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Circulation. 2003;107:2072-2075
doi: 10.1161/01.CIR.0000069329.70061.68
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(Circulation. 2003;107:2072.)
© 2003 American Heart Association, Inc.

Mini-Review: Expert Opinions

Vulnerable Atherosclerotic Plaque

A Multifocal Disease

Ward Casscells, MD; Morteza Naghavi, MD; James T. Willerson, MD

From the Division of Cardiology, Department of Internal Medicine, Medical School, The University of Texas Health Science Center at Houston; The Texas Heart Institute at St. Luke’s Episcopal Hospital; and President Bush Center for Cardiovascular Health at Memorial Hermann Hospital, Houston, Tex.

Correspondence to Ward Casscells, MD, The University of Texas Medical School at Houston, 6431 Fannin St, MSB 1.252, Houston, TX 77030. E-mail s.ward.casscells{at}uth.tmc.edu


*    Introduction
up arrowTop
 *Introduction
down arrowConclusion
 down arrowReferences
 
The recent proliferation of invasive and noninvasive techniques to locate vulnerable atherosclerotic plaques raises important questions. Will such techniques add useful prognostic information? If so, will the information prevent myocardial infarction, stroke, or death in at least some patients at risk? Will it lead to new research advances? Will the benefits justify the costs?

Plaque Progression: Often Abrupt, Rarely Predictable
Some facts are now certain. First, plaque progression and clinical outcome are not always closely related, and each is poorly predicted by clinical and angiographic variables.1–4 Second, many plaques progress episodically because of episodes of thrombosis triggered by rupture, erosion (denudation), or occasionally endothelial activation or inflammation.5,6 Unless there is a relatively hypercoagulable state, at least some thrombi remain mural rather than occlusive and produce few if any symptoms unless they embolize7; and if lysis is incomplete and followed by re-endothelialization, the result is a plaque growth. Another mechanism of rapid plaque growth is hemorrhage into the plaque, which is particularly important in the pathogenesis of carotid artery rupture.8,9 Still other plaques develop foci of rapidly proliferating smooth muscle cells.10

Independent Progression of Individual Plaques:
Third, plaques within a given patient often progress largely independently.11 This frustrating unpredictability of patient outcomes—even in patients without heart failure or arrhythmias (whose prognosis reflects variables outside the scope of this review)—is probably due in part to fluctuation of risk factors and "triggers," eg, day-to-day changes in diet, activity, stress, cold weather, pollution, smoking, infection, hydration, and blood pressure. Nevertheless, independent plaque behavior in a given patient must be due in large measure to the marked heterogeneity of plaque histology and to differences in the physical forces to which plaques are subjected.12,13

Vulnerable Plaque Versus Stenotic Plaque
In the past decade, it has become clear that most plaques that underlie a fatal or nonfatal myocardial infarction are, as shown by angiography, less than 70% stenosed. Approximately 60% are caused by rupture of plaques with a large, thrombogenic core of lipid and necrotic debris (including foci of macrophages, T cells, old hemorrhage, angiogenesis, and calcium). The ruptured cap is thin, presumably because macrophages digest it as they cross into and out of the plaque, and because smooth muscle cells (which synthesize the cap) have become sparse because of senescence or apoptosis caused by inflammatory cytokines.

Plaque Inflammation
Another 30% to 40% of coronary thrombi overlie plaques denuded of endothelium, and many if not most of these have luminal inflammation.14,15 Activated T cells in the non-culprit arteries and systemic circulation of patients with unstable angina,16,17 together with recent demonstrations that serum levels of C-reactive protein (CRP) predicts the risk of myocardial infarction (MI) or stroke better than total and low-density lipoprotein cholesterol levels,18 help explain why techniques such as thermography to detect foci of plaque inflammation before the development of thrombosis have been developed.19,20

However, the lack of data on the natural history of such plaques poses problems. Does everyone with coronary artery disease have vulnerable plaques, or just a subset, such as those with unstable angina and/or elevated serum CRP levels? Do all of these plaques rupture, erode, or thrombose? Do some quiesce or heal? Can these plaques be localized noninvasively or will catheterization be required? Although an elevated serum CRP does not distinguish coronary from aortic, carotid, or peripheral disease (or from infection, malignancy, trauma, or other causes of inflammation), would it be sufficient for screening purposes to combine serum CRP values with some noninvasive techniques such as electron beam computed tomography (EBCT) coronary calcium score?

