Vulnerable Plaque: Pathobiology and Clinical Implications

As early as 1926, Benson [1] postulated that coronary thrombi result from disruption of the intima that exposes lipid to flowing blood. In 1966, Constantinides [2] was the first to establish conclusively that plaque rupture was the immediate cause of coronary thrombosis. He examined 17 consecutive cases of coronary thrombosis seen on autopsy and concluded that fracture of the fibrous lining of the atherosclerotic plaques led to thrombus formation. Subsequently, in a series of studies [3-7], Davies and colleagues established the importance of plaque fissuring and subsequent thrombosis in myocardial infarction, unstable angina, and sudden death due to ischemia. In 1980, angiographic studies by DeWood and coworkers [8] revealed that occlusive thrombus was responsible for most cases of acute myocardial infarction. Thrombus formation was subsequently implicated in the pathogenesis of unstable angina [9]. At that time, the prevailing concept was that myocardial infarction resulted from occlusion at a site of high-grade stenosis. The establishment of coronary thrombosis as the most common cause of myocardial infarction led to the development and use of thrombolytic agents. In 1986, Brown and colleagues [10] used quantitative angiography to show that after thrombolysis, residual stenosis at the site of thrombus formation averaged only 56%. In 1988, Little and colleagues [11] studied 42 consecutive patients who underwent coronary angiography before and up to a month after having an acute myocardial infarction. They concluded that most of the infarctions resulted from a coronary occlusion that had previously shown stenosis of less than 50% on angiography. The severity of coronary stenosis on angiography did not accurately predict the location of a subsequent coronary occlusion. Ambrose and associates [12], in the same year, confirmed that myocardial infarction often developed in territories supplied by coronary arteries with noncritical stenoses. With these studies emerged the concept of the vulnerable atherosclerotic plaque. Such plaque does not cause high-grade stenosis, yet it may result in an acute coronary syndrome, such as unstable angina, myocardial infarction, or sudden death. Identifying and stabilizing the vulnerable plaque will be important challenges in cardiology in the coming years. In this review, we focus on the pathobiology of vulnerable coronary atherosclerotic plaque and the clinical implications of studies of plaque biology. Methods English-language articles were identified through a search of the MEDLINE database from 1966 to the present by using the terms atherosclerotic plaque, myocardial revascularization, and plaque stabilization. Of 3462 articles, 202 reports of experimental, clinical, and basic research studies related to coronary atherosclerotic plaques. Both human and animal studies related to pathobiology and therapy were considered. Selected references cited in identified articles were also reviewed. The incidence of nonfatal myocardial infarction was studied in randomized trials comparing medical treatment with mechanical revascularization (coronary angioplasty or coronary artery bypass grafting). The same end point was also studied in multicenter randomized trials comparing routine angiography and revascularization with a more conservative strategy in the management of acute coronary syndromes. Plaque Vulnerability and Disruption Rupture of a fibrous cap overlaying a vulnerable plaque is the most common cause of coronary thrombosis. In up to 25% of cases, however, thrombosis may result from superficial erosion over a plaque [13]. Plaques prone to rupture are characterized by a large lipid core and a thin fibrous cap, but plaques with erosion vary in size and composition [14]. Inflammatory activity has been associated with plaque erosion and may have a role in the pathogenesis of endothelial damage [15]. However, Farb and colleagues [16] have shown that erosions and subsequent thrombosis can develop in plaques that are relatively rich in proteoglycan matrix and smooth-muscle cells and that lack a superficial lipid core. In the discussion below, we focus predominantly on plaque rupture, which results from intrinsic plaque vulnerability, mechanical stresses, and extrinsic triggers. Bases of Plaque Vulnerability Atherosclerotic plaques prone to rupture have certain characteristic structural, cellular, and molecular features (Figure 1, Table 1). A plaque with a thin fibrous cap overlaying a large lipid core is at high risk for rupture [17, 18]. Gertz and Roberts [19] examined the lipid composition of plaques from 17 infarction-related arteries at autopsy and noted that lipid cores were much larger in the 39 segments with plaque disruption than in the 229 segments with intact surfaces. The nature of the lipid present in a plaque may also be a factor. Lipid in the form of cholesteryl ester softens the plaque, whereas crystalline cholesterol may have the