Brachial Artery Flow-mediated Dilation Research Articles

The acute effect of a laboratory shame induction protocol on endothelial function in young, healthy adults.

What is the central question of this study? Shame is a form of social stress that involves internalizing social devaluations imposed by others. The aim of this study was to determine, for the first time, how acutely experienced shame impacts endothelial function. What is the main finding and its importance? Brachial artery flow-mediated dilatation, an index of endothelial function, was impaired after an intervention that acutely increased self-reported shame. This occurred without increases in cortisol or tumor necrosis factor alpha receptor binding. Frequent or prolonged shame-induced endothelial dysfunction could have important cardiovascular consequences. The objective of this study was to examine the impact of a shame induction protocol on endothelial function. Fifteen participants (n=7 men, n=8 women) completed both a written shame induction protocol and a control protocol on two different experimental days. Pre- and post-protocol we assessed: (1) endothelial function and arterial shear rate via a standard brachial artery reactive hyperaemia flow-mediated dilatation (FMD) test across two post-intervention time points (15 and 35min post); (2) perceived shame via the experiential shame scale (ESS); and (3) cortisol and soluble tumor necrosis factor alpha receptor (sTNFαRII) through oral fluid analysis. Shame increased after the shame induction protocol (pre, 2.9±0.6 vs. post, 3.7±0.5, P<0.001) but not the control protocol (pre, 3.0±0.5 vs. post, 2.8±0.5, P=0.15; protocol by time interaction, P<0.001). When all three time points were included in the analysis, %FMD did not change over time. Considering only the lowest post time point, %FMD decreased significantly in response to the shame protocol (pre, 4.8±1.9 vs. post, 3.2±1.6, P<0.001) but not the control protocol (pre, 4.2±1.8 vs. post, 3.8±1.5, P=0.45; protocol by time interaction, P=0.035). Covariation of the shear rate stimulus for FMD did not alter the FMD results. When including both the control and shame protocols, but not the shame protocol alone, increased shame was significantly associated with decreased FMD (r=-0.37, P<0.046). There were no significant time by protocol interaction effects for cortisol or sTNFαRII. In conclusion, temporary increases in shame might cause transient endothelial dysfunction which, if chronically repeated, could manifest as reduced vasoprotection against atherosclerosis.

Cholecalciferol supplementation and angiogenic markers in chronic kidney disease.

Vitamin D plays an important role in proliferation and differentiation of cells and deficiency of vitamin D disturbs angiogenic balance. Previous studies in animal models have reported an association between serum levels of vitamin D and balance between pro- and anti-angiogenic factors. There is insufficient evidence about the effect of vitamin D on mediators of angiogenesis in patients with CKD. We investigated the effect of cholecalciferol supplementation on serum levels of angiogenic markers in non-diabetic patients with CKD stage 3–4. In this secondary analysis on stored samples of our previously published randomized, double-blind, placebo-controlled trial, stable patients of either sex, aged 18–70 years, with non-diabetic CKD stage 3–4 and vitamin D deficiency (serum 25-hydroxyvitamin D ≤20 ng/ml) were randomized to receive either two directly observed oral doses of cholecalciferol (300,000 IU) or matching placebo at baseline and 8 weeks. The primary outcome was change in brachial artery flow-mediated dilatation at 16 weeks. Changes in levels of serum angiogenesis markers (angiopoietin-1, angiopoietin-2, VEGF-A, VEGEF-R, and Tie-2) between groups over 16 weeks were compared. A total 120 patients were enrolled. Supplementation with cholecalciferol led to significant improvement in FMD. Serum 25(OH)D levels were similar in both groups at baseline (13.21±4.78 ng/ml and 13.40±4.42 ng/ml; p = 0.888). At 16 weeks, the serum 25(OH)D levels increased in the cholecalciferol group but not in the placebo group (between-group difference in mean change:23.40 ng/ml; 95% CI, 19.76 to 27.06; p<0.001). Serum levels of angiogenic markers were similar at baseline. At 16 weeks, angiopoietin-2 level decreased in cholecalciferol group (mean difference:-0.73 ng/ml, 95%CI, -1.25 to -0.20, p = 0.002) but not in placebo group (mean difference -0.46 ng/ml, 95%CI, -1.09 to 0.17, p = 0.154), however there was no between-group difference at 16 weeks (between-group difference in mean change: -0.27 ng/ml, 95%CI, -1.09 to 0.55, p = 0.624). Serum angiopoietin-1 level increased [mean change: 5.63 (0.51 to 10.75), p = 0.018] and VEGF-R level decreased [mean change: -87.16 (-131.89 to -42.44), p<0.001] in placebo group but did not show any change in cholecalciferol group. Our data shows the changes in Ang-1, Ang-2 and Ang-1/Ang-2 ratio after high dose oral cholecalciferol supplementation in patients with non-diabetic G3-4 CKD. The data suggests changes in circulating levels of angiogenic markers which needs to be confirmed through an adequately powered study.