Multifocal Nature of Vulnerable Plaques
Recent studies21,22 have emphasized that, by some criteria, many unstable patients have a second or even a third vulnerable plaque, and have called for an emphasis on proven systemic therapies, such as a Mediterranean diet, statins, angiotensin-converting enzyme (ACE) inhibitors, and clopidogrel, rather than unproven approaches, such as stenting. Another promising approach is vaccination against influenza. In hypercholesterolemic mice, the influenza infection exacerbated plaque inflammation and caused thrombosis.23 Clinical studies suggest that many MIs, strokes, and deaths may be avoided by influenza vaccination.24

Clinico-Pathological Correlation
Nevertheless, we believe that finding and treating individual vulnerable plaques may also prove useful. Our rationale begins with the fact that, in autopsy studies of victims of fatal MI, a second occlusive thrombus is found in 6% to 16% of victims, though most of these individuals have a second vulnerable plaque (rarely three).25,26 Approximately half of these have rupture or erosion with a mural (non–infarct-related) thrombus. In patients with stable symptoms, arterial inflammation is not diffuse, and in these patients most plaques are predominantly fibrotic. Even a study that reported diffuse vascular inflammation in these patients reveals, in its table, that only 2.5% of plaques had moderate or marked infiltration by both macrophages and T cells.14

Angiographic Studies
By coronary angiography, progression of stenoses over 2 years was noted in only 22% of patients with angina pectoris, even in the pre-statin era. Patients with progression averaged only 1.1 progressing lesion, which suggests that simultaneous progression of 2 plaques must be rare.27 Ge et al28 found no instances of a second vulnerable plaque in an angiographic and ultrasound study of angina patients. Another group found a second suspicious lesion in 14% of patients.29 In a series of patients medically stabilized after presenting with unstable angina, Kaski et al30 found 22% of stenoses progressed over 8 months, but no patient had progression in 2 lesions. However, in a series of unstable angina patients, the same researchers described an average of 2.6 vulnerable lesions per patient, using the single criterion of angiographic thrombus or irregularity. In patients who had experienced a fatal MI and in whom plaque rupture and thrombus were correlated with post-mortem angiography, no second thrombi or ruptures were described.31 Subsequently, Goldstein et al32 found that 40% of patients with MI had a second vulnerable plaque designed by angiographic evidence for at least 2 of the following 4 criteria: slow flow, ulceration, irregular surface, or mobile filling defect.

IVUS Studies
The finding of more than 1 ruptured or vulnerable plaque in patients with MI or unstable angina is also supported by a recent intravascular ultrasound study by Riofoul et al,33 who found 2 or more plaque ruptures in 79% of patients with acute coronary syndromes. However, another study described a single plaque rupture in half of patients who presented with unstable angina.28

Angioscopic Studies
Angioscopy almost always reveals only 1 thrombus in patients with an MI. However, yellow plaques, which have a high risk of progression to rupture, are found in some patients with stable angina, most patients with unstable angina, and nearly all patients with an acute MI.34–39

Thermography Studies
The recent finding that plaques with superficial inflammation are warmer than other plaques whereas normal arteries are uniform in temperature40 has led to the development of thermography catheters. Thermal heterogeneity is found in some patients with stable angina and in almost all patients with unstable angina, with 2 or even 3 hot plaques being present in patients with an acute MI.21 Interestingly, levels of serum CRP were not well correlated with the number of hot plaques, and most patients with stable angina and 1 hot plaque had a normal serum CRP level. In the only follow-up study reported to date, thermal heterogeneity was a strong independent predictor of adverse events.41

Needed: Clinical Trials of New Techniques For Detecting Vulnerable Plaques
Because not all ruptured or eroded plaques are yellow, warm, calcified, etc, it is logical to ask what combination of new techniques might be optimal for risk stratification. The ideal approach would provide both anatomic and functional data. Plaques at greatest risk for rupture should have an inflamed, thin (or fissured) cap, a large lipid core, and high wall stress (ie, large lumen). Those at risk of erosive thrombosis would have an irregular or denuded inflamed lumen, and thrombogenic slow flow due to a stenosis upstream or downstream. Patients with either of these types of plaque would be at higher risk if they are in a hypercoagulable state or if the lesion is in the proximal left anterior descending coronary artery, particularly if collaterals are inadequate.

Clinical trials are likely to demonstrate that such plaques can be detected with some combination of MRI or computed tomography (CT) with contrast, angiography, thermography, ultrasound or optical coherence tomography (OCT) (either of which could incorporate elastography or integrated backscatter), near-infrared spectroscopy, and/or angioscopy.42,43

Such an approach would be expensive, but could prove useful. For example, if a patient is found to be at greater risk than predicted by office or bedside techniques, including serum CRP level, this information may lead the patient to reschedule a physically or mentally stressful task in lieu of rest, or of a critical family meeting or reconciliation. Awareness of vulnerability may also improve adherence to diet and medications, as well as influencing the physician’s treatment goals as to weight, blood pressure, lipids, glucose, and even frequency of office visits. In particular, the presence of vulnerability may merit multiple therapies, such as various combinations of aspirin with warfarin or clopidogrel, ACE inhibitors with ß-adrenergic blockers, statins with niacin, fibrates, resins, etc. Finally, as statins may not reduce mortality significantly until 1 year after initiation of therapy, the most vulnerable plaques may merit stenting or some other form of local therapy to "buy time."


