While in stable angina, static coronary luminal narrowing by atherosclerotic plaque and dynamic vasoconstriction lead to limitation in coronary blood flow during stress, in the acute coronary syndromes, it is believed that the central causative event is thrombosis resulting from the sudden rupture of an atherosclerotic plaque.1-6 Plaque rupture exposes the thrombogenic contents of the plaque core to the coronary circulation, activating the coagulation cascade and causing platelet activation, adhesion, and aggregation; this leads to the development of an acute arterial thrombus superimposed on the ruptured plaque, which may abruptly compromise coronary blood flow and have ominous clinical consequences. In addition to thrombus at the site of plaque rupture, downstream embolization of thrombus into the microvasculature may also contribute to acute coronary syndromes. Yet many individuals may suffer an acute coronary syndrome without previously symptomatic (or angiographically significant) atherosclerosis, while still others may present with stable angina and severe three-vessel disease without ever having had a previous coronary event. Thus, the plaque rupture paradigm begs the question: why do some plaques rupture and others don’t?
Coronary Thrombosis in Acute Coronary Syndromes
In the 1970s, coronary thrombosis was thought to be a secondary event rather than the primary cause of acute myocardial infarction. 7 In a seminal study in 1980, DeWood observed by coronary angiography that total coronary occlusion with associated thrombus was frequent in the early hours after myocardial infarction. 8 Further investigation in the years that followed supported this concept that coronary thrombosis was the basis for acute myocardial infarction, unstable angina, and sudden death. Autopsy studies demonstrated that seventy to eighty percent of coronary thrombi occur at sites of plaque fissure or rupture; that the resultant thrombus extends into the ruptured plaque as well as into the arterial lumen; and that the thrombus propagates upstream from the site of the plaque rupture. 9-12 Angiographic studies defined the distinctive radiographic appearance of the ruptured plaque, characterized by an eccentric stenosis with narrow or irregular borders or containing intraluminal lucencies. 13-16 A wealth of data derived from surgical, angioscopic, histological, and biochemical studies has also illuminated the critical role of plaque rupture and subsequent thrombosis in causing the acute coronary syndromes. 17-23
Plaque Vulnerability: One of these plaques is not like the others
The atherosclerotic plaque has two major anatomic components: a fibrous cap, which can vary in thickness and cellularity, and a central core, which can vary in size and composition. A third plaque component is an inflammatory cellular infiltrate, which can vary in degree, location, and activity. Lastly, the arterial wall around the plaque has a dynamic relationship with the plaque itself. Pathologic study has revealed a number of variations in these components that characterize plaques that have ruptured. Typical characteristics of ruptured plaques include:
a thin fibrous cap
a large lipid-laden core
positive arterial remodeling around the plaque
inflammatory cell infiltration of the fibrous cap and the adventitia,
and increased plaque neovascularity. 1,24-34
By inference, a plaque is considered vulnerable if it possesses these features prior to rupture.
