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(Circulation. 2008;117:823-831.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Symptomatic Peripheral Arterial Disease in Women

Nontraditional Biomarkers of Elevated Risk

Aruna D. Pradhan, MD, MPH; Sanjay Shrivastava, MD, MPH; Nancy R. Cook, ScD; Nader Rifai, PhD; Mark A. Creager, MD; Paul M Ridker, MD, MPH

From the Center for Cardiovascular Disease Prevention (A.D.P., S.S., N.R.C., P.M.R.), Donald W. Reynolds Center for Cardiovascular Research (A.D.P., N.C., P.M.R.), Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disorders (P.M.R.), and Division of Cardiovascular Medicine (M.A.C., P.M.R.), Brigham and Women’s Hospital and Harvard Medical School; Division of Cardiology, VA Boston Medical Center (A.D.P.); Department of Cardiology, Harvard Vanguard Medical Associates (S.S.); and Department of Pathology, Children’s Hospital Medical Center and Harvard Medical School (N.R.), Boston, Mass.

Correspondence to Aruna D. Pradhan, MD, MPH, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215–1204. E-mail apradhan{at}partners.org

Received June 13, 2007; accepted November 27, 2007.

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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
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