Flow-mediated Dilation Response Research Articles

Increasing plant protein in the diet induces changes in the plasma metabolome that may be beneficial for metabolic health. A randomized crossover study in males

Background & aimDietary shifts replacing animal protein (AP) with plant protein (PP) sources have been associated with lowering cardiometabolic risk (CMR), but underlying mechanisms are poorly characterized. This nutritional intervention aims to characterize the metabolic changes induced by diets containing different proportions of AP and PP sources in males at CMR. DesignThis study is a 4-week, crossover, randomized, controlled-feeding trial in which 19 males with CMR followed two diets providing either 36% for the control diet (CON-D) or 64% for the flexitarian diet (FLEX-D) of total protein intake from PP sources. Plasma nontargeted metabolomes (LC-MS method) were measured in the fasted state and after a high-fat challenge meal at the end of each intervention arm. Lipogenesis and protein synthesis fluxes, flow-mediated dilatation (FMD) and gluco-lipidic responses were assessed after the challenge meal. Data were analyzed with mixed models, and univariate and multivariate models for metabolomics data. ResultsIn both arms CMR improved with time, with decreased body weight (-0.9%), insulin resistant (-34%, HOMA-IR, Homeostatic Model Assessment for Insulin Resistance) and low-density lipoproteins (LDL)-cholesterol (-11%). Diet had no effect on FMD or metabolic fluxes, but a trend was observed for a stronger decrease in HOMA-IR and lower postprandial glucose after FLEX-D vs CON-D. The abundance of 21 and 37 metabolites differed between diets at fasted and fed states, respectively, including food intake biomarkers of AP (methylhistidine, eicosapentaenoic acid, hydroxyprolines) and PP sources (trigonelline, N-acetyl-ornithine). In fasted or fed states, indole acrylic acid and indole propionic acid, both products of tryptophan catabolism, were higher after FLEX-D vs CON-D, while the indispensable amino acids-related metabolites alpha-aminoadipic acid, hydroxymethylbutyric acids and propionylcarnitine were lower. In the postprandial state only, the ω-oxidation products dodecanedioic, tetradecanedioic and hexadecanedioic acids were higher after FLEX-D vs CON-D. ConclusionsDespite little changes in risk factors after 4 wk, this study evidenced subtle metabolic adaptations in amino acids and lipid metabolism and gut microbiota activity occurring after higher PP source intake that may be beneficial to CMR. ClinicalTrials.gov study identifierNCT04236518 Clinical Trial RegistryNCT04236518 on ClinicalTrials.gov

Five weeks of intermittent hand exposures to alternating cold and hot stimuli do not modify finger cold-induced vasodilatation response.

We tested the hypothesis that prolonged intermittent hand exposures to transient contrast thermal stimuli would enhance the finger cold-induced vasodilatation (CIVD) response during localized cooling. Eight healthy men participated in a 5-week regimen, during which they immersed, thrice per week, the non-dominant (EXP) hand in 8° and 43°C water, sequentially and at 3-min intervals, for a total period of 60min. The contralateral (i.e., dominant) hand served as the control (CON) hand. Before and after the regimen, subjects conducted two 30-min hand cold (8°C water) provocation trials, one with the EXP hand and the other with the CON hand. In addition, a flow-mediated dilatation test was performed in the brachial artery of the EXP arm. Regardless of the hand tested, the average finger skin temperature [CON hand: pre-trial=10.5 (1.2)°C, post-trial=10.8 (1.3)°C and EXP hand: pre-trial=10.7 (1.1)°C, post-trial 10.9 (1.1)°C; p=0.79], and the incidence of CIVD events [CON hand: pre-trial=1.1 (1.2) events, post-trial=1.2 (1.1) events and EXP hand: pre-trial=1.1 (0.8) events, post-trial=1.1 (0.8) events; p=0.88] were not affected by the 5-week regimen. The sensation of cold-induced pain was transiently alleviated following the regimen (p=0.02). The flow-mediated dilatation response of the EXP brachial artery remained unaltered [pre-trial=5.4 (3.2)%, post-trial=4.7 (3.6)%; p=0.51]. Therefore, five weeks of intermittent hand exposures to alternating cold and hot stimuli do not improve finger temperature responsiveness to sustained localized cold.

Peripheral venous dilation using flow-mediated dilation response: A randomized crossover study.

