Inflammation in pathogenesis of acute coronary syndromes

The understanding ofthe pathogenesis ofthe acute thrombotic complications of atherosclerosis has burgeoned in recent years. It is now understood that many acute thrombotic coronary occlusions do not necessarily result from critically stenosed sites in the arteries (17). Rather, lesions that do not cause critical stenosis often underlie thrombi that cause acute coronary syndromes (ACSs). This distinction between lesion vs lumen has challenged the traditional reliance on coronary anatomy as revealed by angiogram as the sole arbiter ofthe risk ofACS (18). Much ofthe thinking about ACS has shifted from a hydraulic viewpoint to a more nuanced biological perspective (19). As in the initiation and progression of atherosclerosis, ample data support the participation of inflammation in these thrombotic complications of atherosclerosis.

Pathological analysis of plaques that cause fatal coronary thrombosis supports this concept. Pathologists have taught researchers that physical disruption ofatherosclerotic plaques most often provokes acute coronary thrombosis (20). Plaques that tend to cause fatal coronary thrombi share certain morphological characteristics. Notably, plaques that rupture and cause thrombosis tend to have large accumulations of inflammatory cells and a relative paucity of SMCs. Moreover, plaques that have ruptured and caused fatal thrombi typically have a thin protective fibrous cap that overlies the thrombogenic lipid core.

The fragility of the fibrous cap depends fundamentally on inflammation (Fig. 2) (19,21). Inflammatory mediators released from lesional lymphocytes, in particular interferon (IFN)-y, can impair the ability of SMCs to synthesize collagen fibrils, the mainstay of the biomechanical integrity of the plaque's fibrous cap. Inflammatory mediators can also heighten the production of enzymes that specialize in breaking down fibrillar collagen in the plaque's fibrous cap. Human atherosclerotic lesions overexpress all three known human interstitial collagenases, members of the matrix metalloproteinase (MMP) family (22). Inflammatory stimuli augment the production ofthe interstitial collagenases MMP-1, MMP-13, and MMP-8 from several cell types found in atherosclerotic plaques. Human atherosclerotic plaques also contain elevated levels of active forms of MMP-9, an enzyme with gelatinolytic activity that can continue the catabolism of collagen cleaved by the interstitial collagenases (23). Inflammatory mediators regulate this enzyme, which can also degrade elastin (24,25). These data indicate a pivotal role for inflammation in regulating the level of collagen in the plaque's fibrous cap, a key determinant of its ability to resist rupture (26). Thus, inflammatory processes critically regulate the fragility ofthe plaque's fibrous cap (Fig. 3).

Inflammation signaling also controls the thrombogenicity of the content of atheromata. The proximal trigger to coronary thrombosis, tissue factor, also depends on inflammatory signaling. The inflammatory mediator CD40L plays a particularly important role in augmenting tissue factor expression by lesional MO, the major source of this potent procoagulant in human atherosclerotic plaques (27).

Inflammatory mediators such as IL-1 can also promote the production of plasminogen activator inhibitor-1 (PAI-1), a potent blocker of endogenous fibrinolytic pathways that protect against thrombus accumulation. Therefore, inflammation not only enhances thrombogenicity of the plaque but also can limit fibrinolysis, two parallel processes that conspire to augment accumulation ofthrombi and, hence, precipitate ACS (28). Thus, from plaque

Fig. 2. Inflammation regulates the metabolism offibrillar collagen, the major barrier to atherosclerotic plaque disruption. Proinflammatory cytokines such as IFN-y released from the T-lymphocyte (lower left) inhibit the ability of SMCs to synthesize new collagen required to repair and maintain the col-lagennous matrix of the plaque's fibrous cap, which protects the plaque from rupture. Another T-cell-derived cytokine, CD40L, stimulates mononuclear phagocytes (center) to elaborate interstitial collagenases, including MMP-1, MMP-8, and MMP-13, that catalyze the initial proteolytic cleavage ofthe intact collagen fibril. The cleaved collagen becomes susceptible to further degradation by gelat-inases such as MMP-9. In this way, inflammation can threaten the stability of atherosclerotic plaques; increase their propensity to rupture; and, hence, cause thromboses that underlie most ACSs. TGFp, transforming growth factor p.

Fig. 2. Inflammation regulates the metabolism offibrillar collagen, the major barrier to atherosclerotic plaque disruption. Proinflammatory cytokines such as IFN-y released from the T-lymphocyte (lower left) inhibit the ability of SMCs to synthesize new collagen required to repair and maintain the col-lagennous matrix of the plaque's fibrous cap, which protects the plaque from rupture. Another T-cell-derived cytokine, CD40L, stimulates mononuclear phagocytes (center) to elaborate interstitial collagenases, including MMP-1, MMP-8, and MMP-13, that catalyze the initial proteolytic cleavage ofthe intact collagen fibril. The cleaved collagen becomes susceptible to further degradation by gelat-inases such as MMP-9. In this way, inflammation can threaten the stability of atherosclerotic plaques; increase their propensity to rupture; and, hence, cause thromboses that underlie most ACSs. TGFp, transforming growth factor p.

Fig. 3. Inflammation affects all phases of atherosclerosis. Recruitment of inflammatory cells from peripheral blood initiates the atherosclerotic changes in the arterial intima that set the stage for athero-genesis (upper left). The generally prolonged and silent or clinically stable stage of lesion evolution involves migration and proliferation ofSMCs. Abundant experimental data support a role for inflammation in this intermediary phase of atherogenesis (middle). Arterial thrombosis, often owing to plaque rupture, also depends on inflammatory signaling (lower right;see also Fig. 2). (Reproduced from ref. 29, with permission.)

Fig. 3. Inflammation affects all phases of atherosclerosis. Recruitment of inflammatory cells from peripheral blood initiates the atherosclerotic changes in the arterial intima that set the stage for athero-genesis (upper left). The generally prolonged and silent or clinically stable stage of lesion evolution involves migration and proliferation ofSMCs. Abundant experimental data support a role for inflammation in this intermediary phase of atherogenesis (middle). Arterial thrombosis, often owing to plaque rupture, also depends on inflammatory signaling (lower right;see also Fig. 2). (Reproduced from ref. 29, with permission.)

initiation through the long, generally silent, or clinically stable phase of lesion progression and, finally, the culmination of the ultimate clinical complications of atherosclerosis, inflammatory signaling participates prominently in this disease (29).

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