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(Circulation. 2009;120:1041-1047.)
© 2009 American Heart Association, Inc.

Epidemiology and Prevention

Metabolic Syndrome, Inflammation, and Risk of Symptomatic Peripheral Artery Disease in Women

A Prospective Study

David Conen, MD, MPH; Kathryn M. Rexrode, MD, MPH; Mark A. Creager, MD; Paul M Ridker, MD, MPH; Aruna D. Pradhan, MD, MPH

From the Center for Cardiovascular Disease Prevention (D.C., A.D.P., P.M.R.), the Donald W. Reynolds Center for Cardiovascular Research (D.C., A.D.P., P.M.R.), and the Division of Cardiovascular Medicine (M.A.C., P.M.R.) and Preventive Medicine (D.C., K.M.R., P.M.R., A.D.P.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; Department of Medicine (D.C.), University Hospital, Basel, Switzerland; and Division of Cardiology (A.D.P.), VA Boston Medical Center, Boston, Mass.

Reprint requests to Aruna Pradhan, MD, MPH, Division of Preventive Medicine, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail apradhan{at}partners.org

Received March 5, 2009; accepted July 1, 2009.

Background— The metabolic syndrome (MetS) is associated with incident myocardial infarction and stroke and is linked with subclinical inflammation; however, prospective data pertaining to MetS and future peripheral artery disease (PAD) are sparse, with few studies examining the role of inflammation. We therefore evaluated the relationship between MetS, inflammation, and incident PAD.

Methods and Results— We conducted a prospective cohort study among 27 111 women free of baseline cardiovascular disease who were participating in the Women’s Health Study. Subjects were followed for incident symptomatic PAD (n=114; median cohort follow-up 13.3 years). We used Cox proportional hazards models to compare PAD risk among women with and without MetS. We also evaluated relationships between MetS and subclinical inflammation as measured by high-sensitivity C-reactive protein and soluble intercellular adhesion molecule-1 and adjusted for these biomarkers in multivariable models. Women with MetS had a 62% increased risk of future PAD (hazard ratio 1.62, 95% confidence interval 1.10 to 2.38). After multivariable adjustment, MetS remained significantly associated with PAD (adjusted hazard ratio 1.48, 95% confidence interval 1.01 to 2.18), with a 21% risk increase per additional MetS-defining trait (adjusted hazard ratio 1.21, 95% confidence interval 1.06 to 1.39). In women with and without MetS, respectively, median levels of high-sensitivity C-reactive protein were 4.0 versus 1.5 mg/L (P<0.0001), and median levels of soluble intercellular adhesion molecule-1 were 374 versus 333 ng/mL (P<0.0001). When high-sensitivity C-reactive protein and soluble intercellular adhesion molecule-1 were added to multivariable models, risk associated with MetS was substantially attenuated and no longer significant (hazard ratio 1.14, 95% confidence interval 0.75 to 1.73).

Conclusions— MetS is associated with an increased risk of future symptomatic PAD in women. This risk appears to be mediated largely by the effects of inflammation and endothelial activation.

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