Endothelial Dysfunction and Arterial Stiffness in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

Population-based studies have suggested that patients with inflammatory bowel disease (IBD) might be at an increased risk for cardiovascular diseases. A meta-analysis was performed on clinical studies to evaluate endothelial function, arterial stiffness, and carotid intima-media thickness (cIMT) in patients with IBD, after searching PubMed, Embase, Cochrane library, and Web of Science databases. A random-effects model was used to allow for the pooling of studies and for determination of the overall effect. After exclusion, a total of 41 eligible studies with 2330 patients with IBD and 2032 matched controls were identified and included for the analysis. It was found that cIMT was significantly increased in patients with IBD as compared with that in matched controls (Cohen’s d: 0.63; 95% CI: 0.34, 0.93; I2 = 91.84%). The carotid–femoral pulse wave velocity was significantly higher in patients with IBD compared to that in matched controls (Cohen’s d: 0.76; 95% CI: 0.54, 0.98; I2 = 70.03%). The augmentation index was also significantly increased in patients with IBD compared to matched control subjects (Cohen’s d: 0.35; 95% CI: 0.08, 0.63; I2 = 61.37%). Brachial artery flow-mediated dilatation was significantly decreased in patients with IBD than that in matched controls (Cohen’s d: −0.73; 95% CI: −1.10, −0.36; I2 = 81.02%). Based on the meta-analysis, it was found that patients with IBD exhibit significant endothelial dysfunction, increased arterial stiffness, and cIMT. Thus, patients with IBD may benefit from aggressive risk stratification for cardiovascular diseases.

Blueberries Improve Endothelial Function in Postmenopausal Women With Above-Normal Blood Pressure via Reductions in Oxidative Stress

ObjectivesResearch suggests blueberries and their (poly)phenols may improve endothelial dysfunction, a major risk factor for cardiovascular disease (CVD). The objective of this study was to investigate the impact of consuming 22 g/day for 12 weeks of freeze-dried highbush blueberry powder on endothelial function and other measures of cardiovascular health, oxidative stress, and circulating (poly)phenol metabolites in postmenopausal women with above-normal blood pressure.MethodsWe performed a randomized, double-blind, placebo-controlled, parallel-arm trial in estrogen-deficient postmenopausal women aged 45–65 years with elevated blood pressure or stage 1-HTN. Endothelial function was assessed as brachial artery flow-mediated dilation (FMD) and normalized to individual shear rate area under the curve (FMD/SRAUC) to control for inter-individual variability in reactive hyperemia-induced shear stress. To assess whether improvements in FMD were mediated by reduced oxidative stress, FMD was assessed before and after intravenous infusion of a supra-physiologic dose of ascorbic acid. Blood pressure, arterial stiffness, and plasma (poly)phenol metabolites were also assessed.ResultsA total of 43 women completed the trial (n = 32 for endothelial function). Compliance in the Blueberry and Placebo groups were 93% and 91%, respectively. Mean total plasma (poly)phenol metabolite concentrations were increased at 4 (250,053 nmol/L, P < 0.05) and 8 (303,053 nmol/L, P < 0.05) weeks in the Blueberry group compared to baseline (125,798 nmol/L) with a strong trend at 12 weeks (227,971 nmol/L, P < 0.05), and no changes in Placebo. Blood pressure and arterial stiffness were unchanged with both treatments. At 12 weeks, FMD/SRAUC was increased by 96% from baseline (P < 0.05) in the Blueberry group but unchanged in Placebo, and changes in FMD/SRAUC from baseline to 12 weeks were higher (P < 0.05) than Placebo. The response in FMD/SRAUC to ascorbic acid infusion was lower (P < 0.05) at 12 weeks compared to baseline in the Blueberry group but not Placebo.ConclusionsThese findings suggest blueberries improve endothelial function, and is mediated, in part, by reduced oxidative stress in postmenopausal women with above-normal blood pressure, a high-risk population for developing CVD.Funding SourcesUS Highbush Blueberry Council and USDA National Institute of Food and Agriculture.

