Myocardial Infarction and the Culprit Plaque: Myths, Data and Statistics

Identification of the coronary endoluminal lesion(s) responsible for the process now called acute coronary syndrome (ACS) has become a central focus of both non-invasive and invasive treatment modalities in patients with coronary heart disease. Impressive reductions in cardiovascular mortality seen with lipid lowering agents1–3 and angiotensin-converting enzyme inhibitors4,5 suggest a critical role for pharmacologic alteration of plaque and vessel wall dynamics. Increasingly aggressive invasive approaches to the management of patients with coronary heart disease have suggested that catheter-based therapies directed toward a “culprit plaque” may diminish the risk of subsequent ACS.6 The former approach utilizes systemic therapy to treat what is both a local process and a systemic disease while the latter approach posits that a directed, local approach is also efficacious. How did such a dichotomous approach to the prevention of myocardial infarction arise? What are the assumptions surrounding each approach? What are the data? We will attempt to answer these questions and pose additional ones that will hopefully focus our thinking and highlight those areas in need of more information. Atherosclerosis, primarily a disorder of the vascular intima, is characterized by both atherosis and sclerosis. Post mortem studies indicate that the former is typically comprised of soft, pultaceous material while the latter is typically fibrotic.7–10 Importantly, most plaques contain varying amounts of both “hard” and “soft” components with a minority characterized as predominantly one or the other.11–13 The progression of atherosclerosis has been classified into five phases (Table 1),14 which represent the dynamic and progressive nature of atherosclerotic disease. A classification scheme of vascular injury has recently been suggested and describes three distinct stages of injury.15 Notably, considerable overlap exists between this classification scheme and that outlined in Table 1. The first stage of vascular injury is characterized by the functional alteration of endothelial cells without detectable patho-morphologic changes. This stage is recognized by the accumulation of monocytes and lipids in the extracellular space and the subsequent appearance of lipid-laden macrophages (foam cells). The second stage is characterized by endothelial denudation and intimal damage with, however, an intact internal elastic lamina. This stage is also characterized by migration and proliferation of smooth muscle cells and platelet adhesion. The third stage is characterized by a deeper injury to the media with associated thrombus formation. Small thrombi may organize and further contribute to the growth of the atherosclerotic plaque,16–20 while large thrombi may result in an ACS (myocardial infarction, unstable angina, sudden cardiac death).16,19–21 This important classification scheme of the severity of the atherosclerotic lesion and the attendant changes in vessel architecture does not, however, provide insight into the molecular biological mechanisms underlying the observed changes. The recognition of the importance of acute and chronic inflammation in both the formation and destruction of the culprit plaque(s) in ACS provides an important framework for much of the intensive research in this area today.22 It was not appreciated at the outset that the vascular changes described in Table 1 were the result of the release of growth factors, chemokines and cytokines released by endothelial cells, macrophages, leukocytes and platelets. Nor was the critical balance of smooth muscle cell function and death in determining the stability of the fibrous cap surrounding the lipid core appreciated. However, it quickly became clear that the explosive nature of ACS stood in marked contrast to the steady, inexorable course of stable coronary heart disease. The risk of developing an ACS is, of course, directly related to the extent of disease.23–25 Numerous post mortem studies support the extensive nature of atherosclerotic changes in the coronary circulation in patients dying from ACS.24,25 However, coronary atherosclerosis is necessary but not sufficient in patients with fatal ACS. A striking increase in the prevalence of ruptured or fissured plaques, irrespective of the presence of (fresh) thrombus, is a hallmark of fatal ACS.26,27 These findings have been confirmed in numerous studies of survivors of ACS who underwent coronary angiography28,29 and are supported by the striking correlation between angiographically demonstrable lesion complexity and that noted on histopathologic examination.30 Nevertheless, the fundamental theme of the patho-anatomy of ACS has been the role of thrombus.31 As noted earlier, thrombus is essentially the final common pathway for ACS. Plaque