Molecular and cellular mechanisms of the thrombotic complications of atherosclerosis

Abstract

Clinicians have traditionally regarded the complications of atherosclerosis as a consequence of progressive arterial stenosis leading to critical narrowings that impede blood flow. Our contemporary understanding of the thrombotic complications of atherosclerosis has undergone a transformation based on a body of observations by pathologists and clinicians. In the late 1980s, clinicians had to confront the counterintuitive notion that plaques that cause acute myocardial infarction often do not produce high-grade stenoses (Smith, S. C., Jr. 1996. Risk-reduction therapy: the challenge to change. Circulation. 93: 2205-2211.). Observations from serial angiographic studies and on culprit lesions of acute myocardial infarction postthrombolysis highlighted this apparent paradox. These contrarian clinical findings prompted cardiologists to consider more carefully the findings of generations of pathologists that plaques that cause fatal coronary thrombi often result from a physical disruption of the atheromatous plaque that may not indeed cause critical arterial narrowing. This convergence of clinical and pathological observations highlighted the importance of understanding the mechanisms of disruption of plaques that can precipitate thromboses.

Fig. 1.

Fibrous cap rupture and superficial erosion. Rupture of the fibrous cap (A) triggers two-thirds to three-quarters of all fatal coronary thromboses. Superficial erosion (B) occurs in one-fifth to one-quarter of fatal coronary thromboses. Certain populations, such as diabetics and women, seem to have superficial erosion more often as a mechanism of plaque disruption and thrombosis (42).

Fig. 2.

Inflammation regulates metabolism of fibrillar collagen, which may induce atherosclerotic plaque disruption. The T-lymphocyte releases proinflammatory cytokines, including IFN-γ (lower left), that prevent smooth muscle cells from generating the new collagen needed to lay down the collagenous matrix of the plaque's fibrous cap, which protects the plaque from rupture. The T-cell-derived cytokine CD40L stimulates mononuclear phagocytes (center) to elaborate interstitial collagenases, such as MMP-1, MMP-8, and MMP-13, which catalyze the initial proteolytic cleavage of the intact collagen fibril. The cleaved collagen can then experience additional degradation by gelatinases such as MMP-9. In this way, inflammation can threaten the stability of atherosclerotic plaques; increase their propensity to rupture; and, as a result, cause thromboses that trigger most acute coronary syndromes. TGFβ, transforming growth factor β (43).