Venodilation is crucial in enhancing the success rate of peripheral intravenous cannulation. Flow-mediated dilation (FMD) is a vasodilatory response initiated by temporary ischemia followed by reperfusion. This crossover study aimed to test the hypothesis that FMD induces dilation of the peripheral veins of the forearm. Fifteen healthy volunteers underwent the FMD and control conditions in a randomized order. FMD involved a 5-min occlusion of blood flow in the brachial artery, followed by reperfusion, achieved by inflating and deflating a cuff placed on the upper arm. The control condition involved participants remaining at rest. The primary outcome measure was a change in the cross-sectional area of the cephalic vein post-intervention. The secondary outcomes included changes in venous diameter and perfusion index (PI). FMD significantly increased the cross-sectional area of the cephalic vein compared with the control condition (relative change to baseline: 37.7% (31.4) vs 2.2% (11.7)), with a mean difference of 35.4% (95% confidence interval (CI): 16.4-54.5, p = 0.001). Both longitudinal and transverse diameters were significantly expanded with FMD compared to the control (relative change to baseline: 15.7% (15.4) vs 2.6% (3.6), p = 0.004; 18.9% (15.6) vs -0.0 (10.2), p = 0.003, respectively). Additionally, PI significantly increased with FMD compared with the control (relative change to baseline: 77.8% (56.9) vs 14.6% (36.0)), with a mean difference of 63.2% (95% CI: 31.2-95.2, p = 0.001). FMD application induced dilation of the cephalic vein of the forearm. The findings suggest that FMD is an effective technique for dilating the venous area and potentially improving the success rate of peripheral intravenous cannulation.

Effect of Microencapsulated Cocoa Polyphenols on Macro- and Microvascular Function after Eccentric Exercise

Background: Evidence has demonstrated that non-habitual exercise, such as eccentric exercise, can increase reactive oxygen species and induce endothelial dysfunction, which plays a central role in the development of cardiovascular disease. Polyphenol-rich foods, such as cocoa, have been widely investigated in vascular function due to their antioxidant effect. Aims: The goal of this study was to evaluate the impact of microencapsulated cocoa (MC) polyphenols in the flow-mediated dilation (FMD) response and forearm muscle oxygenation (StO2) parameters after an eccentric exercise. Methods: Thirteen physically active adults were enrolled in a randomized, double-blind, and crossover study. FMD and StO2 were evaluated before and after 24 h, 48 h, and 72 h of eccentric exercise and MC or placebo supplementation. Results: No significant difference in FMD response and StO2 parameters was observed after MC and placebo (p > 0.05). Conclusions: A single dose of MC did not change FMD and muscle StO2 parameters after eccentric exercise in healthy individuals.

Impact of moderate-intensity aerobic exercise in combined hypoxic and hot conditions on endothelial function.

There is no study that has investigated the impact of exercise in a combined hypoxic and hot environment on endothelial function. Therefore, we tested whether aerobic exercise in a combined hypoxic and hot conditions induces further enhancement of endothelial function. Twelve healthy males cycled at a constant workload (50% of their maximal oxygen uptake under normoxic/thermoneutral conditions) for 30 min in four different environments: exercise under normoxic condition (NOR: fraction of inspiratory oxygen or FiO2 = 20.9%, 20°C), exercise under hypoxic condition (HYP: FiO2 = 14.5%, 20°C), exercise under hot condition (HOT: FiO2 = 20.9%, 30°C), and exercise under combined hypoxia and hot conditions (HH: FiO2 = 14.5%, 30°C). Before, during, and after exercise, cardiovascular variables (e.g., heart rate, blood flow, and shear rate), blood variables, and endothelial function evaluated by flow-mediated dilation (FMD) were assessed. Heart rates were significantly higher throughout the HH trial's experimental period than the other trials (p < 0.05). However, in the HH trial, brachial artery blood flow and shear rate did not differ from those in other trials after exercise. Plasma catecholamines (epinephrine, norepinephrine, and dopamine) elevations in response to exercise were significantly higher in the HH trial than in the other three trials (p < 0.05). No considerable differences were observed in FMD responses among trials before and after the exercise. In conclusion, aerobic exercise in a combined hot and hypoxic environment further activated sympathetic nervous activity but did not considerably enhance blood flow, shear rate, or endothelial function.

Pharmacological Targeting of Endothelial KCa Channels In Vivo Augments Vasodilatory Responses in Rat Femoral and Coronary Arteries in Health and Disease

