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Background: Excessive reactive oxygen species from endothelial mitochondria in type 2 diabetes individuals (T2DM) may occur through multiple related mechanisms, including production of mitochondrial reactive oxygen species (mtROS), inner mitochondrial membrane (Δψ m ) hyperpolarization, changes in mitochondrial mass and membrane composition, and fission of the mitochondrial networks. Inner mitochondrial membrane proteins uncoupling protein-2 (UCP2) and prohibitin (PHB) can favorably impact mtROS and mitochondrial membrane potential (Δψ m ). Circulating levels of UCP2 and PHB could potentially serve as biomarker surrogates for vascular health in patients with and without T2DM., Methods: Plasma samples and data from a total of 107 individuals with (N = 52) and without T2DM (N = 55) were included in this study. Brachial artery flow mediated dilation (FMD) was measured by ultrasound. ELISA was performed to measure serum concentrations of PHB1 and UCP2. Mitochondrial membrane potential was measured from isolated leukocytes using JC-1 dye., Results: Serum UCP2 levels were significantly lower in T2DM subjects compared to control subjects (3.01 ± 0.34 vs. 4.11 ± 0.41 ng/mL, P = 0.04). There were no significant differences in levels of serum PHB. UCP2 levels significantly and positively correlated with FMDmm (r = 0.30, P = 0.03) in T2DM subjects only and remained significant after multivariable adjustment. Within T2DM subjects, serum PHB levels were significantly and negatively correlated with UCP2 levels (ρ = - 0.35, P = 0.03)., Conclusion: Circulating UCP2 levels are lower in T2DM patients and correlate with endothelium-dependent vasodilation in conduit vessels. UCP2 could be biomarker surrogate for overall vascular health in patients with T2DM and merits additional investigation.

The relationship between obesity and high blood pressure is not as strong among African Americans (AA) as compared to Caucasians. We designed the current study to determine the effect of adiposity on vascular endothelial function (a harbinger of hypertension) among young healthy AA without additional cardiovascular disease risk factors. A total of 108 AA subjects (46 women) between the ages of 18 and 45 years were recruited. All the subjects were normotensive, nonsmokers, and normoglycemic. Anthropometric and cardiovascular disease risk factor measurements (lipid, insulin resistance, and inflammatory markers) were obtained. Vascular endothelial function was measured by brachial artery flow-mediated dilation (FMD). Adiposity distribution was measured by using magnetic resonance imaging scan. There were no gender differences in age and levels of blood pressure, lipids, insulin resistance, and inflammatory markers. Women had higher total body fat percentage and higher peripheral adiposity compared to men. We observed that total and central adiposity did not correlate significantly with brachial artery FMD in women (r = -0.12 and r = 0.23, respectively; P = NS). However, in men, waist circumference was positively associated with FMD (r = 0.3, P ≤ .05). Hyperemic flow was negatively correlated significantly with total and central adiposity in men (r = -0.34 and r = -0.48, respectively; P < .05), but not in women (r = -0.26 and r = 0.03, respectively; P = NS). Our study suggests that increased adiposity may pose greater risk to AA men compared to AA women by adversely affecting resistance vessel function (as measured by hyperemic flow). Larger studies are necessary to validate these findings., (Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: Age-related endothelial dysfunction and vascular stiffening are associated with increased cardiovascular (CV) risk. Many groups have encouraged goals of ≥10 000 steps/day or ≥30 min/day of moderate intensity physical activity (MPA) to reduce age-related CV risk. The impact of MPA on the vasculature of older adults remains unclear., Methods and Results: We randomized 114 sedentary older adults ages ≥50 to 12 weeks of either no intervention (group 1), a pedometer-only intervention (group 2), or a pedometer with an interactive website employing strategies to increase the adoption of habitual physical activity (PA, group 3). Endothelial function by brachial flow-mediated dilation (FMD%), vascular stiffness by tonometry, step-count by pedometer, and PA intensity/distribution by accelerometer were measured. Step-count increased in groups 2 (5136±1554 to 9596±3907, P<0.001) and 3 (5474±1512 to 8167±3111, P<0.001) but not in group 1 (4931±1667 to 5410±2410). Both groups 2 and 3 increased MPA ≥30 min/day. Only group 3 increased MPA in continuous bouts of ≥10 minutes (P<0.001) and improved FMD% (P=0.001). Neither achievement of ≥10 000 steps/day nor ≥30 min/day of MPA resulted in improved FMD%. However, achieving ≥20 min/day in MPA bouts resulted in improved FMD%. No changes in vascular stiffness were observed., Conclusions: MPA reverses age-related endothelial dysfunction, but may require MPA to be performed in bouts of ≥10 minutes duration for ≥20 min/day to be effective. Commonly encouraged PA goals do not guarantee improved endothelial function and may not be as effective in reducing CV risk., Clinical Trial Registration Url: Clinicaltrials.gov. UNIQUE IDENTIFIER: NCT-01212978.

