development of several risk prediction models, traditional CHD risk factors fail to predict the development of CHD in a large group of cases (25% [139] to 50% [3, 140, 141]). Risk prediction models developed on the basis of data from long-term populationbased follow-up studies may not be able to predict short-term risks for individual persons. The pioneering studies by Ridker et al. [95] who noted a greater impact of an inflammatory marker such as serum CRP than LDL levels, is of interest. Several risk factor assessment models (e.g., Framingham [142], Sheffield [143, 144], New Zealand [145, 146], Canadian [147], British [148], European [149], Dundee [150], Munster [PROCAM] [151], and MONICA [152]) have been developed. However, all of them are based on the traditional risk factors known to contribute to the chronic development of atherosclerosis. Addition of emerging risk factors, particularly those indicative of the activity of the disease (i.e., plaque inflammation), may allow individualized risk assessments to be made. The traditional risk assessment has been shown to predict long-term outcome in large populations. However, they fall short in predicting near-future events particularly in individual clinical practice. For example, a high Framingham risk score, although capable of forecasting an adverse cardiovascular event in 10 years, clearly falls short in accurately predicting events in individual patients and cannot provide a clear clinical route for cardiologists to identify and treat, to prevent near-future victims of acute coronary syndromes and sudden death. The same is true for coronary evaluations using electrocardiography, myocardial perfusion tests, and coronary angiography. A positive test for coronary stenosis or reversible perfusion defect (ischemia), although considered as a major risk factor, must be coupled in the future with emerging methods of risk assessment for the detection of vulnerable patients to predict more accurately the near-future outcome and prognosis. Those who have no indication of coronary stenosis or myocardial ischemia and who may even lack traditional risk factors may benefit from the techniques now under development that evaluate plaque biology and inflammation.
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Naghavi and Falk Table 9 Available techniques for electrophysiological risk stratification of vulnerable myocardium Diagnostic criteria Arrhythmia QT dispersion QT dynamics T-wave alternans Ventricular late potentials Heart rate variability Diagnostic techniques Noninvasive Resting ECG Stress ECG Ambulatory ECG Signal-averaged ECG Surface high-resolution ECG Invasive Programmed ventricular stimulation Real-time 3D magnetic-navigated activation map
New Risk Assessment Strategies We propose a Cumulative Vulnerability Index based on the following: • Vulnerable plaque/artery • Vulnerable blood (prone to thrombosis) • Vulnerable myocardium (prone to life-threatening arrhythmia)
This proposal is by no means intended to disregard the predictive value of traditional risk assessment strategies that have been proven in predicting long-term outcome but instead to strengthen their value in providing higher accuracy, especially for near-term outcomes. Atherosclerosis is a diffuse and multisystem, chronic inflammatory disorder involving vascular, metabolic, and immune systems with various local and systemic manifestations. Therefore, it is essential to assess total vulnerability burden and not just search for a single, unstable coronary plaque. A composite risk score (e.g., a vulnerability index) that comprises the total burden of atherosclerosis and vulnerable plaque in the coronaries (and aorta and carotid, femoral, etc., arteries) and that includes blood and myocardial vulnerability factors, should be a more accurate method of risk stratification. Such a vulnerability index would indicate the likelihood that a patient with certain factors would have a clinical event in the coming year. Use of the state-of-the-art bioinformatics tools such as neural networks may provide substantial improvement for risk calculations [153]. The information used for developing such risk stratification in the future is likely to come from a combination of smaller prospective studies (e.g., from new imaging techniques) and retrospective cohort studies (e.g., for serum factors) in which the risks for near-future cardiovascular events can be quantitatively calculated. A few such studies have been conducted or are underway [94, 154].
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Fig. 7. The Vulnerable Patient Pyramid. This pyramid illustrates a speculative roadmap in search of vulnerable patients (numbers represent population in the United States). The major need is to develop noninvasive, relatively inexpensive, readily available, and accurate screening/diagnostic tools allowing multistep screening of an apparently healthy population and those with known atherosclerosis but whose risks for acute events are uncertain.
In Search of the Vulnerable Patient The ideal method for screening vulnerable patients should be (1) inexpensive, (2) relatively noninvasive, (3) widely reproducible, (4) readily applicable to an asymptomatic population, and (5) capable of adding predicted value to measurements of established risk factors. Such a method should provide a cost-effective, stepwise approach designed to further stratify risk and provide reliable diagnosis and pathways for monitoring therapy. Obviously, these goals are hard to achieve with today’s tools. However, it is well within our reach, if academia and industry in the field of cardiovascular medicine undertake a coordinated effort to embark on developing new screening and diagnostic techniques to identify vulnerable patients (Fig. 7). The Vulnerable Patient Pyramid This pyramid illustrates a speculative roadmap in search of vulnerable patients (numbers represent population in the United States). The major need is to develop noninvasive, relatively inexpensive, readily available, and accurate screening/diagnostic tools allowing multistep screening of an apparently healthy population and those with known atherosclerosis but whose risks for acute events are uncertain. *The vulnerable patient consensus writing group: Morteza Naghavi, MD; Peter Libby, MD; Erling Falk, MD, PhD; S. Ward Casscells, MD; Silvio Litovsky, MD; John Rumberger, MD; Juan Jose Badimon, PhD; Christodoulos Stefanadis, MD; Pedro Moreno, MD; Gerard Pasterkamp, MD, PhD; Zahi Fayad, PhD; Peter H. Stone, MD; Sergio Waxman, MD; Paolo Raggi, MD; Mohammad Madjid, MD; Alireza Zarrabi, MD; Allen Burke, MD; Chun Yuan, PhD; Peter J. Fitzgerald, MD, PhD; David S. Siscovick, MD; Chris L. de Korte, PhD; Masanori