THE EFFECT OF COVID-19 VACCINE ON ARTERIAL FUNCTION

Objective: To fight the COVID-19 pandemic, messenger RNA (mRNA) vaccines were the first to be adopted by vaccination programs worldwide. We sought to investigate the short-term effect of mRNA vaccine administration on endothelial function and arterial stiffness. Design and method: Thirty-two participants (mean age 37 ± 8 years, 20 men) that received the BNT162b2 mRNA COVID-19 vaccine were studied in 3 sessions in a sequence-randomized, sham-controlled, assessor-blinded, cross-over design. The primary outcome was endothelial function assessed by brachial artery flow-mediated dilatation (FMD), and secondary outcomes were aortic stiffness, evaluated with carotid-femoral pulse wave velocity (PWV) and augmentation index (AIx@75), and inflammation measured by high-sensitivity C-reactive protein (hsCRP) in blood samples. The outcomes were assessed prior to, and at 8 h, 24 h post the 1st dose of vaccination, and 8 h, 24 h, and 48 h post the 2nd. Results: There was an increase in hsCRP that was apparent at 24 h after both the 1st dose (-0.60 [95% Confidence intervals [CI]: -1.60 to -0.20], p = 0.013) and the 2nd dose (max median difference at 48 h -6.60 [95% CI: -9.80 to -3.40], p &lt; 0.001) compared to sham. The vaccine did not change PWV or AIx@75. FMD remained unchanged during the 1st dose but decreased significantly by 1.5% (95% CI: 0.1% to 2.9%, p = 0.037) at 24 h post the 2nd dose. FMD values returned towards baseline at 48 h. Conclusions: Our study shows that the mRNA vaccine causes a prominent increase in inflammatory markers, especially after the 2nd dose, and a transient deterioration of endothelial function at 24 h that returns towards baseline at 48 h. These results confirm the short-term cardiovascular safety of the vaccine.

Persistent vascular dysfunction following an acute nonpharmacological reduction in blood pressure in hypertensive patients.

Vascular dysfunction, an independent risk factor for cardiovascular disease, often persists in patients with hypertension, despite improvements in blood pressure control induced by antihypertensive medications. As some of these medications may directly affect vascular function, this study sought to comprehensively examine the impact of reducing blood pressure, by a nonpharmacological approach (5 days of sodium restriction), on vascular function in 22 hypertensive individuals (14 men/8 women, 50 ± 10 years). Following a 2-week withdrawal of antihypertensive medications, two 5-day dietary phases, liberal sodium (liberal sodium, 200 mmol/day) followed by restricted sodium (restricted sodium, 10 mmol/day), were completed. Resting blood pressure was assessed and vascular function, at both the conduit and microvascular levels, was evaluated by brachial artery flow-mediated dilation (FMD), reactive hyperemia, progressive handgrip exercise, and passive leg movement (PLM). Despite a sodium restriction-induced fall in blood pressure (liberal sodium: 141 ± 14/85 ± 9; restricted sodium 124 ± 12/79 ± 9 mmHg, P < 0.01 for both SBP and DBP), FMD (liberal sodium: 4.6 ± 1.8%; restricted sodium: 5.1 ± 2.1%, P = 0.27), and reactive hyperemia (liberal sodium: 548 ± 201; restricted sodium: 615 ± 206 ml, P = 0.08) were not altered. Similarly, brachial artery vasodilation during handgrip exercise was not different between conditions (liberal sodium: Δ0.36 ± 0.19 mm; restricted sodium: Δ0.42 ± 0.18 mm, P = 0.16). Lastly, PLM-induced changes in peak blood flow (liberal sodium: 5.3 ± 2.5; restricted sodium: 5.8 ± 3.6 ml/min per mmHg, P = 0.30) and the total vasodilatory response [liberal sodium: 2 (0.9-2.5) vs. restricted sodium: 1.7 (1.1-2.6) ml/min per mmHg; P = 0.5] were also not different between conditions. Thus vascular dysfunction, at both the conduit and microvascular levels, persists in patients with hypertension even when blood pressure is acutely reduced by a nonpharmacological approach.

