Current Concept of Vulnerable Plaque

Acute coronary syndrome (ACS—acute myocardial infarction (AMI) or unstable angina) occurs when the myocardial demand for oxygen exceeds the supply from the coronary arteries. Typically, this condition is due to atherosclerotic coronary artery disease (CAD). As atheromatous plaque builds up on the wall of the coronary arteries, it compromises the lumen of the artery. This condition may be diagnosed with coronary angiography, which provides a radiographic image and measurement of the luminal diameter. Classically, stenotic plaques which compromise the coronary arteries by more than 60-70 percent are viewed as potentially clinically or hemodynamically significant and place a patient at higher risk for ACS. This provides the rationale for coronary revascularization procedures.

However, many serial angiographic studies have demonstrated that most acute myocardial infarctions (AMI) occur due to occlusion of coronary arteries that did not previously contain significant stenosis, and that the coronary artery with the most severe stenosis is usually not the "culprit" artery (i.e., the one causing AMI) (Little 1988; Ambrose 1988). Thus, plaque progression and clinical outcome are not always closely related, and each is poorly predicted on clinical and angiographic grounds. In the past decade, it has become clear that most plaques that underlie a fatal or nonfatal MI are less than 70 percent stenosed angiographically (Kullo 1998; Kolodgie 2001).

These observations have led to the development of the concept of vulnerable plaque (VP). Researchers have suggested that the immediate precursor of most of the culprit plaques for ACS is plaque that is at high risk of rupturing and not just the plaque that is stenotic (Davies 1997; Kullo 1998; Kolodgie 2001). The VP is the "short-term precursor" to the culprit plaque, which triggers clinical ACS (i.e., unstable angina and AMI). The concept of the VP has been developed largely by histopathological studies of culprit lesions in the coronary circulation of patients who have died from AMI and is evolving now using imaging techniques and other methods in living subjects.

Plaques of the coronary arteries are characterized by a lipid core encased in a fibrous "cap". Although these plaques may compromise the lumen of the coronary artery and thus be visible on angiography (which visualizes only the vessel lumen and not the vessel wall), it is estimated based on histopathological studies of "culprit" plaques that approximately 60 to 70 percent of AMIs are caused by plaque rupture, with release of the thrombogenic core of lipid and necrotic debris (Davies 1990; Falk 1995). Less frequently—30 to 40 percent on histopathology—thrombi are seen to overlie denuded endothelium, suggesting an erosion of the cap (Davies 1990; Falk 1995). According to this concept, VPs are those plaques at high risk for rupture, or at high risk for having the surface of their fibrous cap denuded, in either case leading to thrombus formation. Thus, determining the degree of stenosis by angiogram, currently the routine method relied on for clinical decisionmaking, will be quite unreliable in predicting future disease since gradual occlusion of the lumen by a progressing stenotic plaque is not felt to be a major cause of AMI.

Instead, based on histological studies of culprit plaques, VPs are generally felt to have three histologic hallmarks compared to stable plaques (Davies 1997; Kullo 1998; Kolodgie 2001; Forrester 2002): a larger lipid core (>40 percent of total lesion area), a thinner fibrous cap (65 to 150 micrometers), and many inflammatory cells.

In addition to the above triad, others (Goldstein 2002; Monroe 2002) have noted certain angiographic features that distinguish patients with ACS from those with stable CAD—complex coronary stenoses and/or coronary plaque fissures/erosions.

Based on the above described "structural" concept of the VP, multiple diagnostic methods have been proposed to identify VPs, including angiography, intravenous ultrasound (IVUS), angioscopy, thermography catheters, optical coherence tomography (OCT), magnetic resonance imaging (MRI), and computed tomography (CT). These methods are currently in the investigational phase, since none is supported by large, prospective natural history studies or by clinical studies demonstrating risk reduction.

In addition to the local features described, there is some evidence that systemic factors may play a role in plaque instability (Rothwell 2000; Naghavi 2003a), including the presence of a systemic inflammatory state. This provides the rationale for the search for serum biomarkers to identify patients with high-risk lesions.

Recently, a review article from a large group of investigators has described a broader concept of VP (Naghavi 2003a). According to this broader concept, the VP signifies any plaque that might cause clinically significant CAD. Thus, the plaque that is vulnerable to rupture and/or denudation is but one sub-type of VP. Nevertheless, it is clearly the major sub-type, and along with "vulnerable myocardium" and "vulnerable blood," "vulnerable plaque" forms the triad of vulnerability that defines the "vulnerable patient." Other lesions prone to causing symptomatic coronary artery disease are depicted in Figure 1 taken from this review.

The "classic" description of the VP is represented by "Plaque A." Despite the fact these authors also consider the other plaques vulnerable, there is consensus that Plaque A (i.e., that histological type most prone to rupture) is the most characteristic lesion. These authors agree that roughly 70% of culprit lesions are caused by rupture and the remaining 30 percent of culprit lesions (i.e., non-ruptured) are caused by erosion (Plaque C), the presence of a calcified nodule (Plaque F), or another cause. Therefore, they have proposed criteria for defining VP based on this broader definition. Major criteria include: active inflammation (monocyte/macrophage +/- T-cell infiltration), thin cap with large lipid core, endothelial denudation with superficial platelet aggregation, fissured plaque, and stenosis >90 percent. Minor criteria include: superficial calcified nodule, glistening yellow appearance, intraplaque hemorrhage, endothelial dysfunction, and outward (positive) remodeling.

As we cautioned earlier in the methods section, although we repeatedly use the term "vulnerable plaque" in the remainder of this report, this usage should not be construed as an affirmation of the validity of the concept described above. Additional studies are needed to either validate or refute this concept.

Stroke is another major cause of cardiovascular disease (CVD) in which the concept of VP might be applicable to carotid artery lesions. However, it should be noted that the concept concerning VP is derived mostly from the CAD literature; the data on carotid artery disease is even more limited.

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