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Aikawa, MD, PhD; K. E. Juhani Airaksinen, MD; Gerd Assmann, MD; Christoph R. Becker, MD; James H. Chesebro, MD; Andrew Farb, MD; Zorina S. Galis, PhD; Chris Jackson, PhD; Ik-Kyung Jang, MD, PhD; Wolfgang Koenig, MD, PhD; Robert A. Lodder, PhD; Keith March, MD, PhD; Jasenka Demirovic, MD, PhD; Mohamad Navab, PhD; Silvia G. Priori, MD, PhD; Mark D. Rekhter, PhD; Raymond Bahr, MD; Scott M. Grundy, MD, PhD; Roxana Mehran, MD; Antonio Colombo, MD; Eric Boerwinkle, PhD; Christie Ballantyne, MD; William Insull, Jr, MD; Robert S. Schwartz, MD; Robert Vogel, MD; Patrick W. Serruys, MD, PhD; Goran K. Hansson, MD, PhD; David P. Faxon, MD; Sanjay Kaul, MD; Helmut Drexler, MD; Philip Greenland, MD; James E. Muller, MD; Renu Virmani, MD; Paul M Ridker, MD; Douglas P. Zipes, MD; Prediman K. Shah, MD; James T. Willerson, MD From The Center for Vulnerable Plaque Research, University of Texas—Houston, The Texas Heart Institute, and President Bush Center for Cardiovascular Health, Memorial Hermann Hospital, Houston (M. Naghavi, S.W.C., S.L., M.M., A.Z., J.T.W.); The Leducq Center for Cardiovascular Research, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (P.L., M.A.); Department of Cardiology and Institute of Experimental Clinical Research, Aarhus University, Aarhus, Denmark (E.F.); Experimental Cardiology Laboratory, Vascular Biology of the University Medical Center in Utrecht, the Netherlands (G.P.); Ohio State University (J.R.); the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (Z.F.); Cardiac Catheterization Laboratory at the VA Medical Center, University of Kentucky, Lexington (P.M.); Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (P.H.S.); Division of Cardiology, New England Medical Center, Boston, Mass (S.W.); Department of Medicine, Section of Cardiology, Tulane University School of Medicine, New Orleans, La (P.R.); Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC (A.B., A.F., R.V.); Department of Radiology, University of Washington, Seattle (C.Y.); Stanford University Medical Center Stanford, Calif (P.J.F.); Cardiovascular Health Research Unit, University of Washington, Seattle (D.S.S.); Department of Cardiology, Athens Medical School, Athens, Greece (C.S.); Catheterization Laboratory, Thorax Center, Erasmus University, Rotterdam, the Netherlands (C.L.d.K.); Division of Cardiology, Department of Medicine, University of Turku, Finland (K.E.J.A.); Institute of Arteriosclerosis Research and the Institute of Clinical Chemistry and Laboratory Medicine, Central Laboratory, Hospital of the University of Münster, Munich, Germany (G.A.); Department of Clinical Radiology, University of Münster, Munich, Germany (C.R.B.); Mayo Clinic Medical School, Jacksonville, Fla (J.H.C.); Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Ga (Z.S.G.); Bristol Heart Institute, Bristol University, Bristol, United Kingdom (C.J.); Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Mass (I.-K.J.); Department of Internal Medicine II, Cardiology, University of Ulm, Ulm, Germany (W.K.); University of Kentucky, Lexington, Ky (R.A.L.); R.L. Roudebush VA Medical Center, Indianapolis, Ind (K.M.); School of Public Health, University of Texas—Houston, Houston, Texas (J.D.); Division of Cardiology, University of California Los Angeles, Los Angeles, Calif (M. Navab); Fondazione Salvatore Maugeri, University of Pavia, Pavia, Italy (S.G.P.); Department of Cardiovascular Therapeutics, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, Mich (M.D.R.); Paul Dudley White Coronary Care System at St. Agnes HealthCare, Baltimore, Md (R.B.); Center for Human Nutrition, University of Texas Health Science Center, Dallas (S.M.G.); Lenox Hill Hospital, New York, NY (R.M.); Catheterization Laboratories, Ospedale San Raffaele and Emo Centro Cuore Columbus, Milan, Italy (A.C.); Human Genetics Center, Institute of Molecular Medicine, Houston, Tex (E.B.); Department of Medicine, Baylor College of Medicine, Houston, Tex (C.B., W.I.); Minneapolis Heart Institute and Foundation, Minneapolis, Minn (R.S.S.); Division of
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Cardiology, University of Maryland School of Medicine, Baltimore, Md (R.V.); Karolinska Institute, Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden (G.K.H.); Section of Cardiology, University of Chicago, Ill (D.P.F.); Vascular Physiology and Thrombosis Research Laboratory of the Atherosclerosis Research Center, Cedars-Sinai Medical Center, Los Angeles, California (S.K.); Cardiology Department, Hannover University, Hannover, Germany (H.D.); Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Ill (P.G.); UCLA School of Medicine and Cedars-Sinai Medical Center, Los Angeles, Calif (P.K.S.); Massachusetts General Hospital, Harvard Medical School and CIMIT (Center for Integration of Medicine and Innovative Technology), Boston, Mass (J.E.M.); Cardiovascular Division, Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Mass (P.M.R.); and Indiana University School of Medicine, Krannert Institute of Cardiology, Indianapolis (D.P.Z.).