*    Conclusion
up arrowTop
 up arrowIntroduction
 *Conclusion
down arrowReferences
 
Trials to answer these questions are now being planned. We predict that these trials will lead to a graded, individualized approach to each patient. Because atherosclerosis is a systemic, multi-genic, and multi-focal disease, optimal care is likely to require systemic and multi-focal diagnosis and therapy, including local plaque therapy in some patients. This more complicated approach will likely be more expensive in the short-term, but could be offset by substantial reductions in morbidity and mortality.


*    Acknowledgments
 
This work was supported in part by Department of Defense grant #DAMD 17–01–2-0047. The authors wish to thank Mohammed Madjid, MD, for his advice and suggestions.


*    Footnotes
 
Drs Casscells, Willerson, and Naghavi are shareholders in Volcano Therapeutics, Inc, a company developing diagnostic and therapeutic modalities for vulnerable plaques.


*    References
up arrowTop
 up arrowIntroduction
 up arrowConclusion
 *References
 

  1. Moise A, Lesperance J, Theroux P, 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.[CrossRef][Medline] [Order article via Infotrieve]
  2. Haft JI, al-Zarka AM. The origin and fate of complex coronary lesions. Am Heart J. 1991; 121: 1050–1061.[CrossRef][Medline] [Order article via Infotrieve]
  3. Singh RN. Progression of coronary atherosclerosis: clues to pathogenesis from serial coronary arteriography. Br Heart J. 1984; 52: 451–461.[Abstract/Free Full Text]
  4. 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.[CrossRef][Medline] [Order article via Infotrieve]
  5. Yokoya K, Takatsu H, Suzuki T, et al. Process of progression of coronary artery lesions from mild or moderate stenosis to moderate or severe stenosis: a study based on four serial coronary arteriograms per year. Circulation. 1999; 100: 903–909.[Abstract/Free Full Text]
  6. Bruschke AV, Kramer JR Jr, Bal ET, et al. The dynamics of progression of coronary atherosclerosis studied in 168 medically treated patients who underwent coronary arteriography three times. Am Heart J. 1989; 117: 296–305.[CrossRef][Medline] [Order article via Infotrieve]
  7. Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart. 1999; 82: 265–268.[Abstract/Free Full Text]
  8. Sillesen H, Nielsen T. Clinical significance of intraplaque hemorrhage in carotid artery disease. J Neuroimaging. 1998; 8: 15–19.[CrossRef][Medline] [Order article via Infotrieve]
  9. 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.[Abstract/Free Full Text]
  10. Flugelman MY, Virmani R, Correa R, et al. Smooth muscle cell abundance and fibroblast growth factors in coronary lesions of patients with nonfatal unstable angina: a clue to the mechanism of transformation from the stable to the unstable clinical state. Circulation. 1993; 88: 2493–500.[Abstract/Free Full Text]
  11. Gibson CM, Sandor T, Stone PH, et al. Quantitative angiographic and statistical methods to assess serial changes in coronary luminal diameter and implications for atherosclerosis regression trials. Am J Cardiol. 1992; 69: 1286–1290.[CrossRef][Medline] [Order article via Infotrieve]
  12. Gertz SD, Roberts WC. Hemodynamic shear force in rupture of coronary arterial atherosclerotic plaques. Am J Cardiol. 1990; 66: 1368–1372.[CrossRef][Medline] [Order article via Infotrieve]
  13. Feldman CL, Stone PH. Intravascular hemodynamic factors responsible for progression of coronary atherosclerosis and development of vulnerable plaque. Curr Opin Cardiol. 2000; 15: 430–440.[CrossRef][Medline] [Order article via Infotrieve]
  14. van der Wal AC, Becker AE, van der Loos CM, et al. 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.[Abstract/Free Full Text]
  15. 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: 269–272.[Abstract/Free Full Text]
  16. Caligiuri G, Paulsson G, Nicoletti A, et al. Evidence for antigen-driven T-cell response in unstable angina. Circulation. 2000; 102: 1114–1119.[Abstract/Free Full Text]
  17. Spagnoli LG, 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.[Abstract/Free Full Text]
  18. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: 1557–1565.[Abstract/Free Full Text]
  19. 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.[CrossRef][Medline] [Order article via Infotrieve]
  20. Stefanadis 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.[Abstract/Free Full Text]
