Ana I. Casanegra

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.

Impaired Vascular Endothelial Growth Factor A and Inflammation in Patients With Peripheral Artery Disease

We compared apoptosis, cellular oxidative stress, and inflammation of cultured endothelial cells treated with sera from 130 patients with peripheral artery disease (PAD) and a control group of 36 patients with high burden of comorbid conditions and cardiovascular risk factors. Second, we compared circulating inflammatory, antioxidant capacity, and vascular biomarkers between the groups. The groups were not significantly different (P > .05) on apoptosis, hydrogen peroxide, hydroxyl radical antioxidant capacity, and nuclear factor κ-light-chain enhancer of activated B cells. Circulating tumor necrosis factor α (TNF-α; P = .016) and interleukin 8 (IL-8; P = .006) were higher in the PAD group, whereas vascular endothelial growth factor A (VEGF-A; P = .023) was lower. The PAD does not impair the endothelium beyond that which already occurs from comorbid conditions and cardiovascular risk factors in patients with claudication. However, patients with PAD have lower circulating VEGF-A than the control group and higher circulating inflammatory parameters of TNF-α and IL-8.

Greater Endothelial Apoptosis and Oxidative Stress in Patients with Peripheral Artery Disease

We compared apoptosis, cellular oxidative stress, and inflammation of cultured endothelial cells treated with sera from 156 subjects with peripheral artery disease (PAD) and 16 healthy control subjects. Furthermore, we compared circulating inflammatory, antioxidant capacity, and vascular biomarkers between the two groups. The PAD group had a 164% higher value for endothelial cell apoptosis (P < 0.001) and a 62% higher value for endothelial cellular reactive oxygen species production (P < 0.001) than the control group. Furthermore, the PAD group had lower systemic antioxidant capacity measured by hydroxyl radical antioxidant capacity activity (P < 0.001), higher inflammatory and vascular measures of high-sensitivity C-reactive protein (P < 0.001), interleukin-8 (P < 0.001), serum amyloid A (P < 0.001), vascular cell adhesion molecule-1 (P < 0.001), adiponectin (P < 0.001), apolipoprotein B (P = 0.013), apolipoprotein CIII (P = 0.035), lower vascular endothelial growth factor-A (P < 0.001), and hepatocyte growth factor (P < 0.001) than the control group. Subjects with PAD have greater endothelial apoptosis and oxidative stress than control subjects with low burden of comorbid conditions and cardiovascular risk factors. Furthermore, subjects with PAD have lower systemic antioxidant capacity and angiogenic measures and higher circulating inflammatory parameters.

Monitored Daily Ambulatory Activity, Inflammation, and Oxidative Stress in Patients With Claudication:

We determined the association between daily ambulatory activity and markers of inflammation and oxidative stress in patients with peripheral artery disease (PAD) and claudication. Patients with PAD (n = 134) limited by claudication were studied. Patients took 3275 ± 1743 daily strides for 273 ± 112 minutes each day, and their average daily cadence was 11.7 ± 2.7 strides/min. High-sensitivity C-reactive protein was significantly and negatively associated with the total number of daily strides (P < .001), total daily ambulatory time (P < .01), peak activity index (P < .01), daily average cadence (P < .05), and the maximum cadences for 60 minutes (P < .05), 30 minutes (P < .05), 20 minutes (P < .05), and 5 minutes (P < .01). Oxidized low-density lipoprotein and soluble vascular cell adhesion molecule 1 were not significantly associated with any of the ambulatory measures (P > .05). We conclude that higher levels of community-based, daily ambulatory activity are associated with lower levels of inflammation but are not associated with markers of oxidative stress.

Endothelial Cell Inflammation and Antioxidant Capacity are Associated with Exercise Performance and Microcirculation in Patients with Symptomatic Peripheral Artery Disease

We determined whether exercise performance and lower extremity microcirculation were associated with endothelial cell inflammation, oxidative stress, and apoptosis and with circulating biomarkers of inflammation and antioxidant capacity in 160 patients with symptomatic peripheral artery disease (PAD). In a multivariate regression model for peak walking time, significant independent variables included ankle–brachial index (P < .001), age (P = .017), hydroxyl radical antioxidant capacity (P = .008), and endothelial cell nuclear factor K-light-chain-enhancer of activated B cells (NF-κB) activity (P = .015). In multivariate analyses for time to minimum exercise calf muscle hemoglobin oxygen saturation (StO2), significant independent variables included endothelial cell NF-κB activity (P = .043) and calf muscle StO2 at rest (P = .007). Endothelial cell inflammation and circulating biomarkers of inflammation and antioxidant capacity were associated with exercise performance and microcirculation of the ischemic calf musculature during exercise. The clinical implication is that interventions designed to alleviate endothelial cell inflammation and circulating inflammatory biomarkers, such as antioxidant therapy, may improve exercise performance of symptomatic patients with PAD.

Prevention of Femoropopliteal In-Stent Restenosis With Cilostazol A Meta-Analysis

Severe peripheral artery disease requires revascularization to relieve life-limiting ischemic symptoms. Postrevascularization in-stent restenosis continues to be a problem after femoropopliteal procedures. Our aim was to evaluate the use of cilostazol to prevent in-stent restenosis among patients with lower extremity arterial stenting. We performed a MEDLINE and EMBASE search and reviewed the abstracts and manuscripts following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The primary efficacy outcome was patency rate after stenting. The odds ratio estimates were pooled using the Mantel–Haenszel random-effects method. We identified 524 studies, and 20 articles were fully abstracted and 4 were included in the meta-analysis. The total number of patients included was 2434. Patients in the cilostazol group had better primary patency rates after endovascular stenting than those not taking cilostazol (odds ratio: 0.55; 95% confidence interval: 0.43-0.71). The use of cilostazol appears to prevent in-stent restenosis of high-risk patients.