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2000;102:2165–2168. 97. Verma SLS, Badiwala MV, Weisel RD, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation. 2002;105:1890–1896. 98. Koukkunen H, Penttila K, Kemppainen A, et al. C-reactive protein, fibrinogen, interleukin-6 and tumour necrosis factoralpha in the prognostic classification of unstable angina pectoris. Ann Med. 2001;33:37–47. 99. Schonbeck U, Varo N, Libby P, et al. Soluble CD40L and cardiovascular risk in women. Circulation. 2001;104: 2266–2268. 100. Hwang SJ, Ballantyne CM, Sharrett AR, et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation. 1997;96:4219–4225. 101. Kiechl S, Egger G, Mayr M, et al. Chronic infections and the risk of carotid atherosclerosis : prospective results from a large population study. Circulation. 2001;103:10641070. 102. Bayes-Genis A, Conover CA, Overgaard MT, et al. Pregnancy-associated plasma protein A as a marker of acute coronary syndromes. N Engl J Med. 2001;345:1022–1029. 103. Beaudeux JL, Burc L, Imbert-Bismut F, et al. Serum plasma pregnancyassociated protein A: a potential marker of echogenic carotid atherosclerotic plaques in asymptomatic hyperlipidemic subjects at high cardiovascular risk. Arterioscler Thromb Vasc Biol. 2003;23:e7–e10. 104. Yamada Y, Izawa H, Ichihara S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med. 2002;347:1916–1923. 105. Lange LA, Lange EM, Bielak LF, et al. Autosomal genome-wide scan for coronary artery calcification loci in sibships at high risk for hypertension. Arterioscler Thromb Vasc Biol. 2002;22:418–423. 106. Ozaki K, Ohnishi Y, Iida A, et al. Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet. 2002;32:650–654. 107. Karnicki K, Owen WG, Miller RS, et al. Factors contributing to individual propensity for arterial thrombosis. Arterioscler Thromb Vasc Biol. 2002;22:1495–1499. 108. Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation. 2001;103:1718–1720. 109. Barakat K, Kennon S, Hitman GA, et al. Interaction between smoking and the glycoprotein IIIa P1(A2) polymorphism in nonST-elevation acute coronary syndromes. J Am Coll Cardiol. 2001;38:1639–1643. 110. Douglas H, Michaelides K, Gorog DA, et al. Platelet membrane glycoprotein Iba gene –5T/C Kozak sequence polymorphism as an independent risk factor for the occurrence of coronary thrombosis. Heart. 2002;87:70–74. 111. Redondo M, Watzke HH, Stucki B, et al. Coagulation factors II, V, VII, and X, prothrombin gene 20210G3A transition, and factor V Leiden in coronary artery disease: high factor V clotting activity is an independent risk factor for myocardial infarction. Arterioscler Thromb Vasc Biol. 1999;19:1020–1025. 112. Reiner AP, Siscovick DS, Rosendaal FR. Hemostatic risk factors and arterial thrombotic disease. Thromb Haemost. 2001;85:584–595. 113. Sambola A, Osende J, Hathcock J, et al. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation. 2003;107:973–977. 114. Passoni F, Morelli B, Seveso G, et al. Comparative short-term prognostic value of hemostatic and inflammatory markers in patients with non-ST elevation acute coronary syndromes. Ital Heart J. 2002;3:28–33. 115. Hoffmeister HM, Heller W, Seipel L. Activation markers of coagulation and fibrinolysis: alterations and predictive value in acute coronary syndromes. Thromb Haemost. 1999;82:76–79. 116. Vaarala O, Puurunen M, Manttari M, et al. Antibodies to prothrombin imply a risk of myocardial infarction in middle-aged men. Thromb Haemost. 1996;75:456–459. 117. Jouhikainen T, Pohjola-Sintonen S, Stephansson E. Lupus anticoagulant and cardiac manifestations in systemic lupus erythematosus. Lupus. 1994;3:167–172.
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118. Osula S, Bell GM, Hornung RS. Acute myocardial infarction in young adults: causes and management. Postgrad Med J. 2002;78:27–30. 119. Burke AP, Kolodgie FD, Farb A, et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation. 2001;103:934–940. 120. Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart. 1999;82:265–268. 121. Servoss SJ, Januzzi JL, Muller JE. Triggers of acute coronary syndromes. Prog Cardiovasc Dis. 2002;44:369–380. 122. Silveira A. Postprandial triglycerides and blood coagulation. Exp Clin Endocrinol Diabetes. 2001;109:S527–S532. 123. McNagny SE, Wenger NK. Postmenopausal hormone-replacement therapy. N Engl J Med. 2002;346:63–65. 124. Koenig W, Sund M, Filipiak B, et al. Plasma viscosity and the risk of coronary heart disease: results from the MONICAAugsburg Cohort Study, 1984 to 1992. Arterioscler Thromb Vasc Biol. 1998;18:768–772. 125. Junker R, Heinrich J, Ulbrich H, et al. Relationship between plasma viscosity and the severity of coronary heart disease. Arterioscler Thromb Vasc Biol. 1998;18:870–875. 126. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: structure, function, and time-dependence of risk. Circulation. 1992;85(Suppl I):I-2–I-10. 127. Kannel WB, Doyle JT, McNamara PM, et al. Precursors of sudden coronary death: factors related to the incidence of sudden death. Circulation. 1975;51:606–613. 128. Schwartz PJ, Vanoli E, Zaza A, et al. The effect of antiarrhythmic drugs on life-threatening arrhythmias induced by the interaction between acute myocardial ischemia and sympathetic hyperactivity. Am Heart J. 1985;109:937–948. 129. Vanoli E, De Ferrari GM, Stramba-Badiale M, et al. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res. 1991;68:1471–1481. 130. Airaksinen KE. Autonomic mechanisms and sudden death after abrupt coronary occlusion. Ann Med. 1999;31:240–245. 131. Airaksinen KE, Tahvanainen KU, Eckberg DL, et al. Arterial baroreflex impairment in patients during acute coronary occlusion. J Am Coll Cardiol. 1998;32:1641–1647. 132. Billman GE, Schwartz PJ, Stone HL. The effects of daily exercise on susceptibility to sudden cardiac death. Circulation. 1984;69:1182–1189. 133. Burke AP, Farb A, Malcom GT, et al. Plaque rupture and sudden death related to exertion in men with coronary artery disease. JAMA. 1999;281:921–926. 134. Jouven X, Desnos M, Guerot C, et al. Predicting sudden death in the population: the Paris Prospective Study I. Circulation. 1999;99:1978–1983. 135. Singh JP, Larson MG, O’Donnell CJ, et al. Heritability of heart rate variability: the Framingham Heart Study. Circulation. 1999;99:2251–2254. 