Semin Vasc Med 2003; 03(4): 347-354
DOI: 10.1055/s-2004-815692
ETIOLOGY OF ACS

Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Pathophysiology of Atherosclerotic Plaque Development and Rupture: An Overview

Luis E.P. Rohde1 , Richard T. Lee2
  • 1Hospital de Clínicas de Porto Alegre, Medical Post-Graduation Program, Medical School of Rio Grande do Sul Federal University, Porto Alegre, Brazil
  • 2Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Further Information

Publication History

Publication Date:
03 February 2004 (online)

ABSTRACT

Atherosclerosis is predominantly a clinically silent process, and a substantial percentage of patients are first aware of its consequences through the acute and catastrophic event of thrombosis. Extensive basic and clinical research in the 1990s revealed that plaque disruption initiates the majority of thromboses. Furthermore, recent studies indicate that inflammation plays a major role in the pathophysiology, from initiation of the atheroma to the actual thrombosis itself. Attention has now focused on morphological, mechanical, and biochemical characteristics that increase plaque vulnerability, as determination of these features may allow identification of plaques that are most likely to cause symptoms and acute events in the future. This article reviews basic pathophysiologic aspects of atherosclerotic plaque development and rupture to provide the necessary background for understanding the crucial role of inflammation in acute coronary syndromes.