THE EFFECT OF RENAL DENERVATION ON PERIPHERAL AND CEREBRAL VASOREACTIVITY IN PATIENTS WITH RESISTANT HYPERTENSION AND TYPE 2 DIABETES MELLITUS

Objective: Vasoreactivity is fundamental mechanisms of the control of tissue perfusion, that distributes supply of blood flow according to metabolic needs and protecting the organs from changes in systemic blood pressure (BP). The presence of vascular risk factors such as hypertension (HTN) and diabetes mellitus (DM) impairs vasoreactivity, leading to an increased risk of stroke and myocardial infarction. The aim of this study was to evaluate the effect of renal denervation (RDN) on peripheral and cerebral vasoreactivity in patients with resistant HTN (RHTN) and type 2 DM at 6 month after procedure. Design and method: The assessment of the effect of RDN on peripheral vasoreactivity was performed in 31 patients with RHTN and type 2 DM, participants in single-arm prospective interventional studies (protocol numbers NCT02667912 and NCT01499810 at ClinicalTrials.gov) (mean age 59.1 ± 8.6 years, mean office (systolic/diastolic) BP (SBP/DBP) 167.7 ± 18.5/86.7 ± 16.6 mmHg, HbA1c 7.8 ± 1.8%, 22 (68%) men), of which cerebral vasoreactivity was evaluated in 21 patients with good visualization. All patients underwent ambulatory 24-hour BP. Flow-mediated dilation (FMD) of brachial artery and vasoreactivity of middle cerebral artery (MCA) during both breath-holding and hyperventilation testes were measured by high-resolution ultrasound at baseline and 6 month follow-up. Results: RDN led to a decrease in mean 24-hour BP (SBP/DBP) (from 157.5 ± 18.2/76.5 ± 9.7 to 147.8 ± 15.6/71 ± 12.8mmHg, p = 0.049/0.096) without significant changes in number of antihypertensive drugs (from 4.7 ± 0.9 to 4.5 ± 1.2, p = 0.52). There were increase in FMD (from 3.4 ± 5.5 to 7.7 ± 4.2%, p = 0.004), but vasoreactivity of MCA to hyperventilation and breath-holding test was not changed. The degree of improvement of FMD not correlated with the baseline BP and its change after RDN. Conclusions: According to our results, RDN in diabetic patients with RHTN improved peripheral vasoreactivity regardless of the degree of BP reduction, but did not significantly change cerebral vasoreactivity at 6 month follow up.