136. Claessens C, Claessens P, Claessens M, et al. Changes in mortality of acute myocardial infarction as a function of a changing treatment during the last two decades. Jpn Heart J. 2000;41:683–695. 137. Jouven X, Charles MA, Desnos M, et al. Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population. Circulation. 2001;104:756–761. 138. Priori SG, Aliot E, Blomstrom-Lundqvist C, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J. 2001;22:1374–1450. 139. Magnus P, Beaglehole R. The real contribution of the major risk factors to the coronary epidemics: time to end the “only-50%” myth. Arch Intern Med. 2001;161:2657–2660. 140. Lefkowitz RJ, Willerson JT. Prospects for cardiovascular research. JAMA. 2001;285:581–587. 141. Nieto FJ. Cardiovascular disease and risk factor epidemiology: a look back at the epidemic of the 20th century. Am J Public Health. 1999;89:292–294. 142. Anderson KM, Odell PM, Wilson PW, et al. Cardiovascular disease risk profiles. Am Heart J. 1991;121:293–298. 143. Ramsay LE, Haq IU, Jackson PR, et al. Targeting lipid-lowering drug therapy for primary prevention of coronary disease: an updated Sheffield table. Lancet. 1996;348:387–388. 144. Wallis EJ, Ramsay LE, Ul Haq I, et al. Coronary and cardiovascular risk estimation for primary prevention: validation of a new Sheffield table in the 1995 Scottish health survey population. BMJ. 2000;320:671–676. 145. 1996 National Heart Foundation clinical guidelines for the assessment and management of dyslipidaemia. Dyslipidaemia Advisory Group on behalf of the Scientific Committee of the National Heart Foundation of New Zealand. N Z Med J. 1996;109:224–231. 146. Jackson R. Updated New Zealand cardiovascular disease risk-benefit prediction guide. BMJ. 2000;320:709–710. 147. McCormack JP, Levine M, Rangno RE. Primary prevention of heart disease and stroke: a simplified approach to estimating risk of events and making drug treatment decisions. CMAJ. 1997;157:422–428. 148. Joint British recommendations on prevention of coronary heart disease in clinical practice: summary. British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, British Diabetic Association. BMJ. 2000;320: 705–708. 149. Wood D, De Backer G, Faergeman O, et al. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Atherosclerosis. 1998;140:199–270. 150. Tunstall-Pedoe H. The Dundee coronary risk-disk for management of change in risk factors. BMJ. 1991;303:744–747.
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3
Pathology of Vulnerability Caused by High-Risk (Vulnerable) Arteries and Plaques Troels Thim, Mette Kallestrup Hagensen, Jacob Fog Bentzon, and Erling Falk Contents Key Points or Topic Pearls Plaque Rupture Key Features of Ruptured Plaques: Core and Cap Atherothrombosis The Vulnerable Patient Conclusions References
Abstract Atherosclerosis is a slowly progressing systemic (multifocal) arterial disease with focal manifestations caused by one or relatively few stenotic and/or thrombosis-prone (vulnerable) plaques. The coronary arteries, carotid arteries, ilio-femoral arteries, and aorta are especially susceptible to atherosclerosis. The most devastating consequences of atherosclerosis, such as heart attack and stroke, are usually caused by thrombosis precipitated by plaque rupture. Although the morphology of ruptured plaques has been known for decades, it remains poorly understood why a single plaque among many plaques becomes vulnerable and suddenly ruptures. Plaque rupture requires the presence of a lipid-rich (necrotic) core covered by a thin fibrous cap, and the development and detection of “core and cap” are currently explored in basic and clinical research. Other plaque and plaque-related features may be useful markers of vulnerability, including plaque inflammation (macrophage density and activity), neovascularization (angiogenesis), hemorrhage, microcalcification, adventitial inflammation (lymphocytes), and expansive remodeling. Vascular imaging and function testing have the potential to provide a comprehensive assessment of atherosclerosis, including detection of plaque burden, plaque vulnerability, and disease activity. The search for better markers of cardiovascular risk must continue. With the traditional risk-factor-based approach in primary prevention, most individuals From: Asymptomatic Atherosclerosis: Pathophysiology, Detection and Treatment Edited by: M. Naghavi (ed.), DOI 10.1007/978-1-60327-179-0_3 © Springer Science+Business Media, LLC 2010 39
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destined for a near-term heart attack or stroke are misclassified and not identified as being at high risk. Consequently, they are not offered appropriate preventive therapy. Detection of subclinical but high-risk atherosclerosis may change this unfortunate situation. Key words: Atherosclerosis; Vulnerable plaque; Plaque rupture; Coronary thrombosis; Risk assessment
Key Points or Topic Pearls • • • • •
A “high-risk” or “vulnerable” plaque is a thrombosis-prone plaque Plaque rupture is the most common cause of thrombosis in coronary and carotid arteries Plaque rupture requires the presence of a lipid-rich (necrotic) core covered by a thin fibrous cap In plaque rupture, the tiny fibrous cap is heavily inflamed at the rupture site Assessment of subclinical atherosclerosis can improve the prediction of cardiovascular risk