REFERENCES

  • 1 Libby P. Molecular bases of acute coronary syndromes.  Circulation . 1995;  91 2844-2850
  • 2 Shah P K. New insights into the pathogenesis and prevention of acute coronary syndromes.  Am J Cardiol . 1997;  79 17-23
  • 3 Ross R. Atherosclerosis-an inflammatory disease.  N Engl J Med . 1999;  340 115-126
  • 4 Davies M J, Gordon J L, Pigott R, Woolf N, Katz D, Kyriakopoulos A. The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis.  J Pathol . 1993;  171 223-229
  • 5 O'Brien K D, Allen M D, McDonald T O. et al . Vascular cell endothelial molecule-1 is expressed in human coronary atherosclerotic plaques.  J Clin Invest . 1993;  92 945-951
  • 6 Li H, Cybulsky M I, Gimbrone Jr A M, Libby P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium.  Arterioscler Thromb . 1993;  13 197-204
  • 7 Nageh M F, Sandberg E T, Marotti K R. et al . Deficiency of inflammatory cell adhesion molecules protects against atherosclerosis in mice.  Arterioscler Thromb Vasc Biol . 1997;  17 1517-1520
  • 8 Johnson R C, Chapman S M, Dong Z M. et al . Absence of P-selectin delays fatty streak formation in mice.  J Clin Invest . 1997;  99 1037-1043
  • 9 Peter K, Nawroth P, Conradt C. et al . Circulating vascular adhesion molecule-1 correlates with the extent of human atherosclerosis in contrast to circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin.  Arterioscler Thromb Vasc Biol . 1997;  17 505-512
  • 10 Rohde L E, Lee R T, Rivero J. et al . Circulating cell adhesion molecules are correlated with ultrasound-based assessment of carotid atherosclerosis.  Arterioscler Thromb Vasc Biol . 1998;  18 1765-1770
  • 11 Libby P, Ridker P M, Maseri A. Inflammation and atherosclerosis.  Circulation . 2002;  105 1135-1143
  • 12 Rohde L E, Hennekens C H, Ridker P M. Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men.  Am J Cardiol . 1999;  84 1018-1022
  • 13 Rohde L E, Hennekens C H, Ridker P M. A cross-sectional study of soluble intercellular adhesion molecule-1 and cardiovascular risk factors in apparently healthy men.  Arterioscler Thromb Vasc Biol . 1999;  19 1595-1599
  • 14 Thompson S G, Kienast J, Pyke S DM, Haverkate F, van de Loo C W J, for the European Concerted Action on Thrombosis, and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.  N Engl J Med . 1995;  332 635-641
  • 15 Harverkate F, Thompson S G, Pyke S D, Gallimore J R, Pepys M G. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action in Thrombolysis and Disabilities Angina Pectoris Study Group.  Lancet . 1997;  349 462-466
  • 16 Kuller L H, Tracy R P, Shaten J, Meinhahn E N, for the MRFIT Research Group. Relation of C-reactive protein and coronary artery disease in the MRFIT nested case-control study.  Am J Epidemiol . 1996;  144 537-547
  • 17 Tracy R P, Lemaitre R N, Psaty B M. et al . Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project.  Arterioscler Thromb Vasc Biol . 1997;  17 1121-1127
  • 18 Ridker P M, Cushman M, Stampfer M J, Tracy R P, Hennekens C H. Inflammation, aspirin, and risks of cardiovascular disease in apparently healthy men.  N Engl J Med . 1997;  336 973-979
  • 19 Ridker P M, Buring J E, Shih J, Matias M, Hennekens C H. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women.  Circulation . 1998;  98 731-733
  • 20 Ridker P M, Rifai N, Pfeffer M A, for the Cholesterol and Recurrent Events (CARE) Investigators. et al . Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels.  Circulation . 1998;  98 839-844
  • 21 Ridker P M, Rifai N, Clearfield M. et al . Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.  N Engl J Med . 2001;  344 1959-1965
  • 22 Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link?.  Lancet . 1997;  350 430-436
  • 23 Kol A, Sukhova G K, Lichtman A H. et al . Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage TNF-α and matrix metalloproteinase expression.  Circulation . 1998;  98 300-307
  • 24 Danesh J, Whincup P, Walker M. et al . Chlamydia pneumoniae IgG titres and coronary heart disease: prospective study and meta-analysis.  BMJ . 2000;  321 208-213
  • 25 Lee R T, Schoen F J. Pathology of unstable coronary plaque. In: Rutherford JD, ed. Unstable Angina New York: Marcel Dekker 1991: 1-25
  • 26 Farb A, Burke A P, Tang A L. et al . Coronary plaque erosion without rupture into a lipid core: a frequent cause of coronary thrombosis in sudden coronary death.  Circulation . 1996;  93 1354-1363
  • 27 Born G VR, Richardson P D. Mechanical properties of human atherosclerosis. In: Glagov S, Newman W, Schaffer S, eds. Pathobiology of the Human Atherosclerotic Plaques New York: Springer-Verlag 1990: 413-424
  • 28 Davies M J, Thomas A C. Plaque fissuring-the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina.  Br Heart J . 1985;  53 363-373
  • 29 Richardson P D, Davies M J, Born G VR. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques.  Lancet . 1989;  2 941-944
  • 30 Lee R T, Libby P. The unstable atheroma.  Arterioscler Thromb Vasc Biol . 1997;  17 1859-1867
  • 31 Libby P, Lee R T. Role of activated macrophages and T-lymphocytes in rupture of coronary plaques. In: Braumwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine Update. Vol. 2. Philadelphia: WB Saunders 1995: 1-9
  • 32 Amento E P, Ehsani N, Palmer H, Libby P. Cytokines positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells.  Arterioscler Thromb . 1991;  11 1223-1230
  • 33 Geng Y-J, Henderson L, Levesque E. 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 2200-2208
  • 34 Nikkari S T, O'Brien K D, Ferguson M. et al . Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis.  Circulation . 1995;  92 1393-1398