Inflammation is critical for atherosclerosis development and may be a target for risk-reduction therapy. In experimental studies, activation of the inflammatory regulator, nuclear factor kappa B (NFlB), contributes to endothelial activation and reduced nitric oxide production. We treated patients with coronary artery disease with sulfasalazine, an inhibitor of NFκB, and placebo in a randomized, double-blind, crossover study design. Brachial artery flow-mediated dilation (FMD) and digital vascular function were measured at baseline and after each 6-week treatment period. Of the 53 patients enrolled in the crossover study, 32 (age 60 ± 10, 22% female) completed all the visits, with a high rate of study withdrawal due to gastrointestinal side effects. In a subset of 10 participants, we compared the effects of 4 days of sulfasalazine treatment (n = 5) to no treatment (n = 5) on NFκB-regulated gene expression in peripheral blood mononuclear cells. Tumor necrosis factor α-stimulated expression of CD69 and NFlB subunit p50 was significantly blunted after 4 days of sulfasalazine treatment but not after no treatment. However, FMD and digital vasodilator response did not significantly change from baseline with long-term sulfasalazine treatment. Short-term sulfasalazine inhibited NFlB activity; however, long-term treatment was poorly tolerated and did not improve endothelial function. Our findings suggest that sulfasalazine therapy is not the optimal anti-inflammatory treatment for reversing endothelial dysfunction in cardiovascular disease. Further studies are warranted to investigate the potential for NFlB inhibition to reduce cardiovascular risk.

