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• Seropositivity which may or may not be of pathological significance.

are rich in extracellular lipid and that the lipid core of these vulnerable or rupture-prone plaques occupies a large proportion of the overall plaque volume. The degree of cross-sectional stenosis involving the vessel lumen is typically <50% (43). In addition to the predominant lipid core, vulnerable plaques are characterized by a thin fibrous cap and high macrophage density (44). Whereas most individuals with atherosclerotic coronary artery disease exhibit a diversity of plaque types, most have a preponderance of one specific type (vulnerable or nonvulnerable) (Fig. 5). The genetic and acquired determinants of plaque type are subjects of intense investigation.

The lipid core of an advanced atherosclerotic plaque is bordered at its luminal aspect by a fibrous cap, at its edges by the shoulder region, and on its abluminal side by the plaque base. Because the lipid core contains a substantial amount of prothrombotic substrate (to be discussed in a subsequent section), the fibrous cap, separating the core from circulating blood components within the vessel's lumen, determines the overall stability of the plaque. In turn, the extracellular matrix of the fibrous cap, consisting of several proteinaceous macromolecules, including collagen (types I and III) and elastin secreted by transformed smooth muscle cells, determines its integrity.

The point should once again be made that core size and fibrous cap thickness are not related to absolute plaque size nor to the degree of luminal stenosis. The determinants of core size have not been fully elucidated, although death of lipid-filling macrophages by apoptosis (programmed cell death) is a possibility. Fibrous cap thickness appears to be related to macrophage and smooth muscle cell activity, particularly their production of metalloproteinases that degrade connective tissue.

Matrix metalloproteinases, part of a superfamily of enzymes that include collage-nases, gelatinases, and elastases, require activation from proenzyme precursors to attain enzymatic activity. Under normal circumstances, tissue inhibitors hold these enzymes in check; however, exposure of smooth muscle cells to the cytokines IL-1 and tumor necrosis factor-a (TNF-a) causes induction of interstitial collagenase and stromelysin. Macrophages exposed to inflammatory cytokines also stimulate the production of matrix-degrading enzymes (45-47).

Coronary atherectomy specimens from patients with acute coronary syndromes contain a 92-kDa gelatinase that is produced predominantly by macrophages and smooth muscle cells (48). Within atherosclerotic plaques, the highest stress regions have a twofold greater matrix metalloproteinase (MMP-1) expression than the lowest stress regions. Overexpression of MMP-1 in vulnerable plaques is associated with a substantial increase in circumferential stress. Degradation and weakening of the collagenous extracellular matrix at critical points of high shear stress may play an important role in the pathogenesis of plaque rupture.

Fibrous cap thickness can be maintained by smooth muscle cell-mediated collagen synthesis (local repair); however, interferon-y (IFN-y), an inflammatory cytokine found within atherosclerotic plaques, decreases the ability of smooth muscle cells to express the collagen gene. Because only T-lymphocytes can elaborate IFN-y (49,50), it has been suggested that chronic immune stimulation within atherosclerotic plaques leads to the production of IFN-a from T cells that subsequently inhibits collagen synthesis in vulnerable regions of the fibrous cap. IFN-y can also contribute to apoptosis and, therefore, may be a key biochemical determinant of plaque vulnerability (Fig. 6).

Human mast cells contain proteoglycans and proteolytic enzymes, including chymase and tryptase. In normal coronary arteries, mast cells amount to 0.1% of all nucleated

Fibrous Cap Rich Lipid Core

Vulnerable plaque Non-vulnerable plaque

Fig. 5. Vulnerable plaques are typified by (i) a prominent lipid core; (ii) a thin fibrous cap; and, (iii) high inflammatory cell density located at the plaque shoulders. By contrast, nonvulnerable plaques contain few extracellular lipid particles and are fibrotic, making disruption a less common event.

Vulnerable plaque Non-vulnerable plaque

Fig. 5. Vulnerable plaques are typified by (i) a prominent lipid core; (ii) a thin fibrous cap; and, (iii) high inflammatory cell density located at the plaque shoulders. By contrast, nonvulnerable plaques contain few extracellular lipid particles and are fibrotic, making disruption a less common event.

Fig. 6. Plaque vulnerability is determined by both structure and intrinsic activity. Macrophages and smooth muscle cells synthesize and secrete matrix metalloproteinases that can degrade the fibrous cap. IFN-y, an inflammatory cytokine secreted by T lymphocytes, participates in programmed cell death (apoptosis) and inhibits collagen synthesis, thereby weakening the plaque's supporting framework.

Fig. 6. Plaque vulnerability is determined by both structure and intrinsic activity. Macrophages and smooth muscle cells synthesize and secrete matrix metalloproteinases that can degrade the fibrous cap. IFN-y, an inflammatory cytokine secreted by T lymphocytes, participates in programmed cell death (apoptosis) and inhibits collagen synthesis, thereby weakening the plaque's supporting framework.

cells; however, within the fibrous cap, lipid core, and shoulder regions of atheromatous lesions, there are 5-, 5-, and 10-fold increased densities, respectively (51). Electron and light microscopic studies of mast cells in the plaque shoulder region have revealed evidence of degradation, a sign of activation that may contribute to matrix degradation and plaque rupture in acute coronary syndromes (52).