The fibrous cap. The fibrous cap consists predominantly of extracellular matrix molecules, such as collagen, elastin, and proteoglycans, and the smooth muscle cells that produce them. The cap protects the deeper, thrombogenic components of the plaque core from exposure to circulating blood in the coronary lumen. Compared to the fibrous caps of intact plaques, those of ruptured plaques are relatively acellular with less smooth muscle cells, and contain less collagen and proteoglycan. 27 Moreover, these caps are often thinner in the vicinity of rupture, especially in the plaque shoulder regions where many ruptures tend to occur. Computer modeling shows that reducing cap thickness dramatically increases circumferential stress in the plaque, a possible mechanism for plaque disruption. 35 A thin fibrous cap is thus considered a marker of plaque vulnerability. This thinning may result from the depletion of the cap’s extra-cellular matrix components by inflammatory cell-mediated dysregulation of matrix synthesis and degradation. 1,2,4,36
The lipid-laden core. The core of the atherosclerotic plaque is lipid-rich, containing free cholesterol, cholesterol esters, and cholesterol crystals. It is believed that the extra-cellular lipid core forms through the accumulation within the plaque of foam cells, which are primarily lipid-laden macrophages and to a lesser extent, smooth muscles cells. These cells subsequently undergo apoptosis and necrosis, releasing their lipid contents into the core. Also, lipids may infiltrate the arterial wall directly from the circulating blood. 1,37
Plaques vary in the size, shape, and content of their cores, and these characteristics impact upon the plaque’s stability. The consistency of the core depends on the relative proportion of cholesterol products. 38,39 More core leads to more vulnerability: of plaques that rupture, the lipid core often makes up more than 40% of the total plaque volume. 26,40 The magnitude of the acute arterial thrombus that forms after plaque rupture depends on the thrombogenicity of the plaque core that is exposed and the state of the hemorrheology of the blood. Lipid-rich cores are more thrombogenic, likely because of the high content of tissue factor that accumulates from macrophage apoptosis. 41-43 The plaques of smokers contain more macrophages and a higher content of tissue factor than non-smokers, which may contribute to smokers’ high thrombotic risk. 44 An eccentric core can also place a plaque at a mechanical disadvantage by redistributing the circumferential stress imposed by coronary blood flow to the weaker shoulder regions of the plaque, where the fibrous cap tends to rupture in nearly 60% of cases. 24,45
The plaque and coronary angiography. The degree of coronary stenosis that is determined by coronary angiography may not be an accurate measure of plaque vulnerability or plaque size. Retrospective and prospective analyses of serial angiography have suggested that the plaques that produce non-flow limiting stenoses account for more cases of plaque rupture and coronary thrombosis than do plaques which produce severe stenoses: in nearly two-thirds of all patients presenting with acute coronary syndromes, a prior coronary angiogram performed weeks to months before the acute event showed the culprit lesion site to have less than 70% diameter narrowing (the usual standard for significant angiographic stenosis). 46-49 Moreover, in patients with stable angina, the site of ischemia determined by stress myocardial perfusion imaging does not accurately predict the future site of acute myocardial infarction. 50
Why would angiographically less obstructive plaques be responsible for more acute coronary events than larger ones? The local arterial wall that surrounds the atherosclerotic plaque is not a static vessel but instead dynamically changes in response to plaque growth. The coronary arterial wall can expand in the area of plaque, in a process called positive remodeling; in doing so, the effective luminal area as seen by coronary angiography may remain constant despite plaque growth. Alternatively, the arterial lumen may shrink in the area of a plaque, in a process called negative remodeling, so that the effective luminal area may be significantly decreased despite a relatively small plaque, creating the angiographic appearance of a significantly stenotic lesion. Thus, the degree of coronary stenosis determined by coronary angiography may be quite different than the actual fraction of coronary lumen occupied by the plaque that is determined on pathological examination. 51,52 This remodeling has a significant impact on plaque vulnerability: computer models show that positive remodeling, through increasing lumen size, places greater circumferential stress on the plaque, predisposing thin fibrous caps to rupture. 35 This occurs through LaPlace’s law, which states that the tension imposed on the plaque surface is directly proportional to the lumen radius and inversely proportional to cap thickness. In contradistinction, negative remodeling, by diminishing lumen size (and increasing the degree of angiographic stenosis) decreases the stress on the plaque, making it less likely to rupture. Indeed, human studies using intravascular ultrasound have shown that positive remodeling is more common at culprit lesion sites in patients with unstable angina, whereas negative remodeling is more common in patients with stable angina. 30
The observation that the plaques that cause less significant stenoses are more often the sources of culprit lesions in acute coronary events may also be due stochastic processes. The number of moderate lesions (30-70% stenoses) in an individual with atherosclerotic disease far outweighs the number of flow-limiting (>70%) ones, by as much as a factor of five to ten. Thus more plaque ruptures and thrombi may evolve from less stenotic plaques simply because they are present in larger numbers. Moreover, plaques causing severe stenoses stimulate collateral growth to the post-stenotic segments. Subsequent plaque rupture and thrombosis of these stenoses may then be clinically silent because collateral recruitment protects the distal myocardium from changes in proximal luminal blood flow.