Nearly all of us develop atherosclerosis, but the speed of development and the clinical consequences vary greatly and are difficult to predict. The preclinical incubation period is long, and most people live with atherosclerosis without feeling it or becoming sick from it. Developing the stenotic and/or high-risk (vulnerable) plaques responsible for clinical disease takes decades, and by then, atherosclerosis is usually severe and generalized [1, 2]. Furthermore, many first events are fatal, and these can, of course, only be averted by intervention in the disease’s preclinical phase. The long incubation period when atherosclerosis is subclinical and harmless offers unique opportunities for the prevention of overt atherosclerotic cardiovascular disease (CVD) by timely detection and treatment of subclinical atherosclerosis. Identification of those in need of preventive therapy remains, however, a major challenge. Causal risk factors for atherosclerotic CVD are known and constitute important therapeutic targets [3], but their predictive power is limited [4–6]. In fact, most first heart attacks occur in previously asymptomatic individuals with unrecognized atherosclerosis who are misclassified by the Framingham Risk Score as being at low or intermediate risk [7]. Thus, when screening is based on risk factors alone, most individuals destined for an acute atherothrombotic event are not identified and, consequently, not offered adequate preventive treatment. Risk factor exposure is obviously not the only determinant of atherosclerotic CVD, individual susceptibility to the disease must also play an important role. The overall “holistic” effects of exposure to risk factors, known as well as unknown, and susceptibility are captured by the actual amount (burden) and character (activity) of the underlying arterial disease. Therefore, tests for subclinical atherosclerosis hold key to reform risk assessment and ensure optimal use of prevention therapy [8]. Atherosclerosis is a systemic arterial disease of multifactorial origin [9]. It begins early in life with multifocal plaque development in medium-sized and large arteries. The coronary arteries, carotid arteries, ilio-femoral arteries, and aorta are particularly susceptible to atherosclerosis. The most devastating consequences of atherosclerosis, such as heart attack and stroke, are caused by superimposed thrombosis [9, 10]. Therefore, the vital question is not why atherosclerosis develops but rather why atherosclerosis, after years of indolent growth, suddenly becomes complicated with luminal thrombosis. If thrombosisprone plaques could be detected and thrombosis averted, atherosclerosis would be a much more benign disease. The most common type of thrombosis-prone plaques, also known as high-risk or vulnerable plaques [11], is the rupture-prone plaque, which constitutes the main focus of this chapter.
Plaque Rupture Because of lack of prospective data, we have learned about plaques assumed to be rupture-prone by extrapolating from what we know about ruptured plaques. Plaque rupture is by far the most common cause of arterial thrombosis, and, consequently, the rupture-prone plaque is the most important type of
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vulnerable plaque and also the best described [11]. Plaque rupture is responsible for approximately 75% of coronary thrombi leading to myocardial infarction and/or death [9, 12] and around 90% of thrombosed carotid plaques causing ischemic stroke [13]. Much less is known about nonrupture related thrombosis and its potential precursor plaques among which the so-called erosion-prone plaque dominates. The ruptured plaque has been defined as “a plaque with deep injury with a real defect or gap in the fibrous cap that had separated its lipid-rich atheromatous core from the flowing blood, thereby exposing the thrombogenic core of the plaque” [11]. Thus, the presence of a lipid-rich core covered by a fibrous cap is required for plaque rupture [11], and the descriptive term thin-cap fibroatheroma (TCFA) has been suggested for intact plaques at risk of rupture [14]. The exposure of the thrombogenic lipidrich core in plaque rupture may lead to thrombosis, which covers the rupture site and extends into the lumen [15, 16]. A ruptured plaque with superimposed thrombosis is shown in Fig. 1. The most extensive and detailed knowledge about ruptured and thus rupture-prone plaques stems from autopsy studies [14–18]. Additional information has been gathered from atherectomy specimen of coronary origin [19, 20] and endarterectomy specimen of carotid origin [13, 21]. Lately, intravascular imaging with optical coherence tomography has provided convincing in vivo evidence of plaque rupture in the coronary arteries of patients with acute myocardial infarction [12]. However, all these techniques have the same limitation: they provide information on the structure and components of ruptured plaques and only by extrapolation do we learn about the features of rupture-prone plaques. A useful animal model, in which the mechanisms leading to spontaneous plaque rupture could be studied prospectively, would overcome some of these problems, but such a model is not yet available [22].
Key Features of Ruptured Plaques: Core and Cap The presence of a lipid-rich (necrotic) core covered by a fibrous cap is a prerequisite for plaque rupture. In the absence of a core there is no fibrous cap, and the plaque cannot rupture. Therefore, the formation of a lipid-rich core is the essential early mechanism in the development of the rupture-prone plaque.
Fig. 1. Fatal coronary thrombosis caused by plaque rupture. There is a defect in the fibrous cap, through which thrombogenic material from the lipid-rich core has been dislodged into the lumen. Plaque hemorrhage is seen beneath the rupture site.
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Fig. 2. Top left panel illustrates a plaque assumed to be rupture-prone. The lipid-rich core occupies approximately 40% of the plaque area and contains multiple cholesterol crystals. The fibrous cap is thin and inflamed with few smooth muscle cells. Plaque microvessels originating from the adventitia are extending through the media into the base of the plaque. Top right panel illustrates the thin and locally weakened fibrous cap. Macrophages are abundantly present whereas smooth muscle cells are scarce. Bottom left panel illustrates the corresponding ruptured plaque with consequent thrombus covering the rupture site.
If lipid-rich core formation could be prevented, no plaque ruptures would occur. Later, when the lipid-rich core has formed, the key process is the thinning of the fibrous cap toward its rupture. If fibrous cap thinning could be prevented, no plaque ruptures would occur. A number of other features are associated with rupture-prone plaques (e.g., angiogenesis, intraplaque hemorrhage, perivascular inflammation, and expansive remodeling). To the extent that these features are causal for plaque rupture, their most likely mode of action is through modulation of the lipid-rich core and the fibrous cap. Figure 2 illustrates the characteristic features of the rupture-prone plaque.
