In otherwise healthy individuals, cytokines that are generated by injured or atherosclerotic vessels do not produce systemic manifestations typically associated with inflammation (115). However, systemic effects are detectable biochemically. Numerous markers of inflammation, such as CRP, IL-1, IL-6, IL-18, serum amyloid A (SAA), TNF-a, soluble adhesion molecules (sICAM, sVCAM, sE-selectin, and sP-selectin), myeloperoxidase, CD 40 ligand, and macrophage inhibitory cytokine-1 are now being considered as predictors of clinical risk (144,145). Of these, high-sensitivity (hs) CRP is the most stable and powerful inflammatory marker of future cardiovascular risk.
CRP is an acute-phase reactant, initially considered to be a simple marker of vascular inflammation (146). However, increasing evidence indicates that CRP directly participates in the inflammatory response. CRP activates endothelial cells to produce ICAM-1, VCAM-1, and E-selectin (146). CRP also stimulates MCP-1 production, induces monocyte release of IL-6 and TNF-a, and decreases eNOS expression and bioactivity (146-148). Hence CRP can directly activate the entire inflammatory recruitment cascade. For these reasons, the role of CRP as a predictor of cardiovascular events has been extensively investigated.
Prospective studies reported that CRP is an independent predictor of risks of future myocardial infarction, stroke, and peripheral vascular disease (144,149-151). In a recent study, a cohort from the Framingham Heart Study, in which the participants were free of cardiovascular disease, the relationship between CRP and coronary calcification was evaluated (152). The authors found that CRP levels were associated with epicardial coronary calcification, even after adjustment for age and the traditional risk factors. The clinical utility of CRP has also been assessed to predict future risk of sudden cardiac death in apparently healthy men who have no clinical evidence of coronary heart disease (144,149,151). In addition to its predictive value for cardiovascular events, CRP has been associated with the development of type II diabetes, metabolic syndrome, and hypertension (153-155). Taken together, these clinical data further support a role for inflammation in cardiovascular disease and reinforce the hypothesis that inflammatory markers, such as CRP, can improve methods of global cardiovascular risk assessment.
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