opposite effect [17]. Figure 1. The features of vulnerable plaque and the consequences of plaque rupture. Table 1. Features of Rupture-Prone Plaques An inflammatory-cell infiltrate is a marker of plaque vulnerability. In one study [15], the site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques was characterized by an inflammatory infiltrate regardless of plaque structure. Several factors, including lipoproteins (principally oxidized lipoproteins); infectious agents; or autoantigens, such as heat-shock proteins, may incite a chronic inflammatory reaction in an atherosclerotic plaque [20]. Influx of activated macrophages and T lymphocytes into the plaque follows, with subsequent elaboration of cytokines and matrix-degrading proteins, leading to a weakening of the connective-tissue framework of the plaque. Smooth-muscle cells may counteract some of these effects by producing matrix, collagen, and inhibitors of the matrix-degrading enzymes called metalloproteinases [20]. At the molecular level, matrix metalloproteinases and certain cytokines are important factors in the pathogenesis of plaque vulnerability. Matrix metalloproteinases are a family of proteolytic enzymes that degrade various components of the extracellular matrix. In the atherosclerotic plaque, foam-cell macrophages, activated T cells, and smooth-muscle cells secrete these enzymes after stimulation by various cytokines, such as interferon-, tumor necrosis factor, interleukin-1, and macrophage colony-stimulating factor [20]. Hansson and colleagues [21] demonstrated the presence of chronically activated, interferon--producing T cells in human atheroma. Interferon- inhibits proliferation of smooth-muscle cells and collagen synthesis and thus may contribute to plaque vulnerability. Mechanical Stresses Mechanical stresses may play an important role in plaque rupture [22, 23]. Irregularity of plaque shapes and the presence of a lipid core result in uneven distribution of wall tension along the arterial wall, with critical elevations at certain points [24]. The thinner the fibrous cap, the less able it is to withstand chronic or progressive wall stress. Richardson and colleagues [24] used computer modeling in simulated plaques to show that circumferential stress in a plaque with an eccentric lipid pool is concentrated near the shoulder of the plaque, the most frequent site of rupture noted at autopsy. Cheng and colleagues [25] computed stress distribution in plaques that had ruptured and confirmed that most fibrous caps (58%) ruptured where the estimated circumferential stress was highest. Sudden accentuation of wall stress may directly trigger plaque rupture. In addition, repetitive stretching, bending, and flexion due to cardiac motion may impose chronic stresses on the coronary arteries [26]. These, in turn, may lead to plaque fatigue, weakening of the fibrous cap, and spontaneous rupture [23]. Trigger Events Although plaque rupture may occur spontaneously, it may be triggered by certain events. Half of patients with myocardial infarction report a trigger event, most often emotional stress or physical activity [27]. A sudden surge in sympathetic activity with an increase in blood pressure, heart rate, force of cardiac contraction, and coronary blood flow may lead to plaque disruption [28]. It has been proposed that coronary vasospasm triggers plaque rupture by compressing the atheromatous core and causing eruption of lipid into the lumen [29]. In certain settings, a hypercoagulable-hypofibrinolytic state may directly promote occlusive thrombus formation and a clinical event [30, 31]. Consequences of Plaque Rupture Plaque rupture usually leads to various degrees of thrombus formation. The factors that determine the extent of thrombus formation and clinical outcome are outlined in Figure 1. Thrombosis may result in unstable angina, myocardial infarction, or sudden death, particularly if collateral flow is inadequate. However, if the plaque disruption is minor, local flow is high, and the fibrinolytic system is active, thrombus formation may be minimal. In such a scenario, plaque rupture may remain clinically silent. Indeed, in up to 8% of patients with coronary atherosclerosis who died of noncardiovascular causes, such as accidents, a small, recent plaque disruption was found at autopsy [32]. In patients with diabetes or hypertension, the frequency of disrupted plaques at autopsy was as high as 22% [32]. In some patients who died of ischemic heart disease, more than one plaque disruption was noted, although one of the thrombi in each case was larger and was considered to be the lesion that had caused death [6]. Plaque disruption may be more frequent than initially thought, with a high proportion of these events remaining clinically silent. Asymptomatic thrombus formation on a disrupted plaque may be an important mechanism of plaque growth and may eventually lead to such symptoms as chronic stable angina [33]. Identification of Vulnerable Plaques Coronary angiogra