Lipid-Rich Core A large lipid-rich core is associated with plaque rupture. In human coronary arteries, the lipid-rich cores of ruptured plaques were larger compared to nonruptured plaques and occupied on average 29–34% of plaque area in ruptured plaques [14, 23, 24]. In the carotid artery of symptomatic patients undergoing carotid endarterectomy, a mean lipid-rich core size of 40% of plaque area was found [21]. Similarly in human aortas, ruptured plaques had larger lipid-rich cores than nonruptured plaques, occupying close to 60% of ruptured plaque area [25, 26].
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The increase in total plaque lipid content in ruptured compared to intact plaques is predominantly due to increased amounts of free cholesterol and cholesteryl esters, and the ratio of free cholesterol to cholesteryl esters is increased [26–28]. The importance of lipid-rich core size for plaque rupture is comprehensible, because (1) the expansion of the lipid-rich core may erode the fibrous cap from below, and (2) the total lack of supporting collagen in the lipid-rich core confers greater tensile stress to the overlying fibrous cap. The mechanism of lipid-rich core formation is poorly understood. It has been suggested that smaller pools of accumulated lipid in the basal intima coalesce to a larger pool that due to apoptosis and necrosis of smooth muscle cells and lipid-filled macrophages (foam cells) becomes acellular [14, 29–31]. Cell surface markers on the macrophages in the basal intima of atherosclerotic plaque differ from those in the superficial intima [32]. This may explain a different propensity for apoptosis and necrosis of macrophages in the basal and superficial intima and thereby why lipid-rich cores form in the basal intima [33]. Because cell death is believed to play an important role in the formation of a lipid-rich core, it is also called a necrotic core. Several sources of lipids contribute to the lipid-rich core and the quantitative importance of these varies between different stages of plaque formation. In atherogenesis in general, the contribution from blood-derived lipoproteins is emphasized [34]. Lipoproteins entering the plaque may be retained and phagocytosed by macrophages which may later die, leaving behind their lipid‐rich content, and thus contributing to the lipid-rich core [35]. However, lipoproteins may also contribute directly without first passing through foam cells [36]. It has been suggested that intraplaque hemorrhage from neovessels within the plaque may lead to rapid growth of the lipid-rich core and increase its free cholesterol content through the delivery of erythrocyte membranes containing high concentrations of cholesterol [37]. The high free cholesterol content facilitates cholesterol crystal formation, and increased number of cholesterol crystals in the lipid-rich core is associated with plaque rupture [14].
Fibrous Cap The fibrous cap is simply defined as the connective tissue layer covering the lipid-rich core. It consists of smooth muscle cells and the extracellular matrix they synthesize (mainly collagen and proteoglycans) [14, 29–31]. The cap also contains inflammatory cells, predominantly macrophage foam cells (Fig. 2). Plaque rupture only occurs when the fibrous cap is extremely thin [17, 38]. In a post mortem series of 41 ruptured coronary plaques, 95% of the fibrous caps were 80 mm Hg or SBP > 120 mm Hg Current smoking Diabetes Cholesterol ³ 240 mg/dL (³ 6.22 mmol/L) DBP ³ 90 mm Hg or SBP ³ 140 mm Hg
1068 72% 91% 52% 7.1% 30% 73% 465 77% 87% 52% 5.6% 39% 71%
8026 62% 83% 40% 3.0% 21% 60% 7188 67% 72% 35% 2.1% 27% 47%
17416 77% 89% 49% 5.6% 37% 56% NA NA NA NA NA NA NA
257996 65% 78% 35% 1.5% 24% 36% NA NA NA NA NA NA NA
Abbreviations: CHA, Chicago Heart Association Detection Project in Industry; CHD, coronary heart disease; DSP, diastolic blood pressure; MRFIT, Multiple Risk Factor Intervention Trial; NA, not applicable; SBP, systolic blood pressure. Adapted from Greenland et al. [6]
matically, can also be considered to be the presence or absence of the underlying subclinical atherosclerosis, and the susceptibility to thrombotic (vulnerable blood) and arrhythmic (vulnerable myocardium) complications. The poor predictive power of major traditional risk factors was clearly demonstrated by Weissler [7] who calculated a weak likelihood ratio of 1.03 to 1.42 for prediction of coronary events in men and women (See Table 2). Despite the high frequency of this risk profile in the population with CHD events. This apparent paradox is attributable to the presence of 1 or more risk factors in a great many individuals with no CHD [7]. The inability of the traditional risk factors to identify the at-risk population is the basis of the “Polypill” strategy, in which people with known CVD or over 55 without known disease , are treated with a single daily pill containing 6 components to reduce the risk factor level, regardless of what current risk assessment algorithms predict [8]; 96% of deaths from CHD or stroke occur in people aged 55 and over [8].