As the primary interface between the blood and organs, the vascular endothelium functions as a key regulator of tissue blood flow by sensing chemical and mechanical stimuli and producing vasoactive signals to dynamically control intraluminal diameter in local arterioles and upstream arteries. Flow-mediated dilation (FMD) is an important physiological mechanism to modify local tissue perfusion in response to dynamic metabolic conditions, and reduced FMD responses are indicative of endothelial dysfunction, the latter being a major risk factor for cardiovascular disease. We have previously reported that pharmacological enhancement of endothelial KCa2.3 and KCa3.1 channel activity by SKA-31 augmented vasodilatory responses in small resistance arteries and intact hearts isolated from healthy and Type 2 Diabetic (T2D) rats (RC Mishra et al, 2014, 2021). In the present study, we have investigated the ability of SKA-31 to enhance endothelium-dependent vasodilation in vivo in femoral and coronary arteries of healthy and T2D male rats. Methods: FMD responses associated with reactive hyperemia were measured in a side branch of the femoral artery by high sensitivity Doppler ultrasound following release of an inflated pressure cuff placed on the distal hind limb of male Sprague Dawley (SD) and T2D Goto-Kakizaki (GK) rats (26-32 weeks of age). Rats were injected i.p. with either 10 mg/kg SKA-31 or drug vehicle ~ 3 hours prior to cuff inflation. M-mode echocardiographic imaging was used to visualize intraluminal diameter changes in the left main coronary artery in the same four treatment groups in response to an increase in inhalational isoflurane from 2% to 5%. Results: Femoral artery blood flow increased ~2-fold during reactive hyperemia in vehicle treated SD rats, as quantified by velocity-time integral, and did not increase further with SKA-31 treatment. In contrast, the FMD response in vehicle treated T2D GK rats was substantially blunted vs. SD rats, and SKA-31 administration restored this response to the level observed in healthy controls, which was still observable 15-24 hours later. In vehicle treated SD rats, exposure to 5% isoflurane increased left main coronary arterial diameter by 50-60%, which reversed to baseline following return to the original 2% isoflurane condition. SKA-31 treatment of SD rats increased basal arterial diameter by ~30%, but did not significantly modify the observed increase in arterial diameter evoked by 5% isoflurane inhalation, compared with vehicle treatment. In vehicle treated T2D GK rats, exposure to 5% isoflurane did not increase coronary artery diameter over a 10 min period, which is suggestive of endothelial dysfunction. However, SKA-31 treatment significantly increased basal coronary arterial diameter by 40-50%, and promoted a rapid and robust increase in diameter following exposure to 5% isoflurane (80-90% increase above that observed in vehicle treated T2D rats), which reversed to baseline upon return to 2% isoflurane inhalation. No enhancement of isoflurane evoked coronary vasodilation was observable in T2D GK rats 15-24 hrs post-SKA-31 treatment. In summary, these data provide the first direct demonstration that low dose administration of a KCa channel activator can enhance vasodilatory responses in vivo. This study was supported by research funding to APB from the Canadian Institutes of Health Research (MOP-142467) and NSERC (RGPIN 2017-04116). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of Acute Isometric Handgrip Exercise on Vascular Function in Children and Emerging Adults with Congenital Heart Disease

Endothelial dysfunction is common in congenital heart disease (CHD). Isometric handgrip (IHG) exercise may improve endothelial function; however, whether this applies to patients with CHD is unknown. We investigated brachial artery flow-mediated dilation (FMD) pre- and post- acute IHG exercise using duplex ultrasound in CHD and healthy controls (CTL; n=19 (7 F) vs. 21 (9 F), age: 13±4 vs. 13±4 y). Whereas IHG improved mean FMD in controls, it had no effect on the mean FMD response in patients with CHD. Subsequently, participants within each group were categorized based on ΔFMD response (post-pre IHG FMD), in which those that experienced a decrease were classified as non-responders (NRESP) and those that experienced an increase were classified as responders (RESP). Among NRESP, ΔFMD was lower in CHD vs. controls ( p=0.0224). Among RESP, ΔFMD was lower in CHD vs. controls ( p=0.0543). Data during pre-occlusion in NRESP from pre- to post-IHG exercise showed improved antegrade shear rate (condition effect, p=0.0078), retrograde shear rate (interaction effect, p=0.0410), and oscillatory shear index (interaction effect, p=0.049) in CHD compared to controls. Potentially, IHG exercise enhanced vascular sensitivity to shear, resulting in an increase in baseline diameter and reduced FMD in CHD NRESP. Thus, reduced FMD after acute IHG exercise is influenced by improvements in resting shear rate parameters in patients with CHD. Saskatchewan Health Research Foundation, Heart and Stroke Foundation of Canada. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Acute and Chronic Endothelial Responses to Home-based High Intensity Interval Training in Healthy Older Adults