Objective: To determine if folic acid supplementation improves vascular function (brachial artery flow-mediated dilation [FMD]) in professional dancers with known endothelial dysfunction., Design: Prospective cross-sectional study., Setting: Academic institution in the Midwestern United States., Subjects: Twenty-two professional ballet dancers volunteered for this study., Main Outcome Measures: Subjects completed a 3-day food record to determine caloric and micronutrient intake. Menstrual status was determined by interview and questionnaire. Endothelial function was determined as flow-induced vasodilation measured by high-frequency ultrasound of the brachial artery. A change in brachial diameter of <5% to hyperemic flow stimulus was defined a priori as endothelial dysfunction. Subjects with abnormal FMD took 10 mg of folic acid daily for 4 weeks, and FMD testing was then repeated. Serum whole blood was measured for folic acid levels before and after supplementation., Results: Sixty-four percent of dancers (n = 14) had abnormal brachial artery FMD (<5%) (mean ± standard deviation, 2.9% ± 1.5%). After 4 weeks of folic acid supplementation (10 mg/day), FMD improved in all the subjects (7.1% ± 2.3%; P < .0001)., Conclusions: This study reveals that vascular endothelial function improves in dancers after supplementation with folic acid (10 mg/day) for at least 4 weeks. This finding may have clinically important implications for future cardiovascular disease risk prevention., (Copyright © 2011 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the prevalence of the 3 components of the female athlete triad [disordered eating, menstrual dysfunction, low bone mineral density (BMD)] and their relationships with brachial artery flow-mediated dilation in professional dancers., Design: Prospective study., Setting: Academic institution in the Midwest., Participants: Twenty-two professional ballet dancers volunteered for this study., Interventions: The prevalence of the female athlete triad and its relationship to endothelial dysfunction., Main Outcome Measures: Subjects completed questionnaires to assess disordered eating and menstrual status/history. They also completed a 3-day food record and wore an accelerometer for 3 days to determine energy availability. Serum baseline thyrotropin, prolactin, and hormonal concentrations were obtained. Bone mineral density and body composition were measured with a GE Lunar Prodigy dual-energy X-ray absorptiometry. Endothelial function was determined as flow-mediated vasodilation measured by high-frequency ultrasound in the brachial artery. An increase in brachial diameter <5% to hyperemic flow stimulus was defined a priori as endothelial dysfunction., Results: Seventeen dancers (77%) had evidence of low/negative energy availability. Thirty-two percent had disordered eating (EDE-Q score). Thirty-six percent had menstrual dysfunction and 14% were currently using hormone contraception. Twenty-three percent had evidence of low bone density (Z-score < -1.0). Sixty-four percent had abnormal brachial artery flow-mediated dilation (<5%). Flow-mediated dilation values were significantly correlated with serum estrogen and whole-body and lumbar BMD. All the 3 components of the triad plus endothelial dysfunction were present in 14% of the subjects., Conclusions: Endothelial dysfunction was correlated with reduced BMD, menstrual dysfunction, and low serum estrogen. These findings may have profound implications for cardiovascular and bone health in professional women dancers.

Recommendations for the measurement of brachial flow-mediated dilation (FMD) typically suggest images be obtained at identical times in the cardiac cycle, usually end diastole (QRS complex onset). This recommendation presumes that inter-individual differences in arterial compliance are minimized. However, published evidence is conflicting. Furthermore, ECG gating is not available on many ultrasound systems; it requires an expensive software upgrade or increased image processing time. We tested whether analysis of images acquired with QRS gating or with the more simplified method of image averaging would yield similar results. We analyzed FMD and nitroglycerin-mediated dilation (NMD) in 29 adults with type 2 diabetes mellitus and in 31 older adults and 12 young adults without diabetes, yielding a range of brachial artery distensibility. FMD and NMD were measured using recommended QRS-gated brachial artery diameter measurements and, alternatively, the average brachial diameters over the entire R-R interval. We found strong agreement between both methods for FMD and NMD (intraclass correlation coefficients = 0.88-0.99). Measuring FMD and NMD using average diameter measurements significantly reduced post-image-processing time (658.9 ± 71.6 vs. 1,024.1 ± 167.6 s for QRS-gated analysis, P < 0.001). FMD and NMD measurements based on average diameter measurements can be performed without reducing accuracy. This finding may allow for simplification of FMD measurement and aid in the development of FMD as a potentially useful clinical tool.

The metabolic syndrome (MS), a clustering of metabolic disturbances, is associated with increased cardiovascular risk. Limited information is available about the relations between MS, insulin resistance, and vascular function. We measured brachial artery flow-mediated dilation (n = 2,123) and reactive hyperemia (n = 1,521) in Framingham Offspring participants without diabetes or clinical cardiovascular disease (mean age 59 +/- 9 years, 57% women). MS, determined by National Cholesterol Education Program criteria, was present in 36% of participants. Insulin resistance was determined using Homeostatic Model Assessment. In age- and gender-adjusted models, MS was associated with lower flow-mediated dilation and reactive hyperemia. There was progressively lower vasodilator function with increasing number of MS components (p for trend <0.0001). In multivariable models adjusting for the 5 MS components as continuous variables, MS (presence vs absence) remained associated with lower flow-mediated dilation (2.84 +/- 0.12% vs 3.17 +/- 0.08%, p = 0.0496) and reactive hyperemia (50.8 +/- 1.0 vs 54.4 +/- 0.7 cm/s, p = 0.009). Insulin resistance was inversely associated with flow-mediated dilation and reactive hyperemia in age- and gender-adjusted models, but these relations were not significant in models adjusting for the MS components. In conclusion, our observations are consistent with the hypothesis that MS and insulin resistance impair vascular function predominantly through the influence of the component metabolic abnormalities that comprise MS.