disruption/rupture with consequent exposure of the highly prothrombotic lipid core to the bloodstream generally results in complete thrombotic occlusion (Q-wave myocardial infarction) or high-grade, intermittent obstruction (non-Q wave myocardial infarction, unstable angina, sudden cardiac death). However, the wealth of information on the diagnosis, natural history and prognosis in coronary heart disease provided by coronary angiography has also led to confusing (and erroneous) interpretations of the relationship between the severity of coronary obstruction and the likelihood of subsequent myocardial infarction. Prospective angiographic studies have shown that the frequency of progression to coronary occlusion is significantly and positively related to the severity of the stenosis at baseline.32,33 However, retrospective angiographic studies, in selected populations, have concluded that stenoses considered non-critical (

1. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4s). Lancet 1994;344:1383–1389. 2. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 3. The LIPID Study Group. Design features and baseline characteristics of the LIPID (Long-Term Intervention with Pravastatin IN Ischemic Disease) Study: A randomized trial in patients with previous acute myocardial infarction and/or unstable angina pectoris. Am J Cardiol 1995;76:474–479. 4. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of angiotensin converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145–153. 5. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992;327:669–677. 6. Kern MJ, Meier B. Evaluation of the culprit plaque and the physiological significance of coronary atherosclerotic narrowings. Circulation 2001;103:3142–3149. 7. Kragel AH, Reddy SG, et al. Morphometric analysis of the composition of atherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarction and in sudden coronary death. Circulation 1989;80:1747–1756. 8. Kragel AH, Reddy SG, et al. Morphometric analysis of the composition of coronary artery plaques in isolated unstable angina pectoris with pain at rest. Am J Cardiol 1990;66:562–567. 9. Dollar AL, Kragel AH, et al. Composition of atherosclerotic plaques in coronary arteries in women = 90 years of age. Am J Cardiol 1991;67:1228–1233. 11. Bouch DC, Montgomery S, et al. Cardiac lesions in fatal cases of recent myocardial infarction from a coronary care unit. Br Heart J 1970;32:795–803. 12. Hangartner JRW, Charleston AJ, et al. Morphological characteristics of clinically significant coronary artery stenosis in stable angina. Br Heart J 1986;56:501–508. 13. Davies MJ. A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation 1990;82(Suppl II):II-38–II-46. 14. Fuster V, Badimon L, et al. The pathophysiology of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:242–250, 310–318. 15. Ip JH, Fuster V, et al. Syndromes of accelerated atherosclerosis: Role of vascular injury and smooth muscle cell proliferation. J Am Coll Cardiol 1990;15:1667–1687. 16. Richardson PD, Davies MJ, et al. Influence of plaque configuration and stress distribution on fissuring of atherosclerotic plaques. Lancet 1989:2:941–944. 17. Stary HC, Chandler AB, 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;92:1355–1374. 18. Davies MJ, Woolf N, et al. Morphology of the endothelium over atherosclerotic plaques in human coronary arteries. Br Heart J 1988;60:459–464. 19. Falk E. Unstable angina with fatal outcome: Dynamic coronary thrombosis leading to infarction and/or sudden death: Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985;71:699–708. 20. Davies MJ, Bland MJ, et al. Factors influencing the presence or absence of acute coronary thrombi in sudden ischemic death. Eur Heart J 1989;10:203–208. 21. Fuster V, Stein B, et al. Atherosclerotic plaque rupture and thrombosis: Evolving concepts. Circulation 1990;82(Suppl II):II-47–II-59. 22. Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature 1993;362:801–810. 23. Moise A, Lesperance J, et al. Clinical and angiographic predictors of new total coronary occlusion in coronary artery disease: Analysis of 313 nonoperated patients. Am J Cardiol 1984;54:1176–1181. 24. Roberts WC, Potkin BN, Solus DE, et al. Mode of death, frequency of healed and acute myocardial infarction, number of major epicardial coronary arteries severely narrowed by atherosclerotic plaque, and heart weight in fatal atherosclerotic coronary artery disease: Analysis of 889 patients studied at necropsy. J Am Coll Cardiol 1990;15:196. 25. Warnes CA, Roberts WC. Sudden coronary death: Relation of amount and distribution of coronary narrowing at necropsy to previous symptoms of myocardial ischemia, left ventricular scarring and heart weight. Am J Cardiol 1984;54:65–73. 26. Davies MJ, Thomas AC, et al. Plaque fissuring — The cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985;53:363–373. 27. 