Pathophysiologic Considerations

Improved understanding of pathophysiologic events leading to coronary thrombosis has been forthcoming over the past two decades. Pathologic, angiographic, and angio-scopic observations have suggested the concept that erosion, fissuring, or rupture of a vulnerable atherosclerotic plaque is the initiating mechanism of coronary occlusion, resulting in coronary spasm, intraplaque hemorrhage, and occlusive luminal thrombosis (19-23). Additional studies have suggested that plaque erosion or rupture most frequently occurs in lipid-laden plaques with the endothelial cap weakened by internal metalloproteinase activity derived primarily from macrophages (24-26).

When the plaque ruptures, elements in the bloodstream are exposed to plaque matrix elements, including collagen and the intensely thrombogenic lipid core with its associated macrophage-derived tissue factor (24) (Fig. 1). The result is stimulation of platelet

"Stable" Plaque

Fig. 1. Schematic diagram showing comparison of the characteristics of "vulnerable" and "stable" plaques. Vulnerable plaques often have a well-preserved lumen because plaques grow outward initially. The vulnerable plaque typically has a substantial lipid core and a thin fibrous cap separating the thrombogenic materials such as macrophage-derived tissue factor from the blood. The nonspecific inflammatory process leads to recruitment and activation of macrophages and smooth muscle cells (SMCs), which release collagenases, degrading the protective cap. At sites of plaque rupture or erosions, increased concentration of inflammatory cells may be found, with active uptake of lipids to create foam cells. By contrast, stable plaque has a relatively thick fibrous cap protecting the often-smaller lipid core from contact with the blood. Adapted with permission from ref. 24.

"Stable" Plaque

Fig. 1. Schematic diagram showing comparison of the characteristics of "vulnerable" and "stable" plaques. Vulnerable plaques often have a well-preserved lumen because plaques grow outward initially. The vulnerable plaque typically has a substantial lipid core and a thin fibrous cap separating the thrombogenic materials such as macrophage-derived tissue factor from the blood. The nonspecific inflammatory process leads to recruitment and activation of macrophages and smooth muscle cells (SMCs), which release collagenases, degrading the protective cap. At sites of plaque rupture or erosions, increased concentration of inflammatory cells may be found, with active uptake of lipids to create foam cells. By contrast, stable plaque has a relatively thick fibrous cap protecting the often-smaller lipid core from contact with the blood. Adapted with permission from ref. 24.

adhesion, activation, and aggregation; secretion of vasoconstrictive and thrombogenic mediators; thrombin generation; and fibrin formation, causing vasospasm and the formation of a platelet- and fibrin-rich thrombus. The result is reduction (non-STE-ACS) or interruption (STE-AMI) of coronary blood flow with rapid onset of myocardial cell dysfunction and death. These and other observations set the stage conceptually and scientifically for the evaluation of reperfusion therapies in clinical AMI.

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