The myth of the "vulnerable plaque": transitioning from a focus on individual lesions to atherosclerotic disease burden for coronary artery disease risk assessment

Abstract

The cardiovascular science community has pursued the quest to identify vulnerable atherosclerotic plaque in patients for decades, hoping to prevent acute coronary events. However, despite major advancements in imaging technology that allow visualization of rupture-prone plaques, clinical studies have not demonstrated improved risk prediction compared with traditional approaches. Considering the complex relationship between plaque rupture and acute coronary event risk suggested by pathology studies and confirmed by clinical investigations, these results are not surprising. This review summarizes the evidence supporting a multifaceted hypothesis of the natural history of atherosclerotic plaque rupture. Managing patients at risk of acute coronary events mandates a greater focus on the atherosclerotic disease burden rather than on features of individual plaques.

Keywords: atherosclerosis; coronary heart disease; coronary imaging; prevention.

Figure 1. Risk of MI/Death Associated With Individual Plaques in the PROSPECT Study

Maximum annualized risks (%) of MI or CV death associated with individual coronary atherosclerotic plaques identified at baseline by virtual histology intravascular ultrasound in the PROSPECT study are shown (18). The rates are on the basis of the occurrence of 6 events (6 myocardial infarctions and 0 deaths) after 3.4 years of follow-up among 1,005 coronary arterial sites with pathological intimal thickening and 595 TCFAs, assuming all events were caused by the respective plaque type, thus representing the worst-case scenario. Considering equal risk among the 3,160 plaques detected at baseline (best-case scenario), the event rate associated with each plaque would be only 0.06%/year. The risk of MI or death associated with individual TCFA or vulnerable plaques is much smaller than what is conventionally considered high-risk, even when maximal risk is assumed. CV = cardiovascular; MI = myocardial infarction; TCFA = thin-cap fibroatheroma.

Figure 2. Changes in TCFAs During 12 Months Follow-Up

Changes in TFCAs observed with virtual histology intravascular ultrasound 12 months after baseline imaging. Of 20 TFCAs, only 5 remained unchanged while 15 (75%) lost vulnerable characteristics and revealed thickening of the fibrous cap or transformed into fibrous plaques. The data (Kubo et al. (43)) demonstrate high metabolic activity in atherosclerotic lesions and the short-lived nature of vulnerable plaque characteristics. None of the 99 patients experienced any events during follow up; thus many of the observed changes were likely the result of subclinical plaque ruptures. Abbreviations as in Figure 1.

Figure 3. Risk from Non-Obstructive Versus Obstructive Coronary Artery Disease

Annualized risk (%) of MI or CV death in 3,242 patients followed for a median of 3.6 years after a baseline CT coronary angiogram, according to the extent and severity of coronary artery disease (70). Risk is low in patients with nonobstructive disease (<50% stenosis) involving 4 or fewer coronary artery segments (limited disease). Conversely, the risk is similarly high in patients with nonobstructive disease if more than 4 segments are affected (extensive disease) compared to patients with obstructive disease (≥50% stenosis). Modified from Bittencourt et al. (70). CT = computed tomography. Other abbreviations as in Figure 1.

Central Illustration. Fate of Ruptured Coronary Atherosclerotic Plaques According to Thrombotic Milieu

The hypothesized interplay of prothrombotic and thrombosis resisting/containing factors that presumably determine the outcome of a ruptured coronary atherosclerotic plaque is shown. (A) In the most common scenario, small thrombus formation associated with plaque rupture is contained and vascular occlusive thrombus is inhibited. (B) In the less common scenario of several prothrombotic factors coinciding (e.g., inflammatory state, large lesion plaque burden, vasoconstriction, circadian rheological changes), local thrombosis associated with plaque rupture cannot be contained and clinically significant vascular thrombosis occurs, triggering an acute coronary syndrome (ACS). The constellation of factors leading to these different outcomes is unknown.