Multiple studies have documented an increased incidence of cardiovascular events in the winter, but the pathophysiologic mechanisms remain incompletely understood. It was hypothesized that brachial flow and flow-mediated dilation (FMD) would vary by season and temperature. Season and temperature were related to ultrasonic brachial artery endothelium-dependent FMD% (n = 2,587), baseline flow velocity, and maximal reactive hyperemia (n = 1,973) in the Framingham Offspring Cohort (mean age 61 +/- 10 years, 53% women). Outdoor temperatures were obtained from National Climate Data Center records for Bedford, Massachusetts (about 14 miles from the testing site), and the examination room temperature was measured. In multivariate models, FMD% was highest in summer and lowest in winter (3.01 +/- 0.09% vs 2.56 +/- 0.10%, respectively, p = 0.02 for differences across all 4 seasons). FMD% was highest in the warmest and lowest in the coldest outdoor-temperature quartiles. In stepwise models adjusting for risk factors and selecting among season, outdoor temperature, and room temperature, FMD% was associated with season (p = 0.02); temperature did not enter the model. In contrast, hyperemic flow velocity was significantly lower for cooler and higher for warmer room temperatures (p = 0.02 overall); season did not enter the model. Season and outdoor and room temperature were each retained in a stepwise model of baseline flow velocity (p <0.0001, p = 0.02, and p <0.0001, respectively). In conclusion, a significant association was observed between season and FMD%. Microvascular vasodilator function, as reflected by hyperemic flow velocity, was more strongly related to temperature than season. Endothelial dysfunction may be 1 of the mechanisms influencing seasonal variation in cardiovascular events.

Introduction: Prior data suggest associations between hearing loss, cardiovascular (CV) risk factors, and CV disease. Whether specific hearing loss patterns, including a strial pattern associated with inner ear vascular disease, are associated with systemic endothelial dysfunction and carotid intima–media thickness (IMT) remains unclear. Methods: We evaluated participants without prevalent CVD in the Framingham Offspring Study who underwent formal audiogram testing and brachial and carotid artery ultrasounds. Audiograms were categorized as normal or as belonging to one of four abnormal patterns: cochlear-conductive, low-sloping, sensorineural, or strial. Endothelial function as measured by brachial artery flow-mediated dilation (FMDmm and FMD%). Internal and common intima–media thicknesses (icIMT and ccIMT, respectively) were compared between audiogram patterns. Results: We studied 1672 participants (mean age 59 years, 57.6% women). The prevalence of each hearing pattern was as follows: 43.7% normal; 20.3% cochlear-conductive; 20.3% sensorineural; 7.7% low-sloping; and 8.0% strial. Strial pattern hearing loss was nearly twice as prevalent (p = 0.001) in those in the highest quartile of ccIMT and nearly 50% higher in those in the highest icIMT quartile (p = 0.04). There were no statistically significant differences between the prevalence of the strial pattern comparing the lowest quartiles of FMDmm and FMD% with the upper three quartiles. Age- and sex-adjusted linear regression models did not show significant associations between the vascular measures and hearing patterns. Conclusion: Abnormal hearing patterns were not significantly associated with impaired brachial FMD and increased carotid IMT after adjusting for age and sex effects, which may reflect age and sex-related distributional differences based on hearing loss pattern. [ABSTRACT FROM AUTHOR]