Current Guidelines in Primary Prevention The current primary prevention guidelines recommend initial risk assessment and then risk classification based on risk factors (e.g. the Framingham Risk Score in the United States and the SCORE in Europe), followed by risk reducing goal-directed therapy when necessary [9–12]. Although this approach may identify persons at very low or very high risk of a heart attack or stroke within the next 10 years, the majority of the population belongs to an intermediate risk group, in which the predictive power of risk factors is low. Since most heart attacks occur in this group (high population attributable risk), many individuals at risk are likely to be not properly identified and, thus, not treated
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Table 2 Predictive power for CHD death, or CHD or nonfatal myocardial infarction, in men and women aged 18–59 Years (From Weissler [7]) % Sensitivity
Specificity
Complement of specificity (100-specificity)
Positive likelihood ratio (95% cl)
Men
87.5
33.0
67.0
1.31 (1.30–1.32)
Women
93.1
33.1
66.9
1.39 (1.35–1.42)
Sex CHD Death
CHD Death or nonfatal myocardial infarction Men
90.4
25.9
84.1
1.07 (1.03–1.11)
Women
87.9
27.6
72.4
1.21 (1.14–1.28)
Abbreviations: CHD, coronary heart disease; CI, confidence interval
to more appropriate “individualized” goals, whereas others are misclassified as being at high risk and are unnecessarily treated with pharmacologic therapy, perhaps for the rest of their lives. This strategy is not cost-effective, and, more importantly, is not good medicine. The serious limitations of current guidelines are recognized by the American Heart Association (AHA), the National Cholesterol Education Program (NCEP) expert panel, and by the European Third Joint Task Force [9–11]. Therefore, the use of non-invasive screening tests that identify abnormal arterial structure and function for risk prediction in a given individual can be an option for advanced risk assessment in appropriately selected persons, particularly in those with multiple risk ww who are judged to be at intermediate (~indeterminate) risk [9–11]. Such tests include carotid intima-media thickness (IMT) measured by ultrasound, coronary artery calcification determined by computed tomography (CT), endothelial vasomotor dysfunction evaluated by ultrasound, ankle/brachial blood pressure ratio (ABI), and magnetic resonance imaging (MRI) techniques [9–11].
CHD Risk Equivalents Patients who already have developed clinical atherosclerotic disease have declared themselves to be at continued high risk (vulnerable) [13]. Current American and European guidelines also recognize groups of patients who are at similar high risk [9–11], including those with diabetes, severe hyperlipidemia or hypertension, as well as patients in whom atherosclerosis and/or its consequences have been demonstrated by non-invasive testing. For example, the presence of myocardial ischemia appropriately identified by stress testing qualifies as a diagnosis of CHD. Moreover, the identification of obstructive atherosclerosis in carotid or ilio-femoral arteries is considered a CHD risk equivalent and should be treated aggressively; atherosclerosis in one vascular bed predicts atherosclerosis in other vascular beds. CHD risk equivalents include peripheral arterial disease (whether diagnosed by ABI, lower limb blood flow studies, or clinical symptoms), carotid artery disease (transient ischemic attack or stroke of carotid origin, or > 50% stenosis on angiography or ultrasound), abdominal aortic aneurysms, as well as 2 or more risk factors with a10-year CHD risk of greater than 20% [9,12]. However, existing guidelines do not recognize severe nonobstructive coronary atherosclerosis as a CHD risk equivalent, a view which demands reconsideration, since most heart attacks originate from nonobstructive coronary plaques.
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Screening for Silent Disease to Prevent Deadly Disease In a recent scientific statement, the American Cancer Society (ACS), the AHA, and the American Diabetes Association announced a new collaborative initiative to create a national commitment to the prevention and early detection of cancer, cardiovascular disease, and diabetes [14]. The ACS recommends that screening for (1) breast cancer begins at age 20 and includes mammography from age 40 (at least annually), (2) cervical cancer begins no later than age 21 (Pap test), (3) colorectal cancer begins at age 50 (several options), and (4) prostate cancer begins at age 50 (prostate-specific antigen test and digital rectal examination annually) (Table 3). The AHA recommends that assessment of cardiovascular risk begins at age 20 and is repeated at regular intervals, preferentially by calculating the Framingham Risk Score (Table 3) [14]. In contrast to cancer, early detection of CVD by screening with the best available technology is not mentioned, although CVD kills more individuals than all cancers combined. In the United States in the year 2001, 56,887 died from colorectoanal cancer, 41,809 from breast cancer, 30,719 from prostate Table 3 General prevention guidelines for all average-risk adults (From [14])
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Conceptual Flow Chart Apparently Healthy At-Risk Population
Step 1
Atherosclerosis Test
Test for Presence of the Disease
Positive
Negative No Risk Factors
+ Risk Factors
400) [56]. In addition, in the previously mentioned study by Nasir et al., 78 and 64% of women with intermediate and high-risk coronary artery calcium scores, respectively, would be ineligible for lipid-lowering therapy based on NCEP ATPIII guidelines, which rely on risk categorization by the FRS [56]. Due to these limitations, a novel risk score termed the Reynolds Risk Score was recently developed to enhance CV risk prediction in women [60]. This algorithm included traditional as well as emerging risk factors and improved measures of global fit and calibration compared with traditional Framingham algorithms, and demonstrated modest improvements in discrimination of CV events as measured by the c-statistic. In addition, this new model reclassified 40–50% of women categorized into the 5- A is associated with plasma LDL-C and LDL-apoB concentrations [20]. The clinical utility of these findings remains unclear as the selection criteria allows for a significant percentage of individuals with potentially dangerous coronary disease to be included in the control groups and the possibility of false positives in the disease groups.
Gene Expression Profiling in Cardiovascular Disease Microarray technology [8] provides a method to rapidly analyze biologic specimens for gene expression patterns of 20,000–38,500 genes that comprise the human genome. Gene expression or transcriptional profiling is especially advantageous in genomic studies designed to detect an environmental stimulus. This extension of the concept to cell culture has permitted investigation of the influence of vascular dynamics on transcripts related to atherosclerosis. Detection of transcripts in circulating cells offers convenient clinical application of transcriptional profiling; however it may not reflect gene expression in atherosclerotic lesions. Transcriptional profiling of platelets in patients with acute coronary syndromes showed changes in gene transcription of megakaryocytesand myeloid-related protein-14, 2 weeks before the onset of symptoms [9]. Previous studies [21] showed augmented expression of 72 genes including HMG-CoA reductase in macrophage-rich tissue of human atherosclerotic lesions as compared with expression profiles of normal intimal tissue and THP-1 macrophage-like cells. In addition, studies on the transcriptional effect of statin therapy on peripheral monocytes [22] demonstrated that statins inhibit expression of inflammatory cytokine interleukin-1b, which are normally present at high levels in subjects with CAD [23]. Such findings show that the potential clinical utility of genomic techniques to identify associated genes also provides incremental values to detect additional drug targets and their effects.
