Abstract-With advancing age, arterial stiffness and wave reflections increase and elevate systolic and pulse pressures. An elevated central pulse pressure is generally ascribed to increased wave reflection and portends an unfavorable prognosis. Using arterial tonometry, we evaluated central (carotid-femoral) and peripheral (carotid-brachial) pulse wave velocity, amplitudes of forward and reflected pressure waves, and augmentation index in 188 men and 333 women in the Framingham Heart Study offspring cohort who were free of clinical cardiovascular disease, hypertension, diabetes, smoking within the past 12 months, dyslipidemia, and obesity. In multivariable linear regression models, advancing age was the predominant correlate of higher carotid-femoral pulse wave velocity; other correlates were higher mean arterial pressure, heart rate, and triglycerides and walk test before tonometry (model R 2 ϭ0.512, PϽ0.001). A similar model was obtained for carotid-brachial pulse wave velocity (model R 2 ϭ0.227, PϽ0.001), although the increase with advancing age was smaller. Owing to different relations of age to central and peripheral stiffness measures, carotid-femoral pulse wave velocity was lower than carotid-brachial pulse wave velocity before age 50 years but exceeded it thereafter, leading to reversal of the normal central-to-peripheral arterial stiffness gradient. In this healthy cohort with a minimal burden of cardiovascular disease risk factors, an age-related increase in aortic stiffness, as compared with peripheral arterial stiffness, was associated with increasing forward wave amplitude and pulse pressure and reversal of the arterial stiffness gradient. This phenomenon may facilitate forward transmission of potentially deleterious pressure pulsations into the periphery.

Background-Digital pulse amplitude augmentation in response to hyperemia is a novel measure of peripheral vasodilator function that depends partially on endothelium-derived nitric oxide. Baseline digital pulse amplitude reflects local peripheral arterial tone. The relation of digital pulse amplitude and digital hyperemic response to cardiovascular risk factors in the community is unknown. Methods and Results-Using a fingertip peripheral arterial tonometry (PAT) device, we measured digital pulse amplitude in Framingham Third Generation Cohort participants (nϭ1957; mean age, 40Ϯ9 years; 49% women) at baseline and in 30-second intervals for 4 minutes during reactive hyperemia induced by 5-minute forearm cuff occlusion. To evaluate the vascular response in relation to baseline, adjusting for systemic effects and skewed data, we expressed the hyperemic response (called the PAT ratio) as the natural logarithm of the ratio of postdeflation to baseline pulse amplitude in the hyperemic finger divided by the same ratio in the contralateral finger that served as control. The relation of the PAT ratio to cardiovascular risk factors was strongest in the 90-to 120-second postdeflation interval (overall model R 2 ϭ0.159). In stepwise multivariable linear regression models, male sex, body mass index, ratio of total to high-density lipoprotein cholesterol, diabetes mellitus, smoking, and lipid-lowering treatment were inversely related to PAT ratio, whereas increasing age was positively related to PAT ratio (all PϽ0.01). Conclusions-Reactive

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...