Advancing age is associated with endothelial dysfunction, a key early event in atherosclerosis development. Endurance exercise is recommended for cardiovascular disease prevention and some studies report endurance exercise training has beneficial effects on endothelial function in older adults. We have recently developed a supervised home-based exercise intervention using high intensity interval training on an all-extremity non-weight-bearing ergometer (HIIT-ANE). We tested the hypotheses that in healthy older adults: 1) endothelial function is improved in response to chronic HIIT-ANE, 2) the acute endothelial responses to HIIT-ANE are different in the trained and untrained states, and 3) the acute and chronic endothelial responses to HIIT-ANE are related. We assessed flow-mediated dilation (FMD), a measure of endothelial function, using brachial artery ultrasonography in twenty healthy sedentary older adults (age: 66±1, means ± SE; 11 postmenopausal women and 9 men). FMD was assessed: 1) in response to chronic HIIT-ANE (at baseline, after 8 weeks of normal lifestyle (control condition), and after 8 weeks of home-based HIIT-ANE) and 2) in response to a single session of HIIT-ANE (at pre-exercise, end of exercise and 1-hr and 24-hrs post-exercise), in the untrained and trained states. Following 8 weeks of HIIT-ANE, FMD was improved compared with baseline (3.39±0.30 vs. 4.18±0.46 %, P=0.005), but was not significantly changed from pre- to post-HIIT-ANE (3.68±0.44 vs. 4.18±0.46 %, P=0.3) or from baseline to post-control (3.39±0.30 vs. 3.68±0.44 %, P=0.4). In the untrained state, FMD was attenuated in response to a single bout of HIIT-ANE from pre- to 1-hr post-exercise (4.15±0.35 vs. 2.92±0.36 %, P=0.0004) and returned to pre-exercise level in 24-hrs post-exercise (4.15±0.35 vs. 3.98±0.40 %, P=1). In the trained state, the acute FMD response to HIIT-ANE was similar to the untrained state (P=0.6 for training state × time). The chronic change in FMD was inversely related with the acute change in FMD in the trained state (ρ=-0.70; p&lt;0.001), but not in the untrained state (ρ=-0.12; P=0.6). Biological sex did not significantly influence the acute or chronic FMD responses to HIIT-ANE (P≥0.1). In healthy older adults: 1) FMD is improved following 8-weeks of home-based remotely supervised HIIT-ANE compared to baseline, 2) FMD is attenuated and normalized within 24 hours of a single session of HIIT-ANE, and 3) chronic changes in FMD are related to acute changes in FMD. This work was supported by the National Institute of Aging grant AG063143. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Jaboticaba berry (Myrciaria jaboticaba) supplementation protects against micro- and macrovascular dysfunction induced by eccentric exercise: a randomized clinical trial.

Physical activities that are unaccustomed and involve eccentric muscle contractions have been demonstrated to temporarily impair macrovascular and microvascular functions, which may be caused by exercise-induced oxidative stress. Jaboticaba (Myrciaria jaboticaba) is a famous Brazilian berry that has been described to exhibit high antioxidant activity. However, no human study has investigated the protective effects of jaboticaba consumption against the vascular damage induced by eccentric exercise. Therefore, the present study aimed to assess whether supplementation with jaboticaba berry juice could positively affect macro- and microvascular functions within 48 hours after eccentric exercise. This randomized, double-blind, placebo-controlled, parallel trial enrolled 24 healthy participants consuming 250 mL per day of jaboticaba berry juice (containing ∼1,300 mg of total polyphenols) or placebo for 6 days. At the baseline, pre-exercise, and 24 h and 48 h postexercise stages, blood samples were taken for analysis of reduced glutathione (GSH) levels. Also, brachial artery flow-mediated dilation (FMD), blood flow, and tissue oxygen saturation (StO2) responses to 5-minute cuff occlusion were assessed using Doppler ultrasound and near-infrared spectroscopy, respectively. Our findings revealed significant decreases in blood GSH (P < 0.001, ES = 0.76), FMD (P = 0.005, ES = 0.48), reperfusion slope of StO2 (P = 0.018, ES = 0.42) at 24 h and blood flow (P = 0.012, ES = 0.42) at 48 h following eccentric exercise in the control group as compared to the jaboticaba berry juice group. Our results demonstrated that jaboticaba berry juice prevented the exercise-induced increase in reactive oxygen species production and protected macro- and microvascular functions against the damage caused by eccentric exercise, suggesting that jaboticaba berry consumption could protect the vascular function under conditions of imbalance in redox homeostasis.

Influence of cardiorespiratory fitness and body composition on resting and post-exercise indices of vascular health in young adults

