Background-Studies in selected samples have linked impaired endothelial function with cardiovascular disease and its risk factors. The clinical correlates and heritability of endothelial function in the community have not been described. Methods and Results-We examined a measure of endothelial function, brachial artery flow-mediated dilation (FMD), expressed as both percent (FMD%) and actual dilation by ultrasound with the occlusion cuff below the elbow in 2883 Framingham Study participants (52.9% women; mean age, 61 years). A subset of 1096 participants performed a 6-minute walk test before FMD determination. Mean FMD% was 3.3Ϯ3.0% in women and 2.4Ϯ2.4% in men. In stepwise multivariable linear regression models, FMD% was inversely related to age, systolic blood pressure, body mass index (BMI), lipid-lowering medication, and smoking, whereas it was positively related to female gender, heart rate, and prior walk test. The estimated heritability of FMD% was 0.14. FMD actual dilation findings were similar, except that female sex and BMI were not significantly associated. Conclusions-Increasing age, systolic blood pressure, BMI, and smoking were associated with lower FMD% in our community-based sample, whereas prior exercise and increasing heart rate were associated with higher FMD%. The estimated heritability of FMD was modest. Future research will permit more complete characterization of the genetic and environmental determinants of endothelial function and its prognostic value in the community. Key Words: endothelium Ⅲ epidemiology Ⅲ risk factors Ⅲ genetics B rachial artery flow-mediated dilation (FMD) serves as a measure of endothelial vasodilator function in humans. 1 Experimental and clinical studies suggest that development of endothelial dysfunction, including reduced NO bioavailability, contributes to the atherosclerosis and pathogenesis of cardiovascular disease (CVD) events. 2 Human studies demonstrate that endothelial dysfunction precedes the development of clinically apparent atherosclerosis in individuals with CVD risk factors such as smoking, 3 hypertension, 4 hyperlipidemia, 5 diabetes mellitus, 5 and obesity. 6 Furthermore, effective treatment of risk factors may reverse endothelial dysfunction. 7 Finally, studies in individuals with risk factors or prevalent CVD have demonstrated that endothelial dysfunction identifies patients at risk for future CVD events. 2,8 Previous investigations relating risk factors to endothelial dysfunction largely were limited to small, highly selected samples. Our objective was to assess the independent correlates of endothelial function in a large community-based sample. MethodsThe Framingham Offspring Study design has been described elsewhere. 9 Participants in the seventh examination (1998 to 2001) were eligible for the present investigation (nϭ3539). Exclusion criteria were residence in a nursing home (nϭ205), mastectomy (nϭ34), Raynaud disease (nϭ9), subject refusal (nϭ83), equipment malfunction/miscellaneous (nϭ15), predigital capture (nϭ177), or technically inade...

Background-In experimental studies, traditional risk factors and proinflammatory processes alter the regulatory functions of the vascular endothelium to promote atherosclerosis. These alterations include expression of leukocyte adhesion molecules and decreased bioavailability of endothelium-derived nitric oxide, an important regulator of vascular homeostasis and tone. The precise relations among risk factors, inflammation, and nitric oxide bioavailability remain uncertain. Methods and Results-To test the hypothesis that inflammation impairs endothelial function in humans, we measured brachial artery flow-mediated dilation, reactive hyperemia, and serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intracellular adhesion molecule-1 (sICAM-1), and monocyte chemotactic protein-1 (MCP-1) in 2701 participants from the Framingham Study (mean age 61 years, 53% women). There were modest unadjusted inverse correlations between flow-mediated dilation and CRP, IL-6, and sICAM-1 (PϽ0.001 for all) that were rendered nonsignificant after accounting for traditional coronary risk factors. For reactive hyperemia, we observed inverse correlations with markers of inflammation in unadjusted models that were attenuated 57% to 74% after accounting for risk factors. However, partial correlations of CRP, IL-6, and sICAM-1 with reactive hyperemia remained significant. Conclusions-Our observations are consistent with the hypothesis that risk factors induce a state of inflammation that impairs vascular function. For flow-mediated dilation, we found no evidence that inflammation has additional effects beyond those attributable to traditional risk factors. The incremental contribution of CRP, IL-6, and sICAM-1 to reactive hyperemia above and beyond known risk factors suggests that systemic inflammation may contribute to impaired vasomotor function in forearm microvessels.

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