META-ANALYSIS ADDRESSING THE EFFECT OF SODIUM-GLUCOSE CO-TRANSPORTER-2 INHIBITORS ON FLOW-MEDIATED DILATION IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Objective: Endothelial dysfunction seems to play a pivotal role in the pathogenesis of cardiovascular disease and related complications among high-risk patients, such as those suffering from type 2 diabetes mellitus (T2DM). Non-invasive peripheral endothelial function assessment with measurement of brachial artery flow-mediated dilation (FMD) has been demonstrated to predict adverse cardiovascular events. Herein, we sought to determine whether SGLT-2 inhibitors provide a significant effect on endothelial function, as assessed through FMD. Design and method: We searched PubMed, Cochrane Library and grey literature from inception to 10th October 2021 for parallel group randomized controlled trials (RCTs) enrolling adult subjects with T2DM, assigned to a SGLT-2 inhibitor versus placebo or active comparator and addressing their effect on FMD. We set as primary efficacy outcome the change in FMD with SGLT-2 inhibitor versus control. Results: We pooled data from 4 trials in a total of 270 subjects with T2DM. We demonstrated that treatment with SGLT-2 inhibitor versus placebo or active comparator produced a significant increase in FMD by 1.66% (95% CI; 0.56 – 2.76, I2 = 28%, p = 0.003). Notably, all eligible RCTs utilized dapagliflozin. Overall risk of bias was evaluated as low across the selected studies. Conclusions: The present meta-analysis demonstrated a clear benefit on endothelial function with SGLT-2 inhibitors compared to placebo or active comparator. Although the sample size is small, it seems that amelioration of endothelial dysfunction with SGLT-2 inhibitors constitutes another significant mechanism that confers to cardio-protection with this drug class. Larger RCTs will shed further light on this important pathophysiologic link.

Flow-mediated slowing shows poor repeatability compared with flow-mediated dilation in non-invasive assessment of brachial artery endothelial function.

Pulse wave velocity (PWV) deceleration to reactive hyperemia–flow-mediated slowing (FMS)–has been suggested as an alternative method to flow-mediated dilation (FMD) to evaluate brachial artery endothelial function. FMS is suggested to address major caveats of the FMD procedure including its suboptimal repeatability and high-operator dependency. However, the repeatability of FMS has not been thoroughly examined, especially given the plethora of methods claiming to measure PWV. We assessed and compared the intra- and inter-day repeatability of FMS as measured by piezoelectric pressure mechanotransducers placed in the carotid and radial arteries, and brachial artery FMD as measured by echo-tracking. Twenty-four healthy male participants aged 23–75 yr, were examined on three separate days to assess intra and inter-day repeatability. All FMD and FMS examinations were conducted simultaneously by the same researcher complying with standardized guidelines. Repeatability was examined with intraclass correlation coefficient (ICC; >0.80), coefficient of variation (CV; <15%), and limits of agreement (95% LOA). Relative (%) FMD and FMS were scaled for baseline brachial artery diameter and PWV, respectively. Intra- (ICC: 0.72; CV: 136%; 95% LOA: -19.38 to 29.19%) and Inter-day (ICC: 0.69; CV: 145%, 95% LOA: -49.50 to 46.08%) repeatability of %FMS was poor, whereas %FMD demonstrated moderate-to-good intra- (ICC: 0.93; CV: 18%, 95% LOA: -3.02 to 3.75%) and inter-day repeatability (ICC: 0.74; CV: 25%, 95% LOA: -9.16 to 7.04%). Scaling FMD reduced the intra-day CV (-5%), and the uncertainty of the 95% LOA (- 37.64 to 35.69%) estimates of FMS. Carotid-radial artery FMS showed poorer repeatability compared to FMD.

Cerebrovascular Function, Vascular Risk, and Lifestyle Patterns in Resistant Hypertension.

Impaired cerebrovascular reactivity (CVR) and blunted cerebral hemodynamic recruitment are thought to be important mechanisms linking hypertension to cerebrovascular and cognitive outcomes. Few studies have examined cardiovascular or dietary correlates of CVR among hypertensives. To delineate associations between cardiometabolic risk, diet, and cerebrovascular functioning among individuals with resistant hypertension from the TRIUMPH trial (n = 140). CVR was assessed by examining changes in tissue oxygenation (tissue oxygenation index [TOI] and oxygenated hemoglobin [HBO2]) using functional near-infrared spectroscopy (fNIRS) during a breath holding test, a standardized CVR assessment to elicit a hypercapnic response. Participants also underwent fNIRS during three cognitive challenge tasks. Vascular function was assessed by measurement of brachial artery flow-mediated dilation and hyperemic flow response. Cardiometabolic fitness was assessed from peak VO2 on an exercise treadmill test and body mass index. Dietary patterns were quantified using the DASH eating score. Cognitive function was assessed using a 45-minute test battery assessing Executive Function, Processing Speed, and Memory. Greater levels fitness (B = 0.30, p = 0.011), DASH compliance (B = 0.19, p = 0.045), and lower obesity (B = -0.30, p = 0.004), associated with greater changes in TOI, whereas greater flow-mediated dilation (B = 0.19, p = 0.031) and lower stroke risk (B = -0.19, p = 0.049) associated with greater HBO2. Similar associations were found for cerebral hemodynamic recruitment, and associations between CVR and cognition were moderated by duration of hypertension. Impaired CVR elevated cardiometabolic risk, obesity, vascular function, and fitness among hypertensives.