Poor cardiorespiratory fitness may mediate vascular impairments at rest and following an acute bout of exercise in young healthy individuals. This study aimed to compare flow mediated dilation (FMD) and vascular augmentation index (AIx75) between young adults with low, moderate, and high levels of cardiorespiratory fitness before and after an acute bout of aerobic exercise. Forty-three participants (22 men; 21 women) between 18 and 29 years of age completed the study. Participants were classified into low, moderate, and high health-related cardiorespiratory fitness groups according to age- and sex-based relative maximal oxygen consumption (V˙O2 max) percentile rankings. FMD was performed using Doppler ultrasound and AIx75 was performed using pulse wave analysis at baseline and 60-min after a 30-min bout of treadmill running at 70% V˙O2 max. A significant interaction (p ​= ​0.047; ηp2 ​= ​0.142) was observed, with the moderate fitness group exhibiting a higher FMD post-exercise compared with baseline ([6.7% ​± ​3.1%] vs. [8.5% ​± ​2.8%], p ​= ​0.028; d ​= ​0.598). We found a significant main effect of group for AIx75 (p ​= ​0.023; ηp2 ​= ​0.168), with the high fitness group exhibiting lower AIx75 compared to low fitness group ([−10% ​± ​10%] vs. [2% ​± ​10%], respectively, p ​= ​0.019; g ​= ​1.07). This was eliminated after covarying for body fat percentage (p ​= ​0.489). Our findings suggest that resting FMD and AIx75 responses are not significantly influenced by cardiorespiratory fitness, but FMD recovery responses to exercise may be enhanced in individuals with moderate cardiorespiratory fitness levels.

Endothelial Dysfunction and Cardiometabolic Risk Factors in Mexican American Adults: The Cameron County Hispanic Cohort

Endothelial dysfunction assessed by impaired brachial flow-mediated dilation (FMD) predicts incident cardiovascular disease (CVD). We have previously shown that clustering of diabetes mellitus, obesity, and metabolic syndrome in young Hispanic patients was associated with subclinical atherosclerosis. This study aimed to assess determinants of impaired FMD response (%FMD), an earlier marker of atherosclerosis, in a population-based sample of asymptomatic Mexican Americans. Cardiometabolic biomarkers and FMD were obtained from 960 Cameron County Hispanic Cohort participants. Gender-specific median values of %FMD were used to categorize participants into those with %FMD below or above the median. The sample was further stratified into those younger and older than 55years. Survey-weighted logistic regression analyses were conducted to evaluate the effects of cardiometabolic biomarkers on the %FMD groups. The low %FMD group was significantly older, had higher visceral adipose tissue, systolic blood pressure, or plasma glucose, and had metabolic syndrome compared with those in the high %FMD group. Multivariable-adjusted age-stratified logistic regression analyses showed that in older participants, male gender (odds ratio [OR]=2.4 [1.4 to 4.2]) and having hypertension (OR=2.3 [1.3 to 4.3]) or prediabetes mellitus (OR=3.4 [1.5 to 7.5]) remained significantly associated with odds of low %FMD. In younger participants, high low-density lipoprotein (OR=2.8 [1.6 to 4.9]) or having the metabolic syndrome (OR=1.9 [1.1 to 3.6]) were significantly associated with odds of low %FMD. In conclusion, we found age-dependent associations between cardiometabolic biomarkers and an FMD response below the gender-specific median in a sample composed of Mexican Americans without previous CVD. Targeting specific risk factors by age may mitigate progression to incident CVD in this high-risk racial disparity group.

Noninvasive Brachial Artery Mechanics and Endothelial Function

I t has been recognized that endothelial dysfunction is an early indication of Arterial disease. Endothelial function can be noninvasively evaluated by Inducing a temporary increase in blood flow and then observing the degree of vasodilation response or flow-mediated dilation. Impaired flow mediated vasodilation is then an indication of impaired endothelium. Vascular ultrasound Imaging has been the typical approach to access vasodilation by flow-mediated dilation most often at the brachial artery. Together with other measures of cardiovascular risk, the flow-mediated dilation response provides a very early noninvasive screen for cardiovascular disease. The skill and equipment required for brachial artery ultrasound imaging have limited the use of flow-mediated dilation as a routine medical test. Moreover, it has been recognized that other vascular parameters such as vessel size and blood pressure may influence the test itself. We have introduced a potential solution to the routine measurement of flow-mediated dilation by Analyzing the response of a simple occlusive arm cuff to obtain the Brachial Artery diameter in a noninvasive way. The analysis for occlusive cuff Plethysmography was provided here in a calibrated manner. This approach is an alternative to ultrasound flow-mediated dilation testing. It requires no special operator skills and may be automated for precision. Two experimental evaluations of the proposed cuff method are provided. First, The cuff- based brachial diameters were compared to Ultrasound obtained diameters. Second, as a sensitivity test, the cuff-based dilation test was used to measure the dilation response of several subjects to blood sugar loading. For further evaluation, the cuff-based measurements were applied to a mechanical model of the brachial artery to reveal a standard error of estimate less than 5%. The results show that the cuff-based diameters compare well to those obtained via ultrasound imaging. Moreover, the cuff-based dilation testing showed the expected reduction in endothelial function response due to a blood sugar load. Additionally, cuff-based flow-mediated dilation testing provides measurements as a function of the subject blood pressure, which Ultrasound generally cannot.

Chronic anemia is associated with systemic endothelial dysfunction.