Models of Plaque Rupture

Shear stress

The coronary arterial intimal surface is constantly exposed to the dynamic influences of circulating blood that creates shear stress. Assuming a constant viscosity, shear stress is described by the following formula: T = Udv/dr,where U is viscosity, V is velocity, and r is the radius of the vessel. Within arterial segments containing laminar flow, shear stress (s) = 4 ^Q/pr3. Therefore, shear stress is directly proportional to flow (Q) and inversely proportional to the cube of the vessel's radius. In coronary atherosclerosis, the lumen is reduced in size and there is increased flow velocity, ultimately leading to increased shear stress.

There is evidence (53) that atherosclerosis typically develops in low-flow/low-shear stress segments of the coronary arterial tree. Low-shear stress may also contribute, at least initially, to impaired vasoreactivity and thromboresistance by reducing the local stimulus to both prostaglandin and nitric oxide synthesis and release. It appears that unsteady (turbulent) flow is particularly detrimental to endothelial cell function (54).

In contrast to plaque development, plaque disruption occurs most often in regions of high shear stress.

Wall Stress

Plaque rupture occurs when the forces acting directly on the plaque exceed its tensile strength. Pressure generated within the arterial lumen exerts both radial and circumferential force, which must be countered by radial and circumferential wall tension. According to the law of Laplace, T (circumferential wall tension) = pr/h, where p is the intraluminal pressure, r is the vessel radius, and h is the wall thickness. Thus, atherosclerotic vessels with a thickened intima and small internal diameter maintain relatively low wall tension. This may explain why plaque rupture is more likely to occur in vessels with less severe stenosis.

Stress Distribution

Computer models have been developed to study the relative stress distribution within atherosclerotic coronary arteries (55). Overall, the circumferential stress is greatest at the intimal layer. In plaques that contain a large lipid pool, most of the stress is localized to the overlying fibrous cap. As the stiffness of the cap increases, the maximal circumferential stress shifts from the center of the cap to the lateral edges or "shoulder" region.

The thickness of the fibrous cap is a major determinant of circumferential stress and the plaque's predisposition to rupture. In the presence of a constant luminal dimension, there is increasing stress with enlargement of the lipid core. With increasing fibrous cap thickness, even in the presence of decreasing luminal area, circumferential stress decreases. Another important feature is the lipid core itself, which, because of its semifluid nature, bears very little circumferential stress. Instead, stress is displaced to the fibrous cap.

Frequency of Stress

Much like fatigue fractures occurring in metal, the frequency, extent, and localization of stress play important roles in plaque rupture. Atherosclerotic plaques, particularly fibrous caps overlying large lipid cores, become progressively more stiff with increasing stress and frequency of stress. Elevations in heart rate have been slow to increase stiffness and circumferential stress at the plaque's shoulder regions (56).

Triggers for Plaque Rupture

Triggering events for plaque rupture are among the most contemplated and investigated areas in cardiovascular medicine. It has become clear, however, that triggers have less impact when they occur in the absence of a vulnerable plaque. This important feature allows for the development of several lines of prevention. Potential triggers include plasma catecholamine surges and increased sympathetic activity, blood pressure surges, exercise, emotional stress, changes in heart rate and myocardial contraction (angulation of coronary arteries), coronary vasospasm, and hemodynamic forces (57-63). This subject is discussed in chapter 3.

Prevention of Plaque Rupture

Plaque rupture is the end result of a dynamic interplay between factors intrinsic to the plaque itself and extrinsic factors. The intrinsic factors primarily relate to rupture vulnerability; the extrinsic forces deliver the final blow. Each can be addressed when contemplating options for prevention.

Lipid-lowering strategies, antioxidants, anti-inflammatory agents, inhibitors of macrophages and their secreted proteins, and gene therapy can be used individually or concomitantly to change the plaque's composition, making it less prone to rupture. b-Adrenergic blockers (64) and angiotensin-converting enzyme inhibitors (65) can reduce extrinsic forces capable of causing damage. The future in both basic and clinical research undoubtedly will devote considerable time, effort, and resources to these areas.

Cellular Plaque Components: Intrinsic Thrombogenicity

Pathologic studies performed on patients who died suddenly or who recently experienced an episode of unstable angina or myocardial infarction (MI) often reveal intralu-minal thrombus anchored to a ruptured atherosclerotic plaque. Primarily based on the results of in vitro experiments and studies conducted in static systems, the thrombogenic capacity of atherosclerotic plaques has been attributed to collagen, fatty acids, and phospholipids. Fuster and colleagues (66) have investigated dynamic thrombus formation using an ex vivo perfusion chamber and reported that the greatest stimulus was, in fact, the atheromatous core, yielding a sixfold greater degree of platelet deposition and thrombus production than other substrates, including foam cell-rich matrix, collagen-rich matrix, collagen-poor matrix without cholesterol crystals, and segments of normal intima. There is mounting evidence that tissue factor is the predominant thrombogenic mediator found within the atheromatous core. This substrate will be discussed in a section to follow.

Cholesterol sulfate, present within human atherosclerotic plaques and plasma, is a substrate for platelet adhesion through a specific, but not yet defined, receptor. It, in all likelihood, plays a role in both atherosclerosis and prothrombotic potential of disrupted plaques (67).

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