High Sodium Intake Differentially Impacts Brachial Artery Flow Mediated Dilation When Evaluated with Reactive Versus Active Hyperemia

OBJECTIVEThis study sought to determine if a high sodium (HS) intake attenuates upper limb flow mediated dilation in response to reactive (RH‐FMD) and sustained (SS‐FMD) hyperemia, and the role of oxidative stress in this response. Our hypothesis is HS intake will similarly impair upper limb vascular function when assessed as both RH‐FMD and SS‐FMD, and that this dysfunction will be reversed following acute antioxidant consumption.METHODSTen young, salt resistant participants (9 Males, 1 Female) consumed a 7‐day HS (6,900 mg/day) or a 7‐day low sodium (LS: 2,300 mg/day) diet in a randomized order. On the last day of the diet, brachial artery RH‐FMD (evaluated after 5 minutes of cuff occlusion) and SS‐FMD (handgrip exercise) were performed following consumption of placebo (PL) and repeated two hours after the consumption of antioxidants [AO; (1000 mg of vitamin C, 800 IU of vitamin E, and 400 mg of alpha lipoic acid]. Handgrip exercise (HG) was performed in 3‐minute workloads, increasing by 8 kg until failure, at a rate of one contraction per second. RH‐FMD responses were evaluated as percentage change from baseline and SS‐FMD was evaluated as brachial artery shear‐to‐dilation slopes assessed across all HG workloads achieved.RESULTSBetween diets, sodium consumption and excretion were significantly greater in the HS condition (p &lt; 0.05 for both), but mean arterial blood pressure was unchanged (LS 85 ± 5; HS 84 ± 7 mmHg; p = 0.5). RH‐FMD was significantly lower during HS compared to LS (p = 0.01), in the placebo condition but not during the AO condition (p = 0.7), with a significant interaction present (HS+PL: 5.9 ± 3.4; HS+AO: 8.2 ± 2.7; LS+PL: 8.8 ± 4.7; LS+AO: 7.0 ± 2.1 %; p = 0.01) due to a significant increase in the HS+AO condition. A comparison of shear‐dilation slopes during SS‐FMD revealed no differences between sodium interventions (p = 0.3), AO condition (p = 0.1), or any interaction effect (p = 0.7) [HS+PL: 0.0031 ± 0.0013; HS+AO: 0.0026 ± 0.0012; LS+PL: 0.0028 ± 0.0012; LS+AO: 0.0022 ± 0.0010; mm.seconds‐1.kg‐1].CONCLUSIONIndependent of changes in MAP, a HS intake impaired peripheral vascular function when assessed via RH‐FMD, which was restored with AO consumption, potentially implicating elevated oxidative stress as a contributor to this dysfunction. However, SS‐FMD, evaluated via HG exercise, was not altered by a HS intake or AO consumption. In conclusion, 7‐days of a HS intake appears to have disparate effects between the two peripheral vascular function techniques, implicating an inability of HS intake to impact exercise‐induced BA dilation.