In acute myocardial infarction and heart failure, anemia is associated with adverse clinical outcomes. Endothelial dysfunction (ED) is characterized by attenuated nitric oxide (NO)-mediated relaxation responses which is poorly studied in chronic anemia (CA). We hypothesized that CA is associated with ED due to increased oxidative stress in the endothelium. CA was induced by repeated blood withdrawal in male C57BL/6J mice. Flow-Mediated Dilation (FMD) responses were assessed in CA mice using ultrasound-guided femoral transient ischemia model. Tissue organ bath was used to assess vascular responsiveness of aortic rings from CA mice, and in aortic rings incubated with red blood cells (RBCs) from anemic patients. In the aortic rings from anemic mice, the role of arginases was assessed using either an arginase inhibitor (Nor-NOHA) or genetic ablation of arginase 1 in the endothelium. Inflammatory changes in plasma of CA mice were examined by ELISA. Expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), myeloperoxidase (MPO), 3-Nitrotyrosine levels, and 4-Hydroxynonenal (4-HNE) were assessed either by Western blotting or immunohistochemistry. The role of reactive oxygen species (ROS) in ED was assessed in the anemic mice either supplemented with N-Acetyl cysteine (NAC) or by in vitro pharmacological inhibition of MPO. The FMD responses were diminished with a correlation to the duration of anemia. Aortic rings from CA mice showed reduced NO-dependent relaxation compared to non-anemic mice. RBCs from anemic patients attenuated NO-dependent relaxation responses in murine aortic rings compared to non-anemic controls. CA results in increased plasma VCAM-1, ICAM-1 levels, and an increased iNOS expression in aortic vascular smooth muscle cells. Arginases inhibition or arginase1 deletion did not improve ED in anemic mice. Increased expression of MPO and 4-HNE observed in endothelial cells of aortic sections from CA mice. NAC supplementation or inhibition of MPO improved relaxation responses in CA mice. Chronic anemia is associated with progressive endothelial dysfunction evidenced by activation of the endothelium mediated by systemic inflammation, increased iNOS activity, and ROS production in the arterial wall. ROS scavenger (NAC) supplementation or MPO inhibition are potential therapeutic options to reverse the devastating endothelial dysfunction in chronic anemia.

Impact of biological sex on the acute flow-mediated dilation response to maximal exercise in healthy older adults

Flow-mediated dilation (FMD) is a noninvasive measure of endothelial function and is a predictor of future cardiovascular disease risk. Previous studies have shown that biological sex modulates the FMD response to acute submaximal exercise in healthy older adults. However, the FMD response to maximal exercise has not been investigated in older adults; thus, whether sex impacts this response remains unknown. Therefore, the purpose of this study was twofold: 1) to investigate the FMD response to maximal exercise in older adults and 2) to test the hypothesis that FMD following maximal exercise will change differently in healthy older men compared with women. We studied twenty sedentary adults (50% women, age: 66±1 vs. 66±1 yrs, men vs. women, mean±SE, P&gt;0.9), free of major clinical disease, who were not on hormone replacement therapy. Women were all postmenopausal. Vascular function was assessed before and after maximal exercise, based on a modified Balke treadmill test. FMD was assessed in response to 5 min forearm occlusion at 250 mmHg using brachial artery ultrasonography. We found pre-occlusion brachial diameter was larger in older men compared with women before (5.04±0.18 vs. 4.27±0.09 mm, P=0.002) and after maximal exercise (4.75±0.16 vs. 3.98±0.12 mm, P=0.001), but there was no sex × time interaction (P=0.1). Peak shear rate was significantly lower in older men compared with women before exercise (1852±81 vs. 2265±129 sec-1, P=0.01) and did not change after maximal exercise in either group (P=0.2). FMD was not significantly different in older men compared with women (P=0.1) before exercise and significantly increased following maximal exercise in both older men (3.84±0.66 vs. 6.55±1.27 %, pre- vs. post-exercise, P=0.009) and women (2.32±0.61 vs. 5.65±1.07 %, P=0.002), but the response was not impacted by sex (P=0.6 for sex × time interaction). When FMD was allometrically scaled to assess the potential effect of pre-occlusion diameter, our findings remained unchanged. Time to peak dilation was delayed in older men and women similarly following maximal exercise (51±2 vs. 75±7 and 56±7 vs. 85±7 sec, pre- vs. post-exercise, P≤0.02; P=0.7 for sex × time interaction). In conclusion, this investigation demonstrated for the first time in older adults that: 1) FMD is enhanced following maximal exercise and 2) biological sex does not influence the FMD response to maximal exercise This work was supported by National Institute of Aging grant AG063143-01. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Particulate Matter 2.5 Level Modulates Brachial Artery Flow-Mediated Dilation Response to Aerobic Exercise in Healthy Young Men