Inflammation. Histopathologic studies have shown that ruptured plaques contain greater numbers of inflammatory cells than stable plaques. 53 These cells consist most of monocyte-macrophages, and to a lesser extent, T-cells and mast cells. They appear to be distributed within the ruptured plaque in a typical way, concentrated in and around the sites of cap-rupture as wells as in areas of the surrounding adventitia where new blood vessels have formed in and around the plaque. 53-55 These inflammatory cells and the cytokines they produce enhance matrix degradation and inhibit matrix synthesis, leading to matrix depletion. This is probably accomplished through pathways involving enzymes that breakdown matrix components, called matrix metalloproteinases (MMPs), and their inhibitors (tissue inhibitors of matrix metalloproteinases, or TIMPs). 56 Inflammatory cells thus contribute to fibrous cap thinning, and in turn, plaque rupture. 57-59 Moreover, as stated above, increased macrophage infiltration and subsequent apoptosis may enhance core thrombogenicity by raising its content of tissue factor. Various factors contribute to inflammatory cell recruitment and activity, including:
oxidized lipids
hypertension
diabetes mellitus
angiotensin II
immune system activation
infections within and remote to the arterial wall. 4
These factors may represent therapeutic targets to attenuate plaque vulnerability.
Neovascularity. Growth of new blood vessels, a phenomenon termed neovascularization, occurs within the arterial adventitia and intima early in the development of atherosclerosis. 60,61 Examination of human coronary atherectomy samples suggests that the culprit lesions of unstable angina patients have more neovascularity compared to lesions in stable angina patients. 34 Neovascularity may enhance the vulnerability of a plaque to rupture by providing an avenue for the infiltration of inflammatory cells. Also, these thin-walled vessels may be especially prone to rupture, causing intra-plaque hemorrhage that leads secondarily to plaque disruption. 62
Extrinsic Factors in Plaque Rupture
A multitude of characteristics intrinsic to the atherosclerotic plaque may thus increase the susceptibility of the plaque to rupture. Yet factors extrinsic to the plaque, in combination with these inherent attributes, may act as triggers that enhance the likelihood of disruption and of the subsequent formation of a superimposed arterial thrombus that may abruptly impede coronary blood flow. Although the exact mechanisms are unclear, triggered rupture may be due to sudden increases in sympathetic tone, such as physical or emotional stress; exposure to agents such as cocaine, marijuana, and amphetamines; acute infections; and exposure to cold temperatures. 63-66 However, the sudden rupture of a vulnerable plaque may occur without any obvious precipitant.
The local thrombotic response to plaque rupture also plays a crucial role in determining the clinical sequelae of the event in that it determines whether there is an acute compromise in luminal flow. Many plaques may rupture silently: multiple plaque ruptures in arteries remote from the acute culprit site have been demonstrated in approximately 40% of cases with acute coronary syndromes. 67 Repetitive subclinical plaque rupture, thrombosis, and subsequent plaque healing and thrombus organization may represent a mechanism for plaque growth. 68 The local thrombotic response to plaque rupture is likely determined by a host of factors, including the intrinsic thrombogenicity of the plaque core that is exposed to circulating blood, the local hemorrheology which is affected by the underlying stenosis severity and shear induced platelet activation, and systemic thrombogenicity and fibronolytic activity. 1
In a subset (20-40%) of cases, thrombi have been observed occurring over plaques with superficial endothelial erosions, not with classical plaque rupture or fissure. 5,69 The culprit plaques do not have a large lipid-core, have a lower prevalence of inflammation, and contain a proteoglycan-rich matrix. The mechanism of this phenomenon is unknown, but may be due to an enhanced systemic thrombogenicity. It tends to be more common in smokers, women, and younger victims of sudden death.
