Background—Most investigations of novel biomarkers for prediction of cardiovascular disease pertain to coronary artery disease. Few large-scale prospective studies have critically assessed plasma-based factors as predictors of peripheral arterial disease (PAD), and comparative data between individual biomarkers and lipid levels are sparse, especially among women.

Methods and Results—We evaluated the relationship between baseline levels of several novel biomarkers and confirmed incident symptomatic PAD (n=100) in a prospective cohort study (median follow-up, 12.3 years) involving 27 935 US female health professionals 45 years of age without diagnosed vascular disease at baseline. Biomarkers assessed were high-sensitivity C-reactive protein, fibrinogen, soluble intercellular adhesion molecule-1 (sICAM-1), homocysteine, lipoprotein(a), hemoglobin A_1c, creatinine, and conventional lipid levels. In univariate analyses, levels of high-sensitivity C-reactive protein, fibrinogen, sICAM-1, homocysteine, lipoprotein(a), creatinine clearance, high-density lipoprotein cholesterol (HDL-C), non–HDL-C, and the ratio of total cholesterol to HDL-C (TC:HDL-C) were significantly related to PAD (all P<0.05). However, after multivariable adjustment, risk associations were significant only for high-sensitivity C-reactive protein (adjusted hazard ratio [HR] extreme tertiles, 2.1; 95% confidence interval, 1.2 to 3.7), sICAM-1 (adjusted HR, 4.0; 95% confidence interval, 1.9 to 8.6), HDL-C (adjusted HR, 0.4; 95% confidence interval, 0.3 to 0.8), and TC:HDL-C (adjusted HR, 2.2; 95% confidence interval, 1.2 to 3.9). In a model simultaneously controlling for traditional risk factors plus these significant biomarkers, sICAM-1 remained independently predictive of PAD (adjusted HR in each tertile, 1.0 [reference], 2.3, and 3.5).

Conclusions—Among a broad range of biomarkers of cardiovascular risk, only 4 factors, sICAM-1, high-sensitivity C-reactive protein, HDL-C, and TC:HDL-C, were significantly associated with incident symptomatic PAD in women. Findings pertaining to novel biomarkers provide clinical confirmation of a prominent role of endothelial activation and leukocyte recruitment in lower-extremity arterial disease.