Particulate matter 2.5 (PM2.5) is an environmental pollutant linked with the risk of cardiovascular disease. Aerobic exercise performed in polluted environments may have fewer benefits because of increased PM2.5 inhalation during exercise. However, the vascular responses to aerobic exercise in high PM2.5 (HPM2.5) conditions remain unknown. This study aimed to examine the acute flow-mediated dilation (FMD) response to moderate-intensity treadmill running in HPM2.5 levels compared to low PM2.5 (LPM2.5) levels in healthy young males. Treadmill running in both HPM2.5 and LPM2.5 levels was completed by nine subjects. Brachial artery FMD was measured before and after the exercise to assess vascular endothelial function. Indoor PM2.5 concentration was significantly higher in HPM2.5 than in LPM2.5 conditions (p &lt; 0.001). Scaled FMD significantly increased after the exercise in LPM2.5 conditions but not in HPM2.5 (p = 0.03), and baseline diameter increased only in HPM2.5 conditions after the exercise (p = 0.001). Baseline diameter and peak diameter were smaller, and time to peak dilation was delayed in HPM2.5 compared to LPM2.5 in pre-exercise intervention measurements (p &lt; 0.05). Therefore, acute PM2.5 exposure can counteract the positive effect of aerobic exercise on vascular endothelial function in young males.

Endothelial dysfunction in children with newly diagnosed Graves’ disease

The most frequent cause of hyperthyroidism in children is Graves’ disease (GD). Vascular endothelium is a specific target of thyroid hormone. The purpose of this study is to assess flow-mediated dilatation (FMD)% and serum von Willebrand factor (vWF) levels in children with newly diagnosed GD to reflect the extent of endothelial dysfunction in those children. In this study, 40 children with newly discovered GD and 40 children who were healthy served as the control group. Both patients and controls had anthropometric assessment, as well as measurements of fasting lipids, glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), TSH, and free thyroxine (FT4 and FT3), thyrotropin receptor antibodies TRAbs and vWF. Noninvasive ultrasound was utilized to quantify the carotid arteries’ intima-media thickness and the brachial artery’s FMD. Patients reported significantly reduced FMD response and greater vWF and hs-CRP levels compared to controls (P = 0.001 for each). In multivariate analysis, we reported that vWF was significantly correlated with TSH (OR 2.5, 95% CI 1.32–5.32, P = 0.001), FT3 (OR 3.4, 95% CI 1.45–3.55, P = 0.001), TRAb (OR 2.1, 95% CI 1.16–2.23, P = 0.01), and FMD% (OR 4.2, 95% CI 1.18–8.23, P = 0.001). Conclusions: Children with newly diagnosed GD have endothelial dysfunction, which is shown by impaired FMD and increased vWF. These findings support the idea that GD may need to be treated as soon as possible.What is Known:• Graves' disease is the most common cause of hyperthyroidism in children.• vWF is a reliable marker for detection of vascular endothelial dysfunction.What is New:• Children with newly diagnosed Graves' disease may have endothelial dysfunction as reflected by impairment of FMD and raised vWF level.• Measurement of vWF level in children with newly diagnosed Graves' disease can be used for early detection of endothelial dysfunction.

Tetrodotoxin Decreases the Contractility of Mesenteric Arteries, Revealing the Contribution of Voltage-Gated Na+ Channels in Vascular Tone Regulation.

Tetrodotoxin (TTX) poisoning through the consumption of contaminated fish leads to lethal symptoms, including severe hypotension. This TTX-induced hypotension is likely due to the downfall of peripheral arterial resistance through direct or indirect effects on adrenergic signaling. TTX is a high-affinity blocker of voltage-gated Na+ (NaV) channels. In arteries, NaV channels are expressed in sympathetic nerve endings, both in the intima and media. In this present work, we aimed to decipher the role of NaV channels in vascular tone using TTX. We first characterized the expression of NaV channels in the aorta, a model of conduction arteries, and in mesenteric arteries (MA), a model of resistance arteries, in C57Bl/6J mice, by Western blot, immunochemistry, and absolute RT-qPCR. Our data showed that these channels are expressed in both endothelium and media of aorta and MA, in which scn2a and scn1b were the most abundant transcripts, suggesting that murine vascular NaV channels consist of NaV1.2 channel subtype with NaVβ1 auxiliary subunit. Using myography, we showed that TTX (1 µM) induced complete vasorelaxation in MA in the presence of veratridine and cocktails of antagonists (prazosin and atropine with or without suramin) that suppressed the effects of neurotransmitter release. In addition, TTX (1 µM) strongly potentiated the flow-mediated dilation response of isolated MA. Altogether, our data showed that TTX blocks NaV channels in resistance arteries and consecutively decreases vascular tone. This could explain the drop in total peripheral resistance observed during mammal tetrodotoxications.

