Novel risk factors for systemic atherosclerosis - A comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease

Context Several novel risk factors for atherosclerosis have recently been p roposed, but few comparative data exist to guide clinical use of these emer ging biomarkers. Objective To compare the predictive value of 11 lipid and nonlipid biomarke rs as risk factors for development of symptomatic peripheral arterial disea se (PAD). Design, Setting, and Participants Nested case-control study using plasma sa mples collected at baseline from a prospective cohort of 14 916 initially h ealthy US male physicians aged 40 to 84 years, of whom 140 subsequently dev eloped symptomatic PAD (cases); 140 age- and smoking status-matched men who remained free of vascular disease during an average 9-year follow-up perio d were randomly selected as controls. Main Outcome Measure Incident PAD, as determined by baseline total choleste rol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol-HDL-C ratio, triglycerides, homocyst eine, C-reactive protein (CRP), lipoprotein(a), fibrinogen, and apolipoprot eins (apo) A-I and B-100. Results In univariate analyses, plasma levels of total cholesterol (P<.001) , LDL-C (P=.001), triglycerides (P=.001), apo B-100 (P=.001), fibrinogen (P =.02), CRP (P=.006), and the total cholesterol-HDL-C ratio (P<.001) were al l significantly higher at baseline among men who subsequently developed PAD compared with those who did not, while levels of HDL-C (P=.009) and apo A- I (P=.05) were lower. Nonsignificant baseline elevations of lipoprotein(a) (P=.40) and homocysteine (P=.90) were observed. In multivariable analyses, the total cholesterol-HDL-C ratio was the strongest lipid predictor of risk (relative risk [RR] for those in the highest vs lowest quartile, 3.9; 95% confidence interval [CI], 1.7-8.6), while CRP was the strongest nonlipid pr edictor (RR for the highest vs lowest quartile, 2.8; 95% CI, 1.3-5.9). In a ssessing joint effects, addition of CRP to standard lipid screening signifi cantly improved risk prediction models based on lipid screening alone (P<.0 01). Conclusions Of 11 atherothrombotic biomarkers assessed at baseline, the tot al cholesterol-HDL-C ratio and CRP were the strongest independent predictor s of development of peripheral arterial disease. C-reactive protein provide d additive prognostic information over standard lipid measures.