The Everlasting Quest for the "Vulnerable" Plaque

In their long-term observational study entitled "Plaque Morphology as Predictor of Late Plaque Events in Patients with Asymptomatic Type 2 Diabetes," Hanlon et al. study the association of coronary atherosclerotic plaque characteristics, assessed by CT angiography, with acute coronary events occurring during a median of 9.2 years follow-up in 499 asymptomatic patients with Type 2 diabetes mellitus.1 Patients with diabetes and at least one additional risk factor, such as arterial hypertension or smoking, were approached for coronary atherosclerotic disease screening by coronary artery calcium scanning and CT coronary angiography. The study was conducted in Israel and the scans were obtained for research—CT coronary angiography is not considered an appropriate test in asymptomatic individuals for screening purposes. The study was conceived before the publication of the faCTor-64 (Screening For Asymptomatic Obstructive Coronary Artery Disease Among High-Risk Diabetic Patients Using CT Angiography, Following Core 64) study for which 900 patients with diabetes were randomized to standard of care versus CT coronary angiography-guided therapy with intent to reduce the risk of death and acute coronary events.2 faCTor-64 revealed no conclusive benefit of (albeit a trend favoring) the CT guided strategy after 4 years of follow up. faCTor-64 was limited by the fact that the annual event rates were only one quarter of what was predicted.

The current study is observational in nature—there is no control group—but the follow-up is substantially longer than in faCTor-64. Remarkably, of the 630 patients initially included only 25 experienced an acute coronary syndrome within 9 years after baseline imaging. The annualized event rate of 0.4% is even lower than in faCTor-64 (0.9%) and indeed is the most striking finding of this study. As the authors acknowledge, contemporary medical therapy results in low rates of adverse cardiovascular events, even in patients with diabetes—fueling the debate as to whether diabetes should be considered a coronary heart disease equivalent.3

After excluding 130 patients from analysis because of absence of coronary atherosclerotic disease, the authors identified 24 plaques on the baseline CT scan they believed to be the culprit for the acute coronary event—in one case they were unable to identify a culprit lesion. Then, they characterized the presumed culprit lesions by lumen obstruction, plaque volume, remodeling, plaque composition and location. In addition, they assessed associations of specific "high-risk" plaque features (plaque volume, low density plaque, mild calcification) with the occurrence of events.

Comparing features among presumed culprit lesions and nonculprit plaques, the authors found many to be associated with increased hazard for events, including plaque length, plaque volume, low density, mild calcification, stenosis ≥50%, bifurcation lesions and plaque eccentricity. The presence of one "high-risk" attribute (plaque volume, low density plaque, mild calcification) was associated with a hazard ratio of 4.6 (95% confidence interval 1.6-13.5) for events compared to plaques without "high-risk" features, increasing to 8.1 (3.2-18.7) when all three "high-risk" attributes were present. Adding stenosis assessment yielded the highest hazard ratio of 8.7 (2.6-29.3). Despite the high hazard ratios, however, the positive predictive values were very low, ranging from 1.7 to 6.5%. Plaques with a combination of "high-risk" characteristics and stenosis ≥50% were associated with greater incidence of events compared to lesions with either feature. The authors concluded that CTA-based plaque characteristics predicted culprit lesions of acute coronary syndromes in their study.

The authors acknowledge the small number of events as a significant limitation of their analysis. However, additional limitations must be also considered. For one, assigning a culprit lesion to an acute coronary event is typically straightforward in the setting of an ST-elevation myocardial infarction (STEMI) but nearly impossible with a non-STEMI. The angiogram rarely reveals the site of a plaque rupture or erosion. Even if myocardial imaging or ECG clearly suggest a territory for the ischemic insult, it remains exceedingly difficult to identify the culprit lesion within a vessel which commonly has atherosclerotic disease at multiple sites. Studies have used the most severe lumen obstruction as the culprit site, but pathology studies have taught us that plaques with mild lumen narrowing may often cause myocardial infarctions.4 Thus, merely 10 STEMI culprit sites among the 25 acute coronary events can be reliably identified, further limiting the analysis.

A common problem with associating plaque features and events is confounding. Increasing coronary atherosclerotic disease burden is strongly linked to greater event risk and the number of vessels with coronary artery stenoses (≥50%) correlate with plaque burden.5,6 Furthermore, the assignment of culprit lesions by lumen obstruction leads to stronger associations with features that are linked to stenoses. For example, baseline plaques with greater lumen obstruction are more likely to have larger plaque burden, calcification, low density plaque, etc., but they are also more likely than smaller lesions to develop into obstructive stenoses overtime (and then being labeled "culprit"). Therefore, many plaque characteristics may convey increased hazard of events merely through their association with a higher-grade stenosis. It is conceivable that some of the features lead to additive prediction of stenoses at follow up. For example, a baseline lesion with ≥50% lumen obstruction and large plaque burden is more likely to increase in stenosis severity than lesions with either characteristic alone.