Apolipoprotein profiles in subjects with and without peripheral artery disease

We compared plasma apolipoprotein profiles in subjects with peripheral artery disease (PAD) treated with statin medications (n = 21), subjects with PAD who are untreated with statins (n = 18), and control subjects (n = 70). Subjects were assessed on plasma apolipoproteins, medical history, physical examination, ankle–brachial index, and exercise performance using a treadmill test. The percentage of subjects with an abnormal value of apolipoprotein B (ApoB) (≥ 95 mg/dL) was 53% in the PAD group untreated with statins, 29% in the treated PAD group, and 13% in the controls (p < 0.001). The PAD group untreated with statins had higher values for ApoB (p < 0.001), triglycerides (p < 0.01), low-density lipoprotein (LDL)-cholesterol / high-density lipoprotein (HDL)-cholesterol ratio (p < 0.05), and glucose (p < 0.01) than the control group. In contrast, when the statin-treated PAD group was compared with controls, none of the variables were different except that the treated PAD group had lower LDL-cholesterol (p < 0.01) and higher glucose (p < 0.01). Furthermore, the PAD group treated with statins had lower ApoB (p < 0.01), triglycerides (p < 0.001), LDL-cholesterol (p < 0.05), LDL-cholesterol / HDL-cholesterol ratio (p < 0.05), and non-HDL-cholesterol (p < 0.05) than the untreated PAD group. In conclusion, subjects with PAD who are untreated with statin medications have higher levels of ApoB than controls, whereas subjects treated with statins have a more favorable risk profile, characterized by lower ApoB, LDL-C, LDL-C / HDL-C ratio, and non-HDL-C concentrations. Statin therapy may be efficacious for improving apolipoprotein profiles in subjects with PAD and intermittent claudication.

INFLUENCE OF DIABETES ON AMBULATION AND INFLAMMATION IN MEN AND WOMEN WITH SYMPTOMATIC PERIPHERAL ARTERY DISEASE.

Highlights • Diabetes and sex were correlated with ambulation and inflammation in patients with claudication.• Men with diabetes have worse ambulation than men without diabetes.• Women with diabetes have greater inflammation than women free of diabetes.• Men and women with diabetes have evidence for high levels of angiogenic inhibition.

Differences in galectin-3, a biomarker of fibrosis, between participants with peripheral artery disease and participants with normal ankle–brachial index

The aim of this study was to determine if galectin-3 levels were different between participants with peripheral artery disease (PAD) and controls, and to describe its relationship with markers of early atherosclerosis. Sixty participants were recruited into two groups: a PAD group (n=31), ankle–brachial index (ABI) ⩽0.90 and a normal ABI group (n=29), ABI 1.0–1.4. PAD participants were older (68.6 vs 61.8 years, p=0.037), more commonly men (68% vs 38%, p=0.02), and with more cardiovascular risk factors (p<0.001). Galectin-3 was 22% higher in PAD participants (mean±SD: 17.6±4.7 vs 14.4±4.1 ng/mL, p<0.01). The odds ratio for galectin-3 in PAD to be 1 ng/mL higher than the participants with normal ABI was 1.19, after adjusting by age and gender (p=0.014). High-sensitivity C-reactive protein (hs-CRP) and homeostatic model assessment (HOMA) were positively associated with galectin-3 in the age- and gender-adjusted model, while arterial elasticity and microalbuminuria were not. In conclusion, galectin-3 levels were higher in participants with PAD.

Sedentary behavior is associated with impaired biomarkers in claudicants.

OBJECTIVE Time spent in sedentary behavior has been associated with worse inflammation and cardiometabolic biomarkers in various populations. However, the association between time spent in sedentary behavior and biomarkers remains unknown in patients with intermittent claudication. The aim of the current study was to analyze the relationship between sedentary behavior and inflammatory and cardiometabolic biomarkers in patients with symptomatic peripheral arterial disease (PAD). METHODS The sample included 297 patients with intermittent claudication. Sedentary behavior was assessed using a step activity monitor. Biomarkers of inflammation, oxidative stress, lipid profile, insulin resistance, and endogenous fibrinolysis were assessed. Demographic data, body mass index, physical activity status, and measures of severity of PAD (ankle-brachial index, peak walking time, and ischemic window) also were obtained. RESULTS Time spent in sedentary behavior was related with high-sensitivity C-reactive protein (b = 0.187; P = .005), glucose (b = 0.238; P < .001), fibrinogen (b = 0.167; P = .017), plasminogen activator inhibitor 1 activity (b = 0.143; P = .036), and high-density lipoprotein cholesterol (b = -0.133; P = .029). After adjustment for sex, age, physical activity status, body mass index, and severity of PAD, sedentary behavior remained related with high-sensitivity C-reactive protein (b = 0.170; P = .015), glucose (b = 0.178; P = .004), fibrinogen (b = 0.189; P = .010), and high-density lipoprotein cholesterol (b = -0.128; P = .032). CONCLUSIONS Time spent in sedentary activities was associated with worse inflammatory and cardiometabolic profile in patients with intermittent claudication.