  • 35 Dellery C M, McEwan J R, Henney A M. Matrix metalloproteinases and cardiovascular disease.  Circ Res . 1995;  77 863-868
  • 36 Galis Z S, Muszynski M, Sukhova G K. et al . Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion.  Circ Res . 1994;  75 181-189
  • 37 Lee E, Grodzinsky A J, Libby P, Clinton S K, Lark M W, Lee R T. Human vascular smooth muscle cell-monocyte interactions and metalloproteinase secretion in culture.  Arterioscler Thromb Vasc Biol . 1995;  15 2283-2289
  • 38 Galis Z S, Sukhova G, Kranzhofer R, Clark S, Libby P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases.  Proc Natl Acad Sci USA . 1995;  92 402-406
  • 39 Shah P K, Falk E, Badimon J J. et al . Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques: potential role of matrix-degrading metalloproteinases and implications of plaque rupture.  Circulation . 1995;  92 1565-1569
  • 40 Lendon C L, Davies M J, Born G VR, Richardson P D. Atherosclerotic plaque caps are locally weakened when macrophages density is increased.  Atherosclerosis . 1991;  87 87-90
  • 41 Lee R T, Grodzinsky A J, Franf E H, Kamm R D, Schoen F J. Structure dependent dynamic mechanical behavior of fibrous caps from human atherosclerotic plaque.  Circulation . 1991;  83 1764-1770
  • 42 Loree H M, Grodzinsky A J, Park S Y, Gibson L J, Lee R T. Static circumferential modulus of human atherosclerotic tissue.  J Biomech . 1994;  27 195-204
  • 43 Loree H M, Tobias B J, Gibson L J, Kamm R D, Small D M, Lee R T. Mechanical properties of model atherosclerotic lesion lipid pools.  Arterioscler Thromb . 1994;  14 230-234
  • 44 Rohde L E, Lee R T. Mechanical stress and strain and the vulnerable atherosclerotic lesion. In: Fuster V, ed. The Vulnerable Atherosclerotic Plaque: Understanding, Identification and Modification Armonk, NY: Futura Publishing 1999: 305-316
  • 45 Loree H M, Kamm R D, Stringfellow R G, Lee R T. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels.  Circ Res . 1992;  71 850-858
  • 46 Cheng G C, Loree H M, Kamm R D, Fishbein M C, Lee R T. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation.  Circulation . 1993;  87 1179-1187
  • 47 Libby P. Current concepts of the pathogenesis of the acute coronary syndromes.  Circulation . 2001;  104 365-372
  • 48 Bogaty P, Hackett D, Davies G, Maseri A. Vasoreactivity of the culprit lesion in unstable angina.  Circulation . 1994;  90 5-11
  • 49 Bevilacqua M P, Schleef R, Gimbrone M AJ. et al . Regulation of the fibrinolytic system of cultured human vascular endothelium by interleukin 1.  J Clin Invest . 1986;  78 587-591
  • 50 Mach F, Schonbeck U, Bonnefoy J-Y, Pober J S, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor.  Circulation . 1997;  96 396-399
  • 51 Mach F, Schönbeck U, Sukhova G K, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signaling.  Nature . 1998;  394 200-203
  • 52 Marx N, Sukhova G K, Collins T. et al . PPAR-α activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells.  Circulation . 1999;  99 3125-3131
  • 53 Marx N, Mackman N, Schoenbeck U. et al . PPAR-α activators inhibit tissue factor expression and activity in human monocytes.  Circulation . 2001;  103 213-219
  • 54 Kato H. Regulation of functions of vascular wall cells by tissue factor pathway inhibitor: basic and clinical aspects.  Arterioscler Thromb Vasc Biol . 2002;  22 539-548
  • 55 Yin X, Yutani C, Ikeda Y. et al . Tissue factor pathway inhibitor gene delivery using HVJ-AVE liposomes markedly reduces restenosis in atherosclerotic arteries.  Cardiovasc Res . 2002;  56 454-463
  • 56 Goldstein J A, Demetriou D, Grines C L, Pica M, Shoukfen M, O'Neill W W. Multiple complex coronary plaques in patients with acute myocardial infarction.  N Engl J Med . 2000;  343 915-922
  • 57 Asakura M, Ueda Y, Yamaguchi O. et al . Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study.  J Am Coll Cardiol . 2001;  37 1284-1288
  • 58 Rioufol G, Finet G, Ginon I. et al . Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study.  Circulation . 2002;  106 804-808
  • 59 Spagnoli L G, Bonanno E, Mauriello A. et al . Multicentric inflammation in epicardial coronary arteries of patients dying of acute myocardial infarction.  J Am Coll Cardiol . 2002;  40 1579-1588
  • 60 Buffon A, Biasucci L M, Liuzzo G, D'onofrio G, Crea F, Maseri A. Widespread coronary inflammation in unstable angina.  N Engl J Med . 2002;  347 5-12
  • 61 Lee R T, Loree H M, Cheng G C, Lieberman E H, Jaramillo N, Schoen F J. Computational structural analysis based on intravascular ultrasound imaging before in vitro angioplasty: prediction of plaque fracture locations.  J Am Coll Cardiol . 1993;  21 777-782
  • 62 Hatsukami T S, Ross R, Polissar N L, Yuan C. Visualization of fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high-resolution magnetic resonance imaging.  Circulation . 2000;  102 959-964
  • 63 Yuan C, Mitsumori L M, Ferguson M S. et al . In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques.  Circulation . 2001;  104 2051-2056
  • 64 Nair A, Kuban B D, Tuzcu M, Schoenhagen P, Nissen S E, Vince D G. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis.  Circulation . 2002;  106 2200-2206
  • 65 Stefanidis C, Diamantopoulos L, Vlachopoulos C. et al . Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo. A new method of detection by application of a special thermography catheter.  Circulation . 1999;  99 1965-1971
  • 66 Stefanidis C, Toutouzaz K, Tsiamis E. et al . Increased local temperature in human coronary atherosclerotic plaques: an independent predictor of clinical outcome in patients undergoing a percutaneous coronary intervention.  J Am Coll Cardiol . 2001;  37 1277-1283
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