Gender and racial differences in endothelial oxidative stress and inflammation in patients with symptomatic peripheral artery disease

Background: We compared (1) cellular reactive oxygen species (ROS) production, inflammation, and apoptosis of cultured endothelial cells treated with sera and (2) circulating inflammatory measures, antioxidant capacity, vascular biomarkers, and calf muscle hemoglobin oxygen saturation (StO₂) in men and women with peripheral artery disease (PAD). A secondary aim was to compare exercise performance and daily ambulatory activity between men and women. We hypothesized that women would have more impaired endothelial cellular ROS, inflammation, and apoptosis than men as well as worse systemic inflammation, antioxidant capacity, vascular biomarkers, calf muscle StO₂, exercise performance, and daily ambulatory activity. Methods: The 148 symptomatic men and women with PAD were characterized on the endothelial effects of circulating factors present in the sera by a cell culture-based bioassay on primary human arterial endothelial cells. Patients were further evaluated by circulating inflammatory and vascular biomarkers, physical examination and medical history, exercise performance, and calf muscle StO₂ during exercise, and ambulatory activity was monitored during 1 week. Results: Cellular ROS production was higher in African American women than in men (P =.021), but there was no gender difference in white individuals (P =.537). Men and women were not significantly different on endothelial cell apoptosis (P =.833) and nuclear factor κB activity (P =.465). For circulating factors, additional gender differences were found when comparisons were made within each race. In African Americans, women had higher intercellular adhesion molecule 1 (P =.022) and leptin (P <.001); whereas in white individuals, women had higher matrix metallopeptidase 9 (P =.047), higher vascular cell adhesion molecule 1 (P =.047), and lower hepatocyte growth factor (P =.046). Overall, women had higher apolipoprotein CIII (P =.035), lower pain-free distance (P =.048) and total distance (P <.001) during the 6-minute walk test, shorter time for calf muscle StO₂ to reach the minimum value during exercise (P =.027), and slower average cadence (P =.004) during daily ambulation. Conclusions: African American women with symptomatic PAD have a heightened oxidative status, likely resulting in increased endothelial oxidative stress, compared with men. Furthermore, women exhibit a more pronounced proinflammatory profile of circulating biomarkers as well as more limited peripheral microcirculation, exercise performance, and ambulatory activity than men do. The clinical significance is that women with symptomatic PAD are in greater need than men of clinical intervention to improve oxidative stress, inflammation, and microcirculation, which may in turn have a favorable impact on their lower exercise performance and daily activity.