title: Symptomatic peripheral arterial disease in women: nontraditional biomarkers of elevated risk.
abstract: 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.
  
  
  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 > or = 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 A1c, 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.
authors.affiliation: Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital and Harvard Medical School, 900 Commonwealth Ave E, Boston, MA 02215-1204, USA. apradhan@partners.org
authors.forename: Aruna D
authors.initials: AD
authors.lastname: Pradhan
authors.forename: Sanjay
authors.initials: S
authors.lastname: Shrivastava
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Cook
authors.forename: Nader
authors.initials: N
authors.lastname: Rifai
authors.forename: Mark A
authors.initials: MA
authors.lastname: Creager
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
mesh_terms: D015415:Biomarkers / Q000097:blood*; D002097:C-Reactive Protein / Q000032:analysis; D008076:Cholesterol, HDL / Q000097:blood; D003404:Creatinine / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood*; D017270:Lipoprotein(a) / Q000097:blood; D008875:Middle Aged; D015999:Multivariate Analysis; D016491:Peripheral Vascular Diseases / Q000097:blood*; D011446:Prospective Studies; D018570:Risk Assessment / Q000379:methods*
chemical_list: D015415:Biomarkers; D008076:Cholesterol, HDL; D017270:Lipoprotein(a); D018799:Intercellular Adhesion Molecule-1; D005340:Fibrinogen; D002097:C-Reactive Protein; D003404:Creatinine