  21. Webster M, Stewart J, Ruygrok P, et al. Intracoronary thermography with a multiple thermocouple catheter: initial human experience. Am J Cardiol. 2002; 90 (suppl): 24H.Abstract.
  22. Uchida Y, Nakamura F, Tomaru T, et al. Prediction of acute coronary syndromes by percutaneous coronary angioscopy in patients with stable angina. Am Heart J. 1995; 130: 195–203.[CrossRef][Medline] [Order article via Infotrieve]
  23. Naghavi M, Wyde P, Litovsky S, et al. Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice. Circulation. 2003; 107: 762–768.[Abstract/Free Full Text]
  24. Meyers DG. Myocardial infarction, stroke, and sudden cardiac death may be prevented by influenza vaccination. Curr Atheroscler Rep. 2003; 5: 146–149.[Medline] [Order article via Infotrieve]
  25. Horie T, Sekiguchi M, Hirosawa K. Coronary thrombosis in pathogenesis of acute myocardial infarction: histopathological study of coronary arteries in 108 necropsied cases using serial section. Br Heart J. 1978; 40: 153–161.[Abstract/Free Full Text]
  26. Qiao JH, Fishbein MC. The severity of coronary atherosclerosis at sites of plaque rupture with occlusive thrombosis. J Am Coll Cardiol. 1991; 17: 1138–1142.[Abstract]
  27. Shub C, Vlietstra RE, Smith HC, et al. The unpredictable progression of symptomatic coronary artery disease: a serial clinical-angiographic analysis. Mayo Clin Proc. 1981; 56: 155–160.[Medline] [Order article via Infotrieve]
  28. Ge J, Chirillo F, Schwedtmann J, et al. Screening of ruptured plaques in patients with coronary artery disease by intravascular ultrasound. Heart. 1999; 81: 621–627.[Abstract/Free Full Text]
  29. Kerensky RA, Wade M, Deedwania P, et al. Revisiting the culprit lesion in non-Q-wave myocardial infarction. Results from the VANQWISH trial angiographic core laboratory. J Am Coll Cardiol. 2002; 39: 1456–1463.[Abstract/Free Full Text]
  30. Kaski JC, Chester MR, Chen L, et al. Rapid angiographic progression of coronary artery disease in patients with angina pectoris: the role of complex stenosis morphology. Circulation. 1995; 92: 2058–2065.[Abstract/Free Full Text]
  31. Levin DC, Fallon JT. Significance of the angiographic morphology of localized coronary stenoses: histopathologic correlations. Circulation. 1982; 66: 316–320.[Abstract/Free Full Text]
  32. Goldstein JA, Demetriou D, Grines CL, et al. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med. 2000; 343: 915–922.[Abstract/Free Full Text]
  33. 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.[Abstract/Free Full Text]
  34. Sherman CT, Litvack F, Grundfest W, et al. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med. 1986; 315: 913–919.[Abstract]
  35. 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.[Abstract/Free Full Text]
  36. Waxman S, Sassower MA, Mittleman MA, et al. Angioscopic predictors of early adverse outcome after coronary angioplasty in patients with unstable angina and non-Q-wave myocardial infarction. Circulation. 1996; 93: 2106–2113.[Abstract/Free Full Text]
  37. de Feyter PJ, Ozaki Y, Baptista J, et al. Ischemia-related lesion characteristics in patients with stable or unstable angina: a study with intracoronary angioscopy and ultrasound. Circulation. 1995; 92: 1408–1413.[Abstract/Free Full Text]
  38. Van Belle E, Lablanche JM, Bauters C, et al. Coronary angioscopic findings in the infarct-related vessel within 1 month of acute myocardial infarction: natural history and the effect of thrombolysis. Circulation. 1998; 97: 26–33.[Abstract/Free Full Text]
  39. Mizuno K, Miyamoto A, Satomura K, et al. Angioscopic coronary macromorphology in patients with acute coronary disorders. Lancet. 1991; 337: 809–812.[CrossRef][Medline] [Order article via Infotrieve]
  40. Madjid M, Naghavi M, Malik BA, et al. Thermal detection of vulnerable plaque. Am J Cardiol. 2002; 90: 36L–39L.[CrossRef][Medline] [Order article via Infotrieve]
  41. Stefanadis C, Toutouzas 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.[Abstract/Free Full Text]
  42. Pasterkamp G, Falk E, Woutman H, et al. Techniques characterizing the coronary atherosclerotic plaque: influence on clinical decision making? J Am Coll Cardiol. 2000; 36: 13–21.[Abstract/Free Full Text]
  43. Naghavi M, Madjid M, Khan MR, et al. New developments in the detection of vulnerable plaque. Curr Atheroscler Rep. 2001; 3: 125–135.[Medline] [Order article via Infotrieve]




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