Plaque Stabilization Therapy
Cardiac risk factor modification has consistently been shown to reduce cardiovascular morbidity and mortality. Angiographic studies have shown that risk factor modification decreases new lesion formation, reduces lesion progression, and in some cases, causes actual lesion regression. However, the magnitude of clinical event reduction achieved through risk factor modification is far greater than can be accounted for by the relatively small changes in stenosis severity alone. An explanation for this discrepancy is that risk factor modification attenuates plaque vulnerability, not by affecting plaque mass or size, but instead by favorably changing plaque composition so that there is less propensity for plaque rupture and thrombosis. 70,71 Several experimental studies in animals have in fact shown that lipid lowering (through diet or statins) or direct administration of apo A-I and HDL-like particles can reduce plaque lipid content, inflammation, MMP, and tissue factor levels and increase collagen content. 72-74
In humans, treatment with pravastatin for three months decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in carotid plaques. 75 It is therefore plausible although still speculative that depleting lipids and inflammation from atherosclerotic plaques may reduce the risk of plaque rupture and subsequent thrombosis, and that such a plaque-stabilizing effect may account in part for the clinical benefits of lipid-modifying drugs, angiotensin converting enzyme inhibitors, and angiotensin II receptor blockers. 4 Future additional approaches may include direct administration of HDL and its apolipoproteins, novel HDL-boosting compounds such as the rexinoids, or therapy with immune modulators. 76-78
New Frontiers: Addressing the Vulnerable Plaque
A large body of evidence now exists that specific characteristics of the atherosclerotic plaque, independent of stenosis severity by coronary angiography, determine future rupture and thrombosis and subsequent myocardial infarction, unstable angina, and sudden death. The challenge, then both inside and outside the catheterization laboratory is to identify the culprit lesion before it inherits its namesake. Emerging invasive and non-invasive imaging technologies could help to differentiate fibrous cap and plaque core thickness, size, and composition, and thereby localize susceptible plaques prior to their rupture. 79 Vulnerable plaques, because they have a greater degree of inflammation than stable plaques, may be identifiable because of their temperature: inflammation releases heat, and thus vulnerable plaques may be warmer than stable ones. Such temperature heterogeneity has indeed been demonstrated in human atherosclerotic lesions obtained from endarterectomy. 80 Thus the evaluation of plaque temperature by thermography could possibly identify dangerous plaques in the coronary, aortic, or carotid circulation. Imaging of plaque architecture by intravascular ultrasound may also help identify dangerous plaque characteristics such as a thin fibrous cap and a large, lipid core. 81-83 In the future, catheter-based optical coherence tomography (OCT), which is similar to ultrasound but uses infrared light rather than acoustic waves, 84 may provide significantly higher resolution images and greater diagnostic capability than IVUS. 85 Magnetic resonance imaging (MRI) of the arterial wall and radioisotope imaging by SPECT or PET with specific tracers may be able to characterize plaque components, although the current technology is not yet adequate for clinical application. 86-88
Conclusion
Acute coronary syndromes are predominantly caused by the formation of acute thrombus at the site of rupture of an atherosclerotic plaque, with subsequent compromise of coronary blood flow. The vulnerability of a plaque to rupture likely depends crucially on its components, its architecture, and the state of the surrounding vasculature. Currently, definitive identification of a vulnerable plaque prior to rupture is not possible, although medical therapy may have clinical benefit through plaque stabilization. Emerging technologies could in the future allow better identification of vulnerable plaques. Once the suspect lesion or lesions are identified, systemic medical therapy may be initiated to modify high-risk plaque features. More speculatively, direct intervention with gene-therapy or non-restenosing, drug-eluting stents may allow for definitive plaque stabilization. Until that time, the standard-of-care regimen of aspirin, beta-blockade, angiotensin-converting enzyme inhibition, lipid-lowering therapy, and life-style modification remains the best therapy for the prevention of cardiovascular events in patients with known coronary artery disease.
1.Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657-671.
2. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844-2850.
3. Fuster V. 50th anniversary historical article. Acute coronary syndromes: the degree and morphology of coronary stenoses. J Am Coll Cardiol. 2000;35:52B-54B.