Objective: To determine if folic acid supplementation improves vascular function (brachial artery flow-mediated dilation [FMD]) in professional dancers with known endothelial dysfunction. Design: Prospective cross-sectional study. Setting: Academic institution in the Midwestern United States. Subjects: Twenty-two professional ballet dancers volunteered for this study. Main Outcome Measures: Subjects completed a 3-day food record to determine caloric and micronutrient intake. Menstrual status was determined by interview and questionnaire. Endothelial function was determined as flow-induced vasodilation measured by high-frequency ultrasound of the brachial artery. A change in brachial diameter of <5% to hyperemic flow stimulus was defined a priori as endothelial dysfunction. Subjects with abnormal FMD took 10 mg of folic acid daily for 4 weeks, and FMD testing was then repeated. Serum whole blood was measured for folic acid levels before and after supplementation. Results: Sixty-four percent of dancers (n = 14) had abnormal brachial artery FMD (<5%) (mean ± standard deviation, 2.9% ± 1.5%). After 4 weeks of folic acid supplementation (10 mg/day), FMD improved in all the subjects (7.1% ± 2.3%; P < .0001). Conclusions: This study reveals that vascular endothelial function improves in dancers after supplementation with folic acid (10 mg/day) for at least 4 weeks. This finding may have clinically important implications for future cardiovascular disease risk prevention. [ABSTRACT FROM AUTHOR]

OBJECTIVE--We evaluated the prevalence of endothelial dysfunction as measured by flow-mediated dilatation (FMD) of the brachial artery and carotid intima-media thickness (c-IMT) in relationship to vascular inflammatory biomarkers in preadolescent children with type 1 diabetes. RESEARCH DESIGN AND METHODS--We studied 21 type 1 diabetic children (aged 8.3 ± 0.3 years with diabetes duration of 4.3 ± 0.4 years) and 15 group-matched healthy siblings (aged 7.6 ± 0.3 years). Fasting plasma glucose (FPG), lipid profile, HbA1c, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, homocysteine, and erythrocyte (red blood cell [RBC]) folate were evaluated in all subjects. Each subject underwent c-IMT and brachial artery FMD percentage (FMD%) measurements using high-resolution vascular ultrasound. RESULTS--Type 1 diabetic children had higher FPG (173.4 ± 7.9 mg/dL vs. 81.40 ± 1.7 mg/ dL; P < 0.0001), HbA1c (8.0 ± 0.2% vs. 5.0 ± 0.1%; P < 0.0001), and hs-CRP (1.8 ± 0.3 vs. 0.70 ± 0.2; P = 0.017) than control children without significant differences in BMI, homocysteine, and fibrinogen levels; RBC folate content; and c-IMT between the groups. Children with type 1 diabetes had lower FMD% than control children (7.1 ± 0.8% vs. 9.8 ± 1.1%; P = 0.04), whereas c-IMT did not differ between groups. CONCLUSIONS--Preadolescent children with type 1 diabetes and mean diabetes duration of 4 years displayed evidence of low-intensity vascular inflammation and attenuated EMD measurements. These data suggest that endothelial dysfunction and systemic inflammation, known harbingers of future cardiovascular risk, are present even in preadolescent children. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies demonstrate an inverse relation between dietary flavonoid intake and cardiovascular risk. Recent studies with flavonoid-containing beverages suggest that the benefits of these nutrients may relate, in part, to improved endothelial function.Objective: We hypothesized that dietary supplementation with epigallocatechin gallate (EGCG), a major catechin in tea, would improve endothelial function in humans.Design: We examined the effects of EGCG on endothelial function in a double blind, placebo-controlled, crossover design study. We measured brachial artery flow-mediated dilation by vascular ultrasound at six time points: prior to treatment with EGCG or placebo, two hours after an initial dose of EGCG (300 mg) or placebo, and after two weeks of treatment with EGCG (150 mg twice daily) or placebo. The order of treatments (EGCG or placebo) was randomized and there was a one-week washout period between treatments.Results: A total of 42 subjects completed the study, and brachial artery flow-mediated dilation improved from 7.1 +/- 4.1 to 8.6 +/- 4.7% two hours after the first dose of 300 mg of EGCG (P = 0.01), but was similar to baseline (7.8 +/- 4.2%, P = 0.12) after two weeks of treatment with the final measurements made approximately 14 hours after the last dose. Placebo treatment had no significant effect, and there were no changes in reactive hyperemia or the response to sublingual nitroglycerin. The changes in vascular function paralleled plasma EGCG concentrations, which increased from 2.6 +/- 10.9 to 92.8 +/- 78.7 ng/ml after acute EGCG (P < 0.001), but were unchanged from baseline after two weeks of treatment (3.4 +/- 13.1 ng/ml).Conclusion: EGCG acutely improves endothelial function in humans with coronary artery disease, and may account for a portion of the beneficial effects of flavonoid-rich food on endothelial function. [ABSTRACT FROM AUTHOR]

