Since inflammation is believed to have a role in the pathogenesis of cardiovascular events, measurement of markers of inflammation has been proposed as a method to improve the prediction of the risk of these events. We conducted a prospective, nested case-control study among 28,263 apparently healthy postmenopausal women over a mean follow-up period of three years to assess the risk of cardiovascular events associated with base-line levels of markers of inflammation. The markers included high-sensitivity C-reactive protein (hs-CRP), serum amyloid A, interleukin-6, and soluble intercellular adhesion molecule type 1 (sICAM-1). We also studied homocysteine and a variety of lipid and lipoprotein measurements. Cardiovascular events were defined as death from coronary heart disease, nonfatal myocardial infarction or stroke, or the need for coronary-revascularization procedures. Of the 12 markers measured, hs-CRP was the strongest univariate predictor of the risk of cardiovascular events; the relative risk of events for women in the highest as compared with the lowest quartile for this marker was 4.4 (95 percent confidence interval, 2.2 to 8.9). Other markers significantly associated with the risk of cardiovascular events were serum amyloid A (relative risk for the highest as compared with the lowest quartile, 3.0), sICAM-1 (2.6), interleukin-6 (2.2), homocysteine (2.0), total cholesterol (2.4), LDL cholesterol (2.4), apolipoprotein B-100 (3.4), HDL cholesterol (0.3), and the ratio of total cholesterol to HDL cholesterol (3.4). Prediction models that incorporated markers of inflammation in addition to lipids were significantly better at predicting risk than models based on lipid levels alone (P<0.001). The levels of hs-CRP and serum amyloid A were significant predictors of risk even in the subgroup of women with LDL cholesterol levels below 130 mg per deciliter (3.4 mmol per liter), the target for primary prevention established by the National Cholesterol Education Program. In multivariate analyses, the only plasma markers that independently predicted risk were hs-CRP (relative risk for the highest as compared with the lowest quartile, 1.5; 95 percent confidence interval, 1.1 to 2.1) and the ratio of total cholesterol to HDL cholesterol (relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.9). The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying persons at risk for cardiovascular events.