Proteomic Profiling in Atherosclerosis Gene association or transcriptional profiling studies cannot assess potentially important post-transcriptional variables including alternative splicing of mRNA, control subjects on protein translation, and post-translational processing of proteins. Protein markers may provide more accurate real-time information about patho-physiology than stable germ-line markers such as SNPs. As with genomics, potential benefits to the clinical community include better tools for diagnosis, cardiac biomarkers, and identification of therapeutic targets. Proteomic assessment of cardiovascular disease starts with the selection of tissue samples. For example, a study on sampled endarterectomy sections containing atherosclerotic plaque showed decreased expression of heat shock protein-27 (HSP27) in plaque compared with healthy tissue, and confirmed these results by showing a similar trend for the amount of soluble HSP27 in plasma of subjects with atherosclerotic cardiovascular disease [24]. Similar to genomic markers, proteomic studies require rigorous validation of technology platforms and experimental results. The pilot phase of the plasma proteome project identified 345 cardiovascular disease-related proteins in human plasma [25, 26]. These catalogs were developed to identify additional novel proteins that might be associated with cardiovascular disease in future proteomic discovery experiments. Such databases accelerate the identification of unknown markers present in atherosclerotic cardiovascular disease.
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Identifying relevant proteomic markers will benefit from comparison with genetic and genomic data. Future experiments should compare fluctuations of cardiovascular biomarkers with other epidemiologic factors such as age, gender, ethnicity, and a variety of environmental exposures already recognized to influence disease risk and outcome.
Complementary Genomic and Proteomic Approaches Analysis of plasma to identify real-time markers of CAD is highly desirable since plasma is easily collected and provides a practical method to test for reproducibility [27]. Contemporary proteomic analysis allows evaluation of the proteome through mass spectrometry, microarray analysis and electrophoresis technology. Characteristic protein expression patterns have been established for a variety of cancers, infectious diseases and inflammatory disorders [28–36]. As noted above, contemporary genomic analysis allows evaluation of the entire genome through microarray technology. This technology has the ability to identify the expression levels of 38,500 individual genes within a sample of peripheral blood monocytes [37]. In a number of studies, complementary genomic and proteomic results have demonstrated a robust method to distinguish disease and control groups [30, 32]. Likewise, the use of novel pattern recognition algorithms has the potential to provide unique and robust patterns that are both sensitive and specific to CAD. These signature patterns will provide the basis for prospective validation testing to determine diagnostic strength and possible clinical utility. The ability of mass spectrometry to generate highly accurate mass-to-charge ratio (m/z) of various protein components in a complex mixture (such as blood plasma), and the subsequent spectra of very high resolution has made it a powerful protein profiling tool. Accurate analysis of huge volumes of resulting data requires mathematical expertise and sophisticated software tools to facilitate pattern recognition. The ability to detect patterns of differential protein expression between control and diseased samples forms the basis for proteomic pattern diagnostics [38]. These diagnostic patterns are highly dependent on the algorithms used to preprocess the raw data to remove background noise, to identify and compare peaks from various spectra, and training algorithms used to recognize common components of patterns [39, 40]. Prior studies using elegant animal models have been instrumental in establishing experimental design and in narrowing our focus to specific regions of interest within the genome and proteome [41]. However, human data will ultimately be necessary to define characteristic gene and protein expression patterns for CAD. Although analyses of atherosclerotic tissue samples have revealed new insights, coronary tissue sampling will never be an acceptable method to screen for disease. Evaluation of individuals with atherosclerotic disease elsewhere in the vascular system (e.g., carotid arterial intimal medial thickness) may also be of limited value where the experimental concern is CAD. The patchy distribution of atherosclerotic disease argues against a paradigm that assumes uniform distribution of disease. Other important limitations of prior studies are poorly defined disease and control groups. Use of secondary evidence through clinical events alone has the risk of including individuals without CAD in the disease group (false positives). Of equal importance is that the absence of secondary evidence of CAD, such as an absence of events or coronary stenosis thresholds on arteriography, does not assure the absence of CAD within the control group (false negatives). Contamination of both disease and control groups markedly limits the ability to understand the implications of the study results. Although many of the human studies mentioned previously are to be commended for their bimolecular methods, each have questionable methods in establishing disease and control groups.
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Clinical Applications of Genomics to Cardiovascular Medicine Genomic-Based Cardiovascular Risk Prediction Models In atherosclerosis, many factors influence disease predisposition and therapeutic response, providing an appropriate testing ground for a personalized medicine approach based on convergence of information. Future risk assessment models will likely incorporate a patient’s genomic, proteomic, and environmental information, using statistical models to identify marker-disease associations and correct for confounders such as gene–environment interactions. Screening for early detection of high-risk (vulnerable) patients with asymptomatic atherosclerosis and monitoring their response to treatments in order to reduce sudden cardiovascular events remain a major challenge in preventive cardiology [3–5]. Pathologic studies of autopsy specimens have attempted to establish stages of CAD within the vessel wall [42]. These stages suggest progressive vessel enlargement (positive remodeling) with the collection of plaque within the vessel wall until luminal stenosis and occlusion occur. Positive, negative and intermediate remodeling have been demonstrated by intravascular ultrasound (IVUS) and CCT [43], where the various forms of remodeling that fall within the disease process are the subject of current investigation [44–48] (Fig. 4). The association between angiographic stenosis severity and acute coronary events (myocardial infarction or unstable angina) is poor. Indeed, the majority of acute coronary syndromes are the result of rupture of plaques that cause
