Role of inflammation and metalloproteinases in plaque disruption and thrombosis.
Numerous pathological, clinical, angiographic and angioscopic studies have demonstrated that acute coronary syndromes (unstable angina, acute myocardial infarction and ischemic sudden death) are most frequently the consequence of plaque disruption (plaque rupture or superficial plaque erosion) and consequent coronary thrombosis. Several serial angiographic studies have demonstrated that nearly 60-70% of acute coronary syndromes evolve from mildly to moderately obstructive atherosclerotic plaques. Coronary plaque disruption appears to be a function of both the composition of the plaque (plaque vulnerability ) as well as extrinsic triggers that may precipitate plaque disruption in a vulnerable plaque. Vulnerability for plaque disruption appears to be largely determined by the size of the lipid-rich atheromatous core, the thickness of the fibrous cap covering the core, and the presence of ongoing inflammation within and underneath the cap. Inflammatory cells may play a critical role in plaque disruption through the elaboration of matrix degrading metalloproteinases or MMPs (collagenases, gelatinases, stromelysins and matrilysin) and by inhibition of function and survival of matrix-synthesizing smooth muscle cells. Inflammatory cells may also play a critical role in triggering thrombosis following plaque disruption through the tissue factor pathway. In addition, stresses resulting from hemodynamic and mechanical forces may precipitate plaque disruption, particularly at points where the fibrous cap is weakest, such as at its shoulders. The degree of thrombosis following plaque disruption is determined by the thrombogenicity of the disrupted plaque, disturbed local rheology and systemic thrombotic-thrombolytic milieu. Surges in sympathetic activity provoked by sudden vigorous exercise, emotional stress -- including anger, or cold weather, may also trigger plaque disruption. These observations have led to the concept of plaque stabilization as a new clinical strategy for the prevention of acute coronary syndromes. Plaque stabilization can be achieved through pharmacologic and lifestyle-modifying interventions that reduce vulnerability to plaque disruption by altering plaque composition and/or inflammatory activity within the plaque.
Shah
P K
PK
Burn and Allen Research Institute and Department of Medicine, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, CA 90048, USA.
D001167:Arteritis / Q000201:enzymology / Q000503:physiopathology*; D001696:Biomechanical Phenomena; D003324:Coronary Artery Disease / Q000201:enzymology / Q000503:physiopathology*; D003328:Coronary Thrombosis / Q000201:enzymology / Q000503:physiopathology*; D003331:Coronary Vessels / Q000473:pathology / Q000503:physiopathology; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D006439:Hemodynamics; D006801:Humans; D066298:In Vitro Techniques; D008666:Metalloendopeptidases / Q000502:physiology*; D012422:Rupture, Spontaneous / Q000503:physiopathology
D008666:Metalloendopeptidases