The PROSPECT study (An Imaging Study in Patients With Unstable Atherosclerotic Lesions) revealed that identifying 596 "high-risk" plaques by intravascular ultrasound in a very high-risk population is associated with only six myocardial infarctions after 3 years of follow up.7 As shown in the present study, the absolute risk associated with individual plaques is exceedingly small—even though the relative risk appears high. In their paper, Hanlon et al. suggest a 12.5% sensitivity for a coronary event for the highest risk constellation of plaque features, suggesting that the vast majority of events are being triggered by other type plaques. Similar findings were reported by Motoyama et al.8

There is strong, consistent evidence that plaque ruptures occur frequently without causing events.9 Indeed, plaque ruptures appear to be part of the common pathway of plaque growth.9 It is only the exceptional case of plaque rupture or erosion that leads to an event, a perfect storm scenario.10

Given the very low absolute risk associated with individual plaques, the critical question is what intervention would be beneficial in this setting—even if identification of such plaques would be possible at low risk and costs. Any mechanical intervention by cardiac catheterization involves much greater risk than the risk of an acute coronary event associated with the lesion. It remains to be seen if specific medical treatment options, such as PCSK-9 inhibitors or anti-inflammatory drugs, can be justified in this scenario.

Coronary heart disease is a systemic illness which requires a comprehensive approach.11 We know that control of blood pressure, lipids, blood glucose, smoking cessation, exercise and diet have a profound effect on patient outcome.12 Unfortunately, data from clinical trials suggest we miss prevention goals in most patients.13 Achieving better prevention is likely to have a profound impact on the risk of adverse events. Assessing the total burden of atherosclerotic disease and its metabolic activity as well as considering systemic risk, such as inflammation, is more likely to aid in the management of patients with coronary heart disease than fixating on individual plaques.11,14 More than a decade after a major collaborative effort to move the field away from our focus on individual, "vulnerable" plaques, we still have not fully embraced the concept of the vulnerable patient.15,16


  1. Halon DA, Lavi I, Barnett-Griness O, et al. Plaque morphology as predictor of late plaque events in patients with asymptomatic type 2 diabetes: a long-term observational study. JACC Cardiovasc Imaging 2018. [Epub ahead of print]
  2. Muhlestein JB, Lappe DL, Lima JA, et al. Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes: the FACTOR-64 randomized clincial trial. JAMA 2014;312:2234-43.
  3. Rana JS. Is Diabetes Really a CHD Risk Equivalent? Apr. 13, 2016. Accessed Oct. 23, 2018.
  4. Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion without rupture into a liquid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 1996;93:1354-63.
  5. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification: observations from a registrty of 25,253 patients. J Am Coll Cardiol 2007;49:1860-70.
  6. Nakagomi A, Celermajer DS, Lumley T, Freedman SB. Angiographic severity of coronary narrowing is a surrogate marker for the extent of coronary atherosclerosis. Am J Cardiol 1996;78:516-9.
  7. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364:226-35.
  8. Motoyama S, Ito H, Sarai M, et al. Plaque characterization by coronary computed tomography angiography and the likelihood of acute coronary events in mid-term follow-up. J Am Coll Cardiol 2015;66:337-46.
  9. Arbab-Zadeh A, Fuster V. The myth of the "vulnerable plaque": transitioning from a focus on individual lesions to atherosclerotic disease burden for coronary artery disease risk assessment. J Am Coll Cardiol 2015;654:846-55.
  10. Arbab-Zadeh A, Nakano M, Virmani R, Fuster V. Acute coronary events. Circulation 2012;125:1147-56.
  11. Arbab-Zadeh A, Fuster V. The risk of continuum of atherosclerosis and its implications for defining CHD by coronary angiography. J Am Coll Cardiol 2016;68:2467-78.
  12. Smith SC, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foudnation endorsed by the World Heart Federation and the Preventive Cardiovascualr Nurses Association. J Am Coll Cardiol 2011;58:2432-46.
  13. Farkouh ME, Boden WE, Bittner V, et al. Risk factor control for coronary artery disease secondary prevention in large randomized trials. J Am Coll Cardiol 2013;61:1607-15.
  14. Oikonomou EK, Marwan M, Desai MY, et al. Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prsopective outcome data. Lancet 2018;392:929-39.
  15. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I. Circulation 2003;108:1664-72.
  16. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a callf or new definitions and risk assessment strategies: part II. Circulation 2003;108:1772-8.

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging, Diet, Hypertension

Keywords: Acute Coronary Syndrome, Plaque, Atherosclerotic, Coronary Angiography, Blood Glucose, Risk Factors, Myocardial Infarction, Constriction, Pathologic, Diabetes Mellitus, Type 2, Diabetes Mellitus, Blood Pressure, Smoking Cessation, Lipids, Factor IX, Coronary Artery Disease, Calcinosis, Coronary Stenosis, Hypertension, Cardiac Catheterization, Diet, Inflammation, Electrocardiography, Metabolic Syndrome X

< Back to Listings