4. Shah PK. Plaque disruption and thrombosis: potential role of inflammation and infection. Cardiol Rev. 2000;8:31-39.
5. Virmani R, Burke AP, Farb A. Plaque rupture and plaque erosion. Thromb Haemost. 1999;82 Suppl 1:1-3.
6. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001;104:365-372.
7. Roberts WC, Buja LM. The frequency and significance of coronary arterial thrombi and other observations in fatal acute myocardial infarction: a study of 107 necropsy patients. Am J Med. 1972;52:425-443.
8. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med. 1980;303:897-902.
9. Friedman M. Pathogenesis of coronary thrombosis, intramural and intraluminal hemorrhage. Adv Cardiol. 1970;4:20-46.
10. Friedman M. The pathogenesis of coronary plaques, thromboses, and hemorrhages: an evaluative review. Circulation. 1975;52:III34-40.
11. Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J. 1983;50:127-134.
12. Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med. 1984;310:1137-1140.
13. Levin DC, Fallon JT. Significance of the angiographic morphology of localized coronary stenoses: histopathologic correlations. Circulation. 1982;66:316-320.
14. Ambrose JA, Winters SL, Stern A, et al. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol. 1985;5:609-616.
15. Ambrose JA, Winters SL, Arora RR, et al. Coronary angiographic morphology in myocardial infarction: a link between the pathogenesis of unstable angina and myocardial infarction. J Am Coll Cardiol. 1985;6:1233-1238.
16. Ambrose JA, Hjemdahl-Monsen CE. Arteriographic anatomy and mechanisms of myocardial ischemia in unstable angina. J Am Coll Cardiol. 1987;9:1397-1402.
17. Kruskal JB, Commerford PJ, Franks JJ, Kirsch RE. Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease. N Engl J Med. 1987;317:1361-1365.
18. DeWood MA, Spores J, Hensley GR, et al. Coronary arteriographic findings in acute transmural myocardial infarction. Circulation. 1983;68:I39-49.
19. DeWood MA, Stifter WF, Simpson CS, Spores J, Eugster GS, Judge TP, Hinnen ML. Coronary arteriographic findings soon after non-Q-wave myocardial infarction. N Engl J Med. 1986;315:417-423.
20. Sherman CT, Litvack F, Grundfest W, et al. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med. 1986;315:913-919.
21. Folts JD, Crowell EB, Jr., Rowe GG. Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation. 1976;54:365-370.
22. Davies MJ, Thomas T. The pathological basis and microanatomy of occlusive thrombus formation in human coronary arteries. Philos Trans R Soc Lond B Biol Sci. 1981;294:225-229.
23. Gorlin R, Fuster V, Ambrose JA. Anatomic-physiologic links between acute coronary syndromes. Circulation. 1986;74:6-9.
24. Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989;2:941-944.
25. Davies MJ, Richardson PD, Woolf N, et al. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J. 1993;69:377-381.
26. 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;17:1337-1345.
27. Burleigh MC, Briggs AD, Lendon CL, et al. Collagen types I and III, collagen content, GAGs and mechanical strength of human atherosclerotic plaque caps: span-wise variations. Atherosclerosis. 1992;96:71-81.
28. Moreno PR, Falk E, Palacios IF, et al. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation. 1994;90:775-778.
29. Moreno PR, Bernardi VH, Lopez-Cuellar J, et al. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation. 1996;94:3090-3097.
30. Schoenhagen P, Ziada KM, Kapadia SR, et al. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes : an intravascular ultrasound study. Circulation. 2000;101:598-603.
31. Davies MJ. Pathophysiology of acute coronary syndromes. Indian Heart J. 2000;52:473-479.
32. Lendon CL, Davies MJ, Born GV, Richardson PD. Atherosclerotic plaque caps are locally weakened when macrophages density is increased. Atherosclerosis. 1991;87:87-90.
33. Depre C, Havaux X, Wijns W. Neovascularization in human coronary atherosclerotic lesions. Cathet Cardiovasc Diagn. 1996;39:215-220.
