Pathology and pathogenesis of the vulnerable plaque
- Frank Kolodgie, PhD
Frank Kolodgie, PhD
- Associate Director
- CVPath Institute, Inc.
- Renu Virmani, MD
Renu Virmani, MD
- President & Medical Director
- CVPath Institute, Inc.
- Clinical Professor of Pathology
- Georgetown University
- Clinical Professor of Pathology
- George Washington University
- Aloke Finn, MD
Aloke Finn, MD
- Associate Professor of Medicine
- University of Maryland
- Medical Director
- CVPath Institute Inc
- Section Editors
- Christopher P Cannon, MD
Christopher P Cannon, MD
- Section Editor — Coronary Heart Disease
- Professor of Medicine
- Harvard Medical School
- Peter Libby, MD
Peter Libby, MD
- Section Editor — Coronary Heart Disease
- Chief, Cardiovascular Medicine
- Brigham and Women's Hospital
- Professor, Harvard Medical School
Acute coronary syndromes represent a clinical spectrum of acute coronary artery disease that includes unstable angina, acute myocardial infarction, and sudden coronary death.(See "Classification of unstable angina and non-ST elevation myocardial infarction" and "Criteria for the diagnosis of acute myocardial infarction" and "Pathophysiology and etiology of sudden cardiac arrest" and "Pathophysiology and etiology of sudden cardiac arrest", section on 'Myocardial ischemia and infarction'.)
Most acute coronary syndromes are believed to result from the loss of integrity of a protective covering over an atherosclerotic plaque; this occurs with plaque rupture when the fibrous cap overlying the plaque gets disrupted or with erosion when the endothelial lining of the plaque is disturbed. This disruption of the protective covering allows blood to come in contact with the highly thrombogenic contents of the necrotic core (in cases of plaque rupture) or collagen of the plaque, which promotes the formation of luminal thrombus [1,2]. Intraluminal thrombosis after exposure of the blood to calcified nodules has also been observed. Acute coronary syndrome can also result from other mechanisms such as a supply-demand mismatch (so called type 2 myocardial infarction).
Autopsy studies have shown that when intraluminal thrombi are identified in patients with sudden cardiac death and acute myocardial infarction, the underlying pathology is rupture 55 to 75 percent of the time, erosion 25 to 40 percent of the time, and 2 to 7 percent for calcified nodules [1,3-10]. In vivo studies in patients presenting with ST-segment elevation myocardial infarction using high resolution optical coherence tomography intravascular imaging of culprit plaques have shown a similar distribution of plaque morphologies .
This topic focuses on the process of plaque progression and the development of the vulnerable plaque. The contribution of plaque rupture to the development of acute coronary syndromes, including the mechanisms of coronary thrombosis, and potential strategies to detect and treat rupture-prone vulnerable plaques, are discussed separately. (See "The role of the vulnerable plaque in acute coronary syndromes".)
PATHOLOGY OF CORONARY ATHEROSCLEROSIS
Atherosclerosis is a dynamic process with multiple stages: intimal thickening, fibrous cap atheroma (fibroatheroma) formation, thin-cap fibroatheroma formation, and plaque rupture (figure 1A-B) . To understand plaque rupture, it is useful to review the stages of development of a plaque .
- Virmani R, Kolodgie FD, Burke AP, et al. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20:1262.
- 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.
- Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med 1984; 310:1137.
- el Fawal MA, Berg GA, Wheatley DJ, Harland WA. Sudden coronary death in Glasgow: nature and frequency of acute coronary lesions. Br Heart J 1987; 57:329.
- Davies MJ, Bland JM, Hangartner JR, et al. Factors influencing the presence or absence of acute coronary artery thrombi in sudden ischaemic death. Eur Heart J 1989; 10:203.
- Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997; 336:1276.
- Burke AP, Farb A, Malcom GT, et al. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women. Circulation 1998; 97:2110.
- Arbustini E, Dal Bello B, Morbini P, et al. Plaque erosion is a major substrate for coronary thrombosis in acute myocardial infarction. Heart 1999; 82:269.
- Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007; 50:933.
- Ino Y, Kubo T, Tanaka A, et al. Difference of culprit lesion morphologies between ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome: an optical coherence tomography study. JACC Cardiovasc Interv 2011; 4:76.
- Higuma T, Soeda T, Abe N, et al. A Combined Optical Coherence Tomography and Intravascular Ultrasound Study on Plaque Rupture, Plaque Erosion, and Calcified Nodule in Patients With ST-Segment Elevation Myocardial Infarction: Incidence, Morphologic Characteristics, and Outcomes After Percutaneous Coronary Intervention. JACC Cardiovasc Interv 2015; 8:1166.
- Yahagi K, Kolodgie FD, Otsuka F, et al. Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat Rev Cardiol 2016; 13:79.
- Velican C. A dissecting view on the role of the fatty streak in the pathogenesis of human atherosclerosis: culprit or bystander? Med Interne 1981; 19:321.