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. 28. Ambrose JA, Winters SL, et al. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol 1985;5:609–616. 29. Ambrose JA, Hjemdahl-Monsen CE, et al. Angiographic demonstration of a common link between unstable angina pectoris and non-Q wave acute myocardial infarction. Am J Cardiol 1988;61:244–247. 30. Levin DC, Fallon JT. Significance of the angiographic morphology of localized coronary stenoses: Histopathologic correlations. Circulation 1982;66:316–320. 31. Fuster V, Stein B, et al. Atherosclerotic plaque rupture and thrombosis: Evolving concepts. Circulation 1990;82(Suppl II):II-47–II-59. 32. Alderman EL, Corley SD, et al. Five-year follow-up of factors associated with progression of coronary artery disease in the Coronary Artery Surgery Study(CASS). J Am Coll Cardiol 1993;22:1141–1154. 33. Waters D, Lesperance J, Francetich M, et al. A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis. Circulation 1990;82:1940–1953. 34. Nobuyoshi M, Tanaka M, et al. Progression of coronary atherosclerosis: Is coronary spasm related to progression? J Am Coll Cardiol 1991;18:904–910. 35. Giroud D, Li JM, 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. 36. Ambrose J, Tannenbaum M, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988;12:56–62. 37. Little WC, Constantinescu M, 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. 38. Glagov S, Zarins C, et al. Hemodynamics and atherosclerosis: Insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med 1988;320:915–924. 39. Nissen SE, Gurley JC, et al. Intravascular ultrasound assessment of lumen size and wall morphology in normal subjects and patients with coronary artery disease. Circulation 1991;84:1087–1099. 40. Schoenhagen P, Zaida KM, et al. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: An intravascular ultrasound study. Circulation 200;101:598–603. 41. Hodgson JM, Reddy KG, et al. Intracoronary ultrasound imaging: Correlation of plaque morphology with angiography, clinical syndrome and procedural results in patients undergoing angioplasty. J Am Coll Cardiol 1993;21:35–44. 42. Kearney P, Erbel R, et al. Differences in the morphology of unstable and stable coronary lesions and their impact on the mechanisms of angioplasty. An in vivo study with intravascular ultrasound. Eur Heart J 1996;17:721–723. 43. Gertz SD, Roberts WC. Hemodynamic shear force in rupture of coronary arterial atherosclerotic plaques. Am J Cardiol 1990;66:1368–1372. 44. Falk E. Morphologic features of unstable atherothrombotic plaques underlying acute coronary syndromes. Am J Cardiol 1989;63(Suppl E):114E–120E. 45. Lendon CL, Davies MJ, et al. Atherosclerotic plaque caps are locally weakened when macrophage density is increased. Atherosclerosis 1991;87:87–90. 46. Moreno PR, Falk E, et al. Macrophage infiltration in acute coronary syndromes: Implications for plaque rupture. Circulation 1994;90:775–778. 47. Matrisian LM. The matrix degrading metalloproteinases. Bioessays 1992;14:455–463. 48. Tofler GH, Stone PH, et al. Analysis of possible triggers of acute myocardial infarction (The MILIS study). Am J Cardiol 1990;66:22–27. 49. Ciampricotti R, El Gammal M, et al. Clinical characteristics and coronary angiographic findings of patients with unstable angina, acute myocardial infarction, and survivors of sudden ischemic death occurring during and after sport. Am Heart J 1990;120:1207–1278. 50. Ciampricotti R, El Gammal M. Unstable angina, myocardial infarction and sudden death after an exercise stress test. Int J Cardiol 1989;24:211–218. 51. Gerlernt MD, Hochman JS. Acute myocardial infarction triggered by emotional stress. Am J Cardiol 1992;69:1512–1513. 52. Meisel SR, Kutz I, et al. Effect of Iraqui missiles war on incidence of acute myocardial infarction and sudden death in Israeli civilians. Lancet 1991;338:660–661. 53. Muller JE, Tofler GH, et al. Probable triggers of onset of acute myocardial infarction. Clin Cardiol 1989;12:473–475. 54. Lee RT, Grodzinsky AJ, Frank EH, et al. Structure dependent dynamic mechanical behavior of fibrous caps from human atherosclerotic plaques. Circulation 1991;83:1764–1770. 55. Mittleman MA, Maclure M, et al. Triggering of acute myocardial infarction by heavy physical exertion. N Engl J Med 1993;329:1677. 56. Willich SN, Lewis M, et al. Physical exertion as a trigger of acute myocardial infarction. N Engl J Med 1993;329:1684. 57. Loree HM, Kamm RD, et al. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res 1992;71:850–858. 58. MacIsaac AI, Thomas JD, et al. Toward the quiescent coronary plaque. J Am Coll Cardiol 1993;22:1228–1241. 59. Fitzgerald JD. By what means might beta blockers prolong life after acute myocardial infarction? Eur Heart J 1987;8:945–951. 60. Goldstein JA, Demetrou D, Grines CL, et al. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000;343:915–922.