Exercise, Vascular Function and Cardiovascular Risk in a

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Evidence suggests that Americans are becoming increasingly sedentary at work and at home due to technological advances. Physical inactivity coupled with excess caloric intake, especially of calorie- rich ?fast? foods, are responsible for the epidemic of obesity in this country. Physical inactivity in obese and non-obese individuals increases the risk of cardiovascular disease and all-cause mortality. Premature cardiovascular disease leads to lost productivity in the work place, impaired quality of life, and escalating health care costs. In response to these concerns, the American Heart Association advocates 30 minutes of aerobic exercise most days; however, busy schedules coupled with a lack of convenient access to exercise equipment (or motivation to use it) limit adoption of regular exercise by many. One year ago, the National Heart, Lung, and Blood Institute (NHLBI) initiated the Keep the Beat program which encourages Institute employees to engage in fifteen minutes of exercise during the work day, and provides exercise equipment at specific work sites to accomplish this goal. Yet, fewer than 10% of NHLBI employees regularly participate in Keep the Beat and many who initially enrolled have failed to continue participation. The purpose of our prospective cohort study is to determine whether participation in the Keep the Beat program can improve an important measure of cardiovascular risk?arterial endothelial function?by stimulating bone marrow-derived endothelial progenitor cells to repair endothelium. We propose to characterize important components of vascular health by measuring endothelial nitric oxide bioactivity, as determined by brachial artery reactivity to shear stress and nitric oxide metabolites in blood, and vascular repair potential, as determined by endothelial progenitor cell number and function, at baseline and at 3 months in National Institutes of Health (NIH) employees who agree to participate in Keep the Beat. Secondary analyses will include other biomarkers of risk, such as C-reactive protein, blood pressure, body mass index, lipid profile, fasting glucose/insulin, and homeostasis model assessment index, to be measured in our study and subgroup analyses of participants at particularly high cardiovascular risk (> 20% over 10 years), minorities, and women. Demonstration of improved vascular function, with implications of reduced cardiovascular risk, may serve as an incentive for greater employee participation in established employer-initiated programs, and for adoption of similar programs by other employers. If objective benefit cannot be demonstrated in vascular function and other biomarkers of risk, modification of the program may be required to reduce cardiovascular risk. Objective: Endothelial dysfunction has been implicated in the development of cardiovascular disease. Our group previously reported that in men without known cardiovascular disease, endothelial progenitor cells colony-forming units (EPC-CFUs) are significantly related to both endothelial function and cardiovascular risk as measured by the Framingham Risk Score (FRS). We assessed the hypothesis that hormonal status may impact women?s EPC, vascular and risk relationships. Methods: We recruited 66 female subjects aged 22-63 (mean ? SD = 43 ? 11) with no history of cardiovascular disease. Peripheral blood mononuclear cells were cultured in fibronectin-coated wells: EPC-CFUs= cell clusters with endothelial outgrowth at 5 days. Endothelial function was determined by brachial artery flow-mediated dilation (% of resting diameter). Results: Endothelial function was significantly associated (r = -0.39, p = 0.001) with cardiovascular risk derived from the FRS for women. In contrast to men, we found no significant relationship between EPC-CFUs and either endothelial function or FRS. Furthermore, we detected no relationship in women between EPC-CFUs and total cholesterol, LDL cholesterol, or frequency of hypertension and diabetes; these variables were significantly related in our male cohort. To explore the potential confounding effects of estrogen on EPC-CFUs and endothelial function in women, we partitioned our cohort by hormonal status based on the ratio of estradiol to follicle stimulating hormone (FSH). There was no relationship between EPC-CFUs and estradiol/FSH, but endothelial function was significantly lower in women with the lowest estradiol/FSH compared to women with higher estradiol/FSH (p< 0.05). As expected, older women had lower estradiol/FSH than younger women (p< 0.001); however, within the tertiles of estradiol/FSH there was no relationship between endothelial function and age. Conclusions: Endothelial function is associated with cardiovascular risk in women; however, in contrast to observations made in men, EPC-CFUs are not a determinant of cardiovascular risk or endothelial function. Our data suggest that women?s hormonal status, independent of age, determines endothelial function and in turn, cardiovascular risk.