- McGill HC Jr, McMahan CA, Zieske AW, et al. Associations of coronary heart disease risk factors with the intermediate lesion of atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Arterioscler Thromb Vasc Biol 2000; 20:1998.
- Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1994; 89:2462.
- Kolodgie FD, Burke AP, Nakazawa G, Virmani R. Is pathologic intimal thickening the key to understanding early plaque progression in human atherosclerotic disease? Arterioscler Thromb Vasc Biol 2007; 27:986.
- Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995; 92:1355.
- Davies MJ, Thomas AC. Plaque fissuring--the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J 1985; 53:363.
- Kolodgie FD, Burke AP, Farb A, et al. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr Opin Cardiol 2001; 16:285.
- Kolodgie FD, Virmani R, Burke AP, et al. Pathologic assessment of the vulnerable human coronary plaque. Heart 2004; 90:1385.
- Siegel RJ, Swan K, Edwalds G, Fishbein MC. Limitations of postmortem assessment of human coronary artery size and luminal narrowing: differential effects of tissue fixation and processing on vessels with different degrees of atherosclerosis. J Am Coll Cardiol 1985; 5:342.
- Tanaka A, Imanishi T, Kitabata H, et al. Morphology of exertion-triggered plaque rupture in patients with acute coronary syndrome: an optical coherence tomography study. Circulation 2008; 118:2368.
- Yonetsu T, Kakuta T, Lee T, et al. In vivo critical fibrous cap thickness for rupture-prone coronary plaques assessed by optical coherence tomography. Eur Heart J 2011; 32:1251.
- Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996; 93:1354.
- Nemerson Y. A simple experiment and a weakening paradigm: the contribution of blood to propensity for thrombus formation. Arterioscler Thromb Vasc Biol 2002; 22:1369.
- Rauch U, Bonderman D, Bohrmann B, et al. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor. Blood 2000; 96:170.
- Kolodgie FD, Burke AP, Farb A, et al. Differential accumulation of proteoglycans and hyaluronan in culprit lesions: insights into plaque erosion. Arterioscler Thromb Vasc Biol 2002; 22:1642.
- Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart 1999; 82:265.
- 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.
- Libby P. Inflammation in atherosclerosis. Nature 2002; 420:868.
- Libby P. Changing concepts of atherogenesis. J Intern Med 2000; 247:349.
- Babior BM. Phagocytes and oxidative stress. Am J Med 2000; 109:33.
- Endemann G, Stanton LW, Madden KS, et al. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem 1993; 268:11811.
- Li AC, Glass CK. The macrophage foam cell as a target for therapeutic intervention. Nat Med 2002; 8:1235.
- Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med 2002; 8:1211.
- Witztum JL, Steinberg D. The oxidative modification hypothesis of atherosclerosis: does it hold for humans? Trends Cardiovasc Med 2001; 11:93.
- Pearson AM. Scavenger receptors in innate immunity. Curr Opin Immunol 1996; 8:20.
- Muzio M, Mantovani A. Toll-like receptors (TLRs) signalling and expression pattern. J Endotoxin Res 2001; 7:297.
- Faure E, Thomas L, Xu H, et al. Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J Immunol 2001; 166:2018.
- Xu XH, Shah PK, Faure E, et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation 2001; 104:3103.
- Stewart CR, Stuart LM, Wilkinson K, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010; 11:155.
- Kruth HS. Localization of unesterified cholesterol in human atherosclerotic lesions. Demonstration of filipin-positive, oil-red-O-negative particles. Am J Pathol 1984; 114:201.
- Guyton JR, Klemp KF. Development of the lipid-rich core in human atherosclerosis. Arterioscler Thromb Vasc Biol 1996; 16:4.
- Katz SS, Shipley GG, Small DM. Physical chemistry of the lipids of human atherosclerotic lesions. Demonstration of a lesion intermediate between fatty streaks and advanced plaques. J Clin Invest 1976; 58:200.
- Felton CV, Crook D, Davies MJ, Oliver MF. Relation of plaque lipid composition and morphology to the stability of human aortic plaques. Arterioscler Thromb Vasc Biol 1997; 17:1337.
- Tabas I. Free cholesterol-induced cytotoxicity a possible contributing factor to macrophage foam cell necrosis in advanced atherosclerotic lesions. Trends Cardiovasc Med 1997; 7:256.
- Kockx MM. Apoptosis in the atherosclerotic plaque: quantitative and qualitative aspects. Arterioscler Thromb Vasc Biol 1998; 18:1519.
- Tabas I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol 2005; 25:2255.
- Schrijvers DM, De Meyer GR, Kockx MM, et al. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25:1256.
- Thorp E, Cui D, Schrijvers DM, et al. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice. Arterioscler Thromb Vasc Biol 2008; 28:1421.