The article presents the author's view concerning shear stress and flow-mediated dilation (FMD). It mentions that since the introduction of brachial artery reactivity testing, the measurement of endothelial function with the use of ultrasonography has proven to be an effective research tool for the assessment of cardiovascular risk while measurement of FMD in the brachial artery future risk remains low. It states that the lack of specificity is credited to the technical limitations of the FMD.

Background: We have previously reported that increasing habitual moderate intensity (3-6 METs) physical activity (PA) reverses aging-associated vascular endothelial dysfunction, a surrogate marker of cardiovascular risk, in previously sedentary adults ≤ 50 years old. However, whether this relationship is in part related to a reduction in sedentary time concomitant with increased PA is unknown. Methods: A post hoc analysis on data from 96 sedentary adults ages ≤ 50 years (average age 62±7 years) who participated in a randomized control trial evaluating the impact of a 12 week intervention to increase PA was performed. The intervention aimed to increase moderate intensity PA using pedometer guidance with or without the aid of an interactive website which taught participants how to integrate PA into their daily routine. Amount and intensity of PA were measured pre- and post-intervention by accelerometer. Subjects were divided into tertiles of based on change in percent of sedentary activity (< 1. 5METs) over the study period: (1) 5% or greater reduction in sedentary time, (2) 0-4.99% reduction, and (3) increase in sedentary time. Vascular endothelial function was measured by brachial artery flow mediated dilation (FMD%) prior to and at the end of a 12 week intervention period. Data were analyzed by two-way mixed ANOVA with post hoc testing as appropriate. Results: Sedentary time decreased in the study population (P=0.001), driven by a 101 minute drop in sedentary time in group 1 (N=27, 653±121 to 552±100 min, P < 0.001), a 42 minute drop in group 2 (N=29, 699±92 to 657±70 min P=0.003), and a 44 minute increase in group 3 (N=40, 629±93 to 673±120 min, P =0.02). While FMD% increased in the entire study population (P=0.008), this increase was not influences by differences in the change in sedentary time (P=0.73, group 1: 5.4±2.9 to 7.0±3.6%, group 2: 5.7±2.9 to 6.9±4.3%, group 3: 6.0±2.5 to 6.7±3.6%). No differences in endothelium-independent vasodilation were seen. Using equal tertiles for change in sedentary time or higher thresholds for reductions in sedentary time (7.5% or 10%) for group 1 did not alter these results. Conclusion: Increasing moderate intensity PA improves endothelial function in adults ≤ 50 years but this improvement is not associated with the reduction in the amount of sedentary time. Greater than a 10% reduction in the amount of sedentary time may be necessary to see its favorable impact on the vascular endothelium. [ABSTRACT FROM AUTHOR]