Vascular Medicine: Metabolic Syndrome, Inflammation, and Risk of Symptomatic Peripheral Artery Disease in Women: A Prospective Study

Abstract

Conclusion: Metabolic syndrome can predict future symptomatic peripheral arterial disease (PAD) in women, with the risk largely mediated by inflammation and endothelial activation. Summary: Metabolic syndrome is a cluster of cardiovascular risk factors associated with insulin resistance and obesity. Its association with a moderate increase in coronary artery disease, stroke, and cardiovascular mortality is well established. The association between metabolic syndrome and PAD is less clear. One prospective study indicated an increased risk of PAD associated with metabolic syndrome; however, much of the risk related to the effect to diabetes alone (Diabetes Care 2007;30:13009-3104). A second study did not find a significant association between metabolic syndrome and incident PAD (Atherosclerosis 2009;203:604-9). High-sensitivity C-reactive protein (hsCRP) is now established as a predictor of cardiovascular morbidity and mortality and as a marker of inflammation associated with atherosclerosis. In this study the authors sought to assess the relationship between metabolic syndrome and inflammation with future symptomatic PAD in a large group of essentially healthy women. This was a prospective cohort study of 27,111 women free of baseline cardiovascular disease who were participating in the Women's Health Study. During a median cohort follow-up of 13.3 years, participants were monitored for development of incident symptomatic PAD as defined by development of intermittent claudication or need for lower extremity arterial revascularization. Of these, 114 women progressed to this end point. Cox proportional hazard models were used to compare PAD risk in women with and without metabolic syndrome. Also investigated were relationships between metabolic syndrome and inflammation as measured by hsCRP and soluble intercellular adhesion molecule-1 (ICAM-1). In women with metabolic syndrome, there was a 62% increase risk of future PAD (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.10-2.38). With risk adjustments, there was an additional 21% risk increase per additional metabolic syndrome-defining trait (adjusted HR, 1.21; 95% CI, 1.06-1.39). In women with and without metabolic syndrome, median levels were, respectively, 4.0 vs 1.5 mg/L for hsCRP (P < .001) and 1374 vs 333 ng/mL for soluble ICAM-1 (P < .0001). Adding hsCRP and soluble ICAM-1 to the multivariable model resulted in risk associated with metabolic syndrome being substantially attenuated and no longer significant (HR, 1.14; 95% CI, 0.75-1.73). Comment: The study suggests a mechanistic link between metabolic syndrome and inflammation with the development of PAD in women. Conclusions are limited by the facts that most of the women were Caucasian and only symptoms or the need for operation were used to define the presence of PAD. Clearly, many asymptomatic patients with PAD could have been missed. Nevertheless, symptomatic PAD is certainly an important clinical end point, and the study does suggest mechanistic links between risk factor clustering and onset of PAD in woman.