- Boisvert WA, Rose DM, Boullier A, et al. Leukocyte transglutaminase 2 expression limits atherosclerotic lesion size. Arterioscler Thromb Vasc Biol 2006; 26:563.
- Kolodgie FD, Gold HK, Burke AP, et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003; 349:2316.
- Sluimer JC, Kolodgie FD, Bijnens AP, et al. Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions relevance of compromised structural integrity for intraplaque microvascular leakage. J Am Coll Cardiol 2009; 53:1517.
- Boyle JJ, Harrington HA, Piper E, et al. Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am J Pathol 2009; 174:1097.
- Finn AV, Nakano M, Polavarapu R, et al. Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques. J Am Coll Cardiol 2012; 59:166.
- Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987; 316:1371.
- Clarkson TB, Prichard RW, Morgan TM, et al. Remodeling of coronary arteries in human and nonhuman primates. JAMA 1994; 271:289.
- Burke AP, Kolodgie FD, Farb A, et al. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation 2002; 105:297.
- Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation 2002; 105:939.
- Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995; 91:2844.
- Lutgens E, van Suylen RJ, Faber BC, et al. Atherosclerotic plaque rupture: local or systemic process? Arterioscler Thromb Vasc Biol 2003; 23:2123.
- Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21:1876.
- Hansson GK, Libby P, Schönbeck U, Yan ZQ. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 2002; 91:281.
- Libby P. Coronary artery injury and the biology of atherosclerosis: inflammation, thrombosis, and stabilization. Am J Cardiol 2000; 86:3J.
- Dollery CM, Owen CA, Sukhova GK, et al. Neutrophil elastase in human atherosclerotic plaques: production by macrophages. Circulation 2003; 107:2829.
- Herman MP, Sukhova GK, Libby P, et al. Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling. Circulation 2001; 104:1899.
- Sukhova GK, Schönbeck U, Rabkin E, et al. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation 1999; 99:2503.
- Sukhova GK, Shi GP, Simon DI, et al. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest 1998; 102:576.
- Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002; 90:251.
- Kolodgie FD, Narula J, Guillo P, Virmani R. Apoptosis in human atherosclerotic plaques. Apoptosis 1999; 4:5.
- Geng YJ, Libby P. Progression of atheroma: a struggle between death and procreation. Arterioscler Thromb Vasc Biol 2002; 22:1370.
- Geng YJ, Henderson LE, Levesque EB, et al. Fas is expressed in human atherosclerotic intima and promotes apoptosis of cytokine-primed human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1997; 17:2200.
- Bennett MR, Evan GI, Schwartz SM. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest 1995; 95:2266.
- Kolodgie FD, Narula J, Burke AP, et al. Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am J Pathol 2000; 157:1259.
- Loree HM, Kamm RD, Stringfellow RG, Lee RT. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res 1992; 71:850.
- Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA 1999; 282:2035.
- Gijsen FJ, Wentzel JJ, Thury A, et al. Strain distribution over plaques in human coronary arteries relates to shear stress. Am J Physiol Heart Circ Physiol 2008; 295:H1608.
- Slager CJ, Wentzel JJ, Gijsen FJ, et al. The role of shear stress in the generation of rupture-prone vulnerable plaques. Nat Clin Pract Cardiovasc Med 2005; 2:401.
- Vengrenyuk Y, Carlier S, Xanthos S, et al. A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc Natl Acad Sci U S A 2006; 103:14678.
- Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol 2006; 47:C13.
- Shin ES, Ann SH, Singh GB, et al. OCT-Defined Morphological Characteristics of Coronary Artery Spasm Sites in Vasospastic Angina. JACC Cardiovasc Imaging 2015; 8:1059.
- Ferrante G, Nakano M, Prati F, et al. High levels of systemic myeloperoxidase are associated with coronary plaque erosion in patients with acute coronary syndromes: a clinicopathological study. Circulation 2010; 122:2505.
- Kramer MC, Rittersma SZ, de Winter RJ, et al. Relationship of thrombus healing to underlying plaque morphology in sudden coronary death. J Am Coll Cardiol 2010; 55:122.
- PATHOLOGY OF CORONARY ATHEROSCLEROSIS
- Intimal thickening and intimal xanthoma
- Pathologic intimal thickening
- Fibrous cap atheroma
- Thin-cap fibroatheroma (vulnerable plaque)
- - Reconsideration of the definition
- Plaque rupture
- Plaque erosion
- Calcified nodule
- Healed rupture
- MECHANISMS OF PLAQUE PROGRESSION
- Inflammation and plaque progression
- Formation and expansion of the necrotic core
- Apoptosis and necrotic core expansion
- Intraplaque hemorrhage
- Coronary arterial remodeling
- MECHANISMS OF PLAQUE RUPTURE
- Collagen synthesis and breakdown in the fibrous cap
- Apoptosis and plaque rupture
- Local mechanical stress and plaque rupture
- MECHANISMS OF EROSION AND PROGRESSION