The associations of markers of endothelial dysfunction with hip fracture risk.

Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk. Participants for this study were 2792 individuals (mean age 78.6years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group. In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable. Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.

Abstract P121: Varying Determinants of Endothelial Dysfunction by Age Group Among Mexican Americans

Endothelial dysfunction assessed by impaired brachial flow-mediated dilation (FMD) is a predictive factor of incident CVD. Most studies included small proportions of Hispanics or Latinos. We aimed to assess determinants of impaired FMD in a large population-based sample of asymptomatic Mexican-Americans. Methods: Cardiometabolic biomarkers, visceral adipose tissue (VAT), and FMD were obtained from 960 participants (57.9% females, mean age 52.1±0.9 years, age 18-85 years) from the Cameron County Hispanic Cohort. Sex-specific median values of %FMD were used to divide participants into two groups: those with FMD below (low %FMD) and above the median (high %FMD). The sample was further stratified into younger (age&lt;55 years) and older (age ≥ 55 years) age groups. Survey-weighted logistic regression analyses were conducted to evaluate the effects of factors on the %FMD groups. Results: There was a high prevalence of obesity (49.1%), hypertension (47.8%), diabetes (26.1%), hypercholesterolemia (46.7%), and metabolic syndrome (38.2%). The median FMD response was 4.2%±0.3% [3.8% (SE 0.4) in males and 4.5% (SE 0.4) in females]. Low %FMD group was significantly older, had higher VAT, SBP, or plasma glucose levels, and had metabolic syndrome compared to those in the high %FMD group. Multivariable-adjusted age-stratified logistic regression analyses showed that among older participants, male gender [OR =2.4 (1.4-4.2)] and having hypertension [OR=2.3 (1.3-4.3)] or pre-diabetes [OR=3.4 (1.5-7.5)] remained significantly associated with odds of low %FMD. Among younger participants, only high LDL [OR=2.8 (1.6-4.9)] or having metabolic syndrome [OR=1.9 (1.1-3.6)] were significantly associated with odds of low %FMD. Conclusion: We found age-dependent associations between cardiometabolic biomarkers and an FMD response below the gender-specific median in a population composed of Mexican-Americans without prior CVD. Targeting specific risk factors by age may mitigate progression to incident CVD in this high-risk group.

PS-P07-7: IMPACT OF INORGANIC NITRATE ON ENDOTHELIAL FUNCTION IN ADULTS A SYSTEMATIC REVIEW OF RANDOMISED CONTROLLED TRIALS AND META ANALYSIS

Aim: Inorganic nitrate which is found in green leafy vegetables and beetroot reduces blood pressure via the nitrate-nitrite-NO pathway and may have other benefits such as improved endothelial function. It is assumed that endothelial dysfunction is key risk factor for CVDs. Therefore, in this systematic review and meta-analysis, we evaluated the impact of inorganic nitrate supplementation on endothelial function. Design and method: MEDLINE, Web of Science, and Scopus databases were searched by two independent authors up to November 2021. We included randomised controlled trials that test oral administration of dietary/non-dietary inorganic nitrate versus a control, adult male and female subjects with/without health conditions, measuring endothelial function by flow mediated dilatation (FMD) as an outcome. Risk and quality assessments were performed using a Cochrane risk of bias score and standardised mean differences of the outcomes were pooled using a random-effects model. Results: 3,521 studies were identified after a database search, of which 12 studies met the inclusion criteria. The pooled sample size was 362 and the number of participants per trial ranged from 10 to 65. Eight studies were acute, four studies were chronic and most of them included healthy participant arms (n = 12) with (n = 4) focusing on unhealthy populations. The mean difference in %FMD for nitrate versus the control was 1.57% (95% CI: 0.76–2.37), p = 0.01; high heterogeneity (I2 = 98.3%) was observed (Figure 1). Subgroup analyses were performed in terms of, nitrate amount (&lt; more or less than 600 mg), type of intervention (dietary or non-dietary), participants health status (healthy and unhealthy), and study duration (acute or chronic). All sub-analysis still showed significant increases in %FMD. In acute studies, FMD response was higher (2.13% (95% CI: 0.87–3.40), p &lt; 0.01, I2 = 98.5%) than chronic studies (0.90% (95% CI: 0.48–1.31), p &lt; 0.01, I2 = 68.6%). Only one study showed low risk of bias; the other studies were classified as “some concern” due to a lack of information about randomisation and lack of pre-specified analysis plans. Conclusions: The meta-analysis provides evidence that inorganic nitrate improves FMD response and may be a useful strategy for preventing further CVD. Change in 1.5% of FMD as seen in this review could results in a reduction in CVD risk of ∼15%. However, due to the high heterogeneity of the results, further studies are needed to build a robust evidence base to inform dietary recommendations.