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

Abstract

Background We compared (a) cellular reactive oxygen species (ROS) production, inflammation, and apoptosis of cultured endothelial cells treated with sera, and (b) circulating inflammatory, antioxidant capacity, vascular biomarkers, and calf muscle hemoglobin oxygen saturation (StO2) in men and women with 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 One hundred forty-eight symptomatic men and women with PAD were characterized on the endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells. Patients were further evaluated on circulating inflammatory and vascular biomarkers, physical examination and medical history, exercise performance, calf muscle StO2 during exercise, and ambulatory activity monitored during one week. Results Cellular ROS production was higher in African-American women than in men (p = 0.021), but there was no gender difference in Caucasians (p = 537). Men and women were not significantly different on endothelial cell apoptois (p = 833) and NF-κB activity (p = 0.465). For circulating factors, additional gender differences were found when comparisons were made within each race. In African-Americans, women had higher intercellular cell adhesion molecule-1 (p = 0.022) and leptin (p < 0.001), whereas in Caucasians, women had higher matrix metallopeptidase 9 (p = 0.047), higher vascular cell adhesion molecule-1 (p = 0.047), and lower hepatocyte growth factor (p = 0.046). Overall, women had higher apolipoprotein CIII (p = 0.035), lower pain-free distance (p = 0.048) and total distance (p < 0.001) during the 6-minute walk test, shorter time for calf muscle StO2 to reach the minimum value during exercise (p = 0.027), and slower average cadence (p = 0.004) during daily ambulation. Conclusions African-American women with symptomatic PAD have a heightened oxidative status likely resulting in increased endothelial oxidative stress than men. Furthermore, women exhibit a more pronounced pro-inflammatory profile of circulating biomarkers than men, as well as more limited peripheral microcirculation, exercise performance, and ambulatory activity than men. The clinical significance is that women with symptomatic PAD are in greater need of clinical intervention to improve oxidative stress, inflammation, and microcirculation than men, which may, in turn, favorably impact their lower exercise performance and daily activity.

Impact of sleep, fatigue, and systemic inflammation on neurocognitive and behavioral outcomes in long‐term survivors of childhood acute lymphoblastic leukemia

“…Acute and chronic stress can induce microglial cell mediated immune activation and inflammation in the brain, and recent studies have demonstrated sex differences in microglial density, function, and morphology in several brain regions 27 . Sex-specific association of oxidative stress and inflammation is also observed in other vascular-related diseases 10 . Since the levels of biomarkers were similar between males and females in our sample, it is plausible that female survivors of ALL may be more sensitive, with a lower physiologic threshold to the effects of chronic inflammation.…”

“…Given evidence to suggest sex-specific associations of oxidative stress and inflammation with vascular-related diseases in the general population 10 , as well as sex differences in reports of fatigue and sleep in cancer patients 3 , all analyses were stratified by sex. For descriptive purposes, neurocognitive, behavioral, and fatigue outcomes were transformed into age-adjusted Z-scores (mean=0, standard deviation=1.0) using national normative data.…”

Clinical Interest of Ambulatory Assessment of Physical Activity and Walking Capacity in Peripheral Artery Disease

“…The authors computed the ratio of walking events to upright events to provide an Event-Based Claudication Index and reported that this index was greater in PAD patients with intermittent claudication than in controls. Other studies reported associations in PAD patients between walking pattern and clinical, physiological, or biological features (Gardner et al, 2010b(Gardner et al, , 2010c(Gardner et al, , 2011b(Gardner et al, , 2012b(Gardner et al, , 2014cRitti-Dias et al, 2011;Gardner et al, 2015).…”

Predictors of Improved Walking after a Supervised Walking Exercise Program in Men and Women with Peripheral Artery Disease

“…We have previously shown that numerous outcome measures are different between men and women with PAD, as women have greater impairment in baseline ambulation [15], vascular function [16], and inflammation [17]. Furthermore, women, particularly those with diabetes, have less increase in COT and PWT following supervised exercise training [18, 19], even though their increase in 6-minute walk distance (6MWD) following a home-based exercise program was similar [10].…”