Natural History of Vulnerable Plaque

Assuming the validity of the vulnerable plaque (VP) concept, in order to investigate its natural history and estimate the risk of clinically significant plaque rupture or ACS over time based on aspects of plaque morphology, plaque thermography, or biochemical markers, an investigator would need a prospective longitudinal cohort study that would in many aspects resemble the Framingham Study. We describe below the design of a hypothetical study to understand the natural history of "VP."

A study would need to enroll a population sufficiently large and sufficiently high-risk (e.g., age 55 with either diabetes mellitus, known CAD, or at high cardiovascular risk according to their Framingham score (>10 percent risk over 10 years)) and followed for a sufficiently long enough time to provide a sufficient number of outcomes to determine which features are important in determining the risk of plaque rupturing. In addition to collecting routine data such as age, gender, presence of diabetes mellitus, hypertension, and known CAD, the cohort should be serially assessed with the following modalities:

• Using one or more of the most promising techniques (e.g., IVUS, OCT, thermography) to characterize the lesions. Because characterizing the lesion in this detail would require invasive techniques and is not intended to alter patient-management or to benefit the patient (who is either asymptomatic or may have only stable angina), this approach may be difficult to justify ethically. It may, therefore, be necessary to begin with a safer albeit inferior technology (e.g., CT angiography).
• Serially measure serum biomarkers, including cellular and inflammatory markers such as hs-CRP, IL-6, IL-18, and MMP-9. Even though these markers have not been explicitly studied for plaques that fall within the proposed VP concept, they have been demonstrated to be associated with ACS events in previous studies.

At the time of any clinical outcomes (ACS events) the culprit lesion should be determined. Using this database, clinical, laboratory, and imaging data can be used to predict the likelihood that a specific plaque will lead to clinically significant events, and what characteristics of plaque morphology and/or biochemistry best predict the likelihood of plaque rupture or progression.

Review of Natural History Studies that Focus on Atherosclerotic Lesions that Progress

Since there is no standard definition for VP, there are no natural history studies for this proposed concept. However, several studies have characterized plaques with angiography at baseline. Additional follow-up data were available to provide some insights into what VP studies, once a standard definition is achieved, might reveal. The studies described below investigated the association of lesion morphology with atherosclerotic progression or ACS occurrence.

Chester (1996) assessed the behavior of complex coronary plaques and diameter stenosis changes in 222 patients with chronic stable angina without prior ACS events. These patients were waiting for single vessel PTCA and underwent serial angiograms. They found that complex stenoses (i.e., poorly defined, irregular, or scalloped borders, abrupt edges to lesions, ulceration, presence of filling defect consistent with thrombus) progressed by 3±13 percent compared with 0.5±7 percent among the smooth (absence of complex features) stenoses (p=0.15). Complex stenoses were 4.2 times more likely to progress than smooth stenoses. The data from that study demonstrated that morphologically complex stenosis may develop without an episode of symptomatic ACS and that individual complex lesions are at a higher risk of progression than individual smooth lesions.

Goldstein (2000) analyzed angiograms from 253 patients for complex coronary plaques characterized by thrombus, ulceration, plaque irregularity, and impaired flow. The data showed that patients with multiple complex plaques, in contrast to those with single complex plaques, were at risk of increased incidence of recurrent ACS (19 percent vs 2.6 percent, p<0.001).

Haft et al. (1993) compared the natural history of smooth coronary lesions with complex lesions. They reported that of 255 patients who had 2 to 4 serial arteriograms within 2.6±1.7 years, 203 patients had a significant coronary lesion on at least one arteriogram. Of 167 patients without intervening coronary bypass surgery, there were 48 complex irregular lesions and 141 smooth lesions on followup arteriograms. Irregular lesions progressed more often than did smooth lesions. The authors concluded that the plaque lesions could be grouped into two major categories of progression: (1) gradual growth of a smooth-walled plaque rupture; or (2) plaque rupture with marked progression to severe irregular lesion.

As part of the Coronary Artery Surgery Study (CASS), which randomized 780 patients to an initial strategy of medical therapy versus bypass surgery, Alderman et al. (1999) evaluated follow-up angiograms at 5 years to identify clinical and angiographic features associated with progression of CAD. Of the 3,888 segments assessed, 2,938 non-bypassed coronary segments in 298 patients were evaluated. Percent stenosis was directly proportional to the risk of a lesion progressing to complete occlusion, in contrast to the findings cited above (Little 1998; Ambrose 1988). Complex stenosis morphology defined as multiple closely spaced lesions and diffuse disease was noted to correlate with disease progression. However, the CASS system of grading of morphology, performed in the 1970s, did not include the more detailed features incorporated in more recent conceptualization of VP.

In a study of 31 men who died suddenly of ischemic heart disease, Mann et al. (1999) examined 39 coronary arteries containing 256 plaques. The authors reported that 16 of 99 plaques (16 percent) with less than 20 percent diameter stenosis showed prior healed disruption on histology. For those arteries with 21 percent to 50 percent stenosis, 16 of 86 plaques (19 percent) showed healed disruption. Fifty-two of 71 plaques (73 percent) with >51 percent stenosis had healed disruption. This finding that most of the high-grade stenotic lesions had prior episodes of plaque disruption suggests that disruption is a stimulus to plaque growth and is a major factor in causing chronic high-grade coronary stenosis.

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