34. Tenaglia AN, Peters KG, Sketch MH, Jr., Annex BH. Neovascularization in atherectomy specimens from patients with unstable angina: implications for pathogenesis of unstable angina. Am Heart J. 1998;135:10-14.
35. Loree HM, Kamm RD, Stringfellow RG, Lee RT. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res. 1992;71:850-858.
36. Davies MJ. The pathophysiology of acute coronary syndromes. Heart. 2000;83:361-366.
37. Guyton JR, Klemp KF. Development of the lipid-rich core in human atherosclerosis. Arterioscler Thromb Vasc Biol. 1996;16:4-11.
38. Lundberg B. Chemical composition and physical state of lipid deposits in atherosclerosis. Atherosclerosis. 1985;56:93-110.
39. Loree HM, Tobias BJ, Gibson LJ, et al. Mechanical properties of model atherosclerotic lesion lipid pools. Arterioscler Thromb. 1994;14:230-234.
40. Davies MJ, Woolf N, Rowles P, Richardson PD. Lipid and cellular constituents of unstable human aortic plaques. Basic Res Cardiol. 1994;89:33-39.
41. Fernandez-Ortiz A, Badimon JJ, Falk E, et al. Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol. 1994;23:1562-1569.
42. Mallat Z, Hugel B, Ohan J, et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation. 1999;99:348-353.
43. Toschi V, Gallo R, Lettino M, et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation. 1997;95:594-599.
44. Matetzky S, Tani S, Kangavari S, et al. Smoking increases tissue factor expression in atherosclerotic plaques: implications for plaque thrombogenicity. Circulation. 2000;102:602-604.
45. Cheng GC, Loree HM, Kamm RD, et al. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation. Circulation. 1993;87:1179-1187.
46. Ambrose JA, Winters SL, Arora RR, et al. Angiographic evolution of coronary artery morphology in unstable angina. J Am Coll Cardiol. 1986;7:472-478.
47. Little WC, Constantinescu M, Applegate RJ, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation. 1988;78:1157-1166.
48. Hackett D, Davies G, Maseri A. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J. 1988;9:1317-1323.
49. Giroud D, Li JM, Urban P, et al. Relation of the site of acute myocardial infarction to the most severe coronary arterial stenosis at prior angiography. Am J Cardiol. 1992;69:729-732.
50. Naqvi TZ, Hachamovitch R, Berman D, et al. Does the presence and site of myocardial ischemia on perfusion scintigraphy predict the occurrence and site of future myocardial infarction in patients with stable coronary artery disease? Am J Cardiol. 1997;79:1521-1524.
51. Fishbein MC, Siegel RJ. How big are coronary atherosclerotic plaques that rupture? Circulation. 1996;94:2662-2666.
52. Schoenhagen P, Ziada KM, Vince DG, et al. Arterial remodeling and coronary artery disease: the concept of –dilated- versus "obstructive" coronary atherosclerosis. J Am Coll Cardiol. 2001;38:297-306.
53. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994;89:36-44.
54. Kaartinen M, van der Wal AC, van der Loos CM, et al. Mast cell infiltration in acute coronary syndromes: implications for plaque rupture. J Am Coll Cardiol. 1998;32:606-612.
55. Laine P, Kaartinen M, Penttila A, et al. Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation. 1999;99:361-369.
56. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994;94:2493-2503.
57. Shah PK, Falk E, Badimon JJ, et al. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation. 1995;92:1565-1569.
58. Shah PK. Role of inflammation and metalloproteinases in plaque disruption and thrombosis. Vasc Med. 1998;3:199-206.
59. Shah PK, Galis ZS. Matrix metalloproteinase hypothesis of plaque rupture: players keep piling up but questions remain. Circulation. 2001;104:1878-1880.
60. Barger AC, Beeuwkes R, 3rd, Lainey LL, Silverman KJ. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med. 1984;310:175-177.
61. Kwon HM, Sangiorgi G, Ritman EL, et al. Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia. J Clin Invest. 1998;101:1551-1556.
62. Barger AC, Beeuwkes R, 3rd. Rupture of coronary vasa vasorum as a trigger of acute myocardial infarction. Am J Cardiol. 1990;66:41G-43G.
63. Muller JE. Triggering of cardiac events by sexual activity: findings from a case-crossover analysis. Am J Cardiol. 2000;86:14F-18F.
64. Mittleman MA, Mintzer D, Maclure M, et al. Triggering of myocardial infarction by cocaine. Circulation. 1999;99:2737-2741.
65. Mittleman MA, Lewis RA, Maclure M, et al. Triggering myocardial infarction by marijuana. Circulation. 2001;103:2805-2809.
66. Willich SN, Klatt S, Arntz HR. Circadian variation and triggers of acute coronary syndromes. Eur Heart J. 1998;19 Suppl C:C12-23.
67. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O'Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med. 2000;343:915-922.
68. 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.
69. 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;93:1354-1363.
70. Shah PK. Pathophysiology of plaque rupture and the concept of plaque stabilization. Cardiol Clin. 1996;14:17-29.
71. Schwartz CJ, Valente AJ, Sprague EA, Kelley JL, Cayatte AJ, Mowery J. Atherosclerosis. Potential targets for stabilization and regression. Circulation. 1992;86:III117-123.
72. Aikawa M, Libby P. Lipid lowering reduces proteolytic and prothrombotic potential in rabbit atheroma. Ann N Y Acad Sci. 2000;902:140-152.
73. Shah PK, Nilsson J, Kaul S, et al. Effects of recombinant apolipoprotein A-I(Milano) on aortic atherosclerosis in apolipoprotein E-deficient mice. Circulation. 1998;97:780-785.
74. Shah PK, Yano J, Reyes O, et al. High-dose recombinant apolipoprotein a-i(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice : potential implications for acute plaque stabilization. Circulation. 2001;103:3047-3050.
75. Crisby M, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation. 2001;103:926-933.
76. Shah PK, Kaul S, Nilsson J, Cercek B. Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming, part I. Circulation. 2001;104:2376-2383.
77. Shah PK, Kaul S, Nilsson J, Cercek B. Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming, part II. Circulation. 2001;104:2498-2502.
78. Schonbeck U, Libby P. CD40 signaling and plaque instability. Circ Res. 2001;89:1092-1103.
79. Naghavi M, Madjid M, Khan MR, Mohammadi RM, Willerson JT, Casscells SW. New developments in the detection of vulnerable plaque. Curr Atheroscler Rep. 2001;3:125-135.
80. Casscells W, Hathorn B, David M, et al. Thermal detection of cellular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet. 1996;347:1447-1451.
81. Ge J, Baumgart D, Haude M, et al. Role of intravascular ultrasound imaging in identifying vulnerable plaques. Herz. 1999;24:32-41.
82. Hiro T, Fujii T, Yasumoto K, et al. Detection of fibrous cap in atherosclerotic plaque by intravascular ultrasound by use of color mapping of angle-dependent echo-intensity variation. Circulation. 2001;103:1206-1211.
83. von Birgelen C, Klinkhart W, Mintz GS, et al. Plaque distribution and vascular remodeling of ruptured and nonruptured coronary plaques in the same vessel: an intravascular ultrasound study in vivo. J Am Coll Cardiol. 2001;37:1864-1870.
84. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science. 1991;254:1178-1181.
85. Brezinski ME, Tearney GJ, Weissman NJ, et al. Assessing atherosclerotic plaque morphology: comparison of optical coherence tomography and high frequency intravascular ultrasound. Heart. 1997;77:397-403.
86. Frank H. Characterization of atherosclerotic plaque by magnetic resonance imaging. Am Heart J. 2001;141:S45-48.
87. Hatsukami TS, Ross R, Polissar NL, 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.
88. Vallabhajosula S, Fuster V. Atherosclerosis: imaging techniques and the evolving role of nuclear medicine. J Nucl Med. 1997;38:1788-1796.