Targeting Endogenous Antioxidant Capacity to Prevent Vascular Dysfunction Induced by Limb Immobilization

BackgroundBrief periods of limb disuse that accompany orthopedic injuries can impair vascular function and increase cardiovascular disease risk. Specifically, limb immobilization elicits a decrease in vascular shear stress which leads to an increase in oxidative stress and impaired vasodilation. We hypothesized that increasing the activation of nuclear factor‐erythroid factor 2‐related factor 2 (Nrf2), a critical transcription factor that regulates expression of endogenous antioxidants, using a novel, naturally occurring, supplement (PB125), would preserve vascular function during 14 days of limb immobilization.MethodsTen young, healthy individuals were randomized to receive either PB125 (100mg, N=6, 3M/3F, 28±5 y, BMI= 25±6 kg/m2) or placebo (N=4, 1M/3F, 23±4 y, BMI=24±3 kg/m2). Utilizing Doppler ultrasound, before and after 14 days of leg immobilization, leg blood flow (LBF) and vascular conductance (LVC) were measured in the common femoral artery at rest and during passive leg movement (PLM), and during knee‐extensor (KE) exercise at 3 relative intensities (40, 60, 80% of max; KE max = 35±10W). Additionally, flow mediated dilation (FMD) and post‐occlusive reactive hyperemia were assessed in the popliteal and brachial arteries.ResultsLower limb immobilization reduced daily step count by 53 ± 19% in both groups (PB125 vs. placebo p &gt; 0.05). Femoral, popliteal, and brachial artery diameters were not significantly different following immobilization. Resting LBF and LVC were lower following immobilization in the placebo group (pre vs. post; LBF: 485±124 vs. 357±106 ml/min, p = 0.001; LVC: 5.2±1.1 vs. 3.7±0.9 ml/min/mmHg, p = 0.001), but were preserved in the PB125 group (LBF: 239±63 vs. 237±78 ml/min, p &gt; 0.05; LVC: 2.6±0.6 vs. 2.6±0.7 ml/min/mmHg, p &gt; 0.05). However, LBF and LVC during KE exercise were not impacted by limb immobilization. Microvascular function, as assessed by the hyperemic response to PLM, was diminished in the placebo group (LVC Δpeak: 6.8±2.8 vs. 3.7±1.4 ml/min/mmHg, p = 0.049), but preserved in the PB125 group (LVC Δpeak: 3.0±0.6 vs. 3.0±1.8 ml/min/mmHg p &gt; 0.05). Conversely, microvascular function, assessed by reactive hyperemia, was unchanged in both the popliteal and brachial arteries. Macrovascular function changes due to immobilization were limb‐specific, with a decrease in popliteal artery FMD with placebo (6.5±4.1 vs. 1.9±1.6 %, p = 0.046) and preservation with PB125 (4.4±3.6 vs. 2.8±1.9 %, p &gt; 0.05), while brachial artery FMD was unchanged in both groups (p &gt; 0.05).ConclusionsLimb immobilization induced both microvascular and macrovascular changes in the leg which may contribute to the attenuated LBF and LVC at rest. Administration of PB125 preserved vascular function during disuse, presumably by mitigating the deleterious impact of oxidative stress. Hence, PB125 supplementation, and, therefore, augmented endogenous antioxidant capacity, appears to mitigate the negative vascular effects of limb disuse.

The Influence of Covid‐19‐Based mRNA Vaccines on Measures of Conduit Artery and Microvascular Endothelial Function

With the emergence of severe acute respiratory syndrome 2 (SARS‐CoV‐2), leading to coronavirus disease 19 (COVID‐19), a new class of messenger RNA (mRNA) vaccines have been broadly used. These vaccines have been associated with inflammatory sides effects such as myo‐ and peri‐carditis. Despite the well‐known link between inflammation and endothelial dysfunction, it is unknown whether these vaccines may transiently impair endothelial function, and therefore increase cardiovascular risk. Aim: To evaluate the influence of COVID‐19‐based mRNA vaccines on macro‐ and micro‐vascular endothelial function in healthy adults. We hypothesized that macro‐ and micro‐vascular endothelial function would be reduced following vaccination.MethodsPrior to, and ~48 hrs following the second dose of COVID‐19‐based mRNA vaccines, brachial artery flow‐mediated dilation (FMD, macrovascular function), reactive hyperemia (microvascular function), and cutaneous intradermal microdialysis coupled with laser Doppler flowmetry (microvascular function) were measured in healthy young adults. For microdialysis, a standard local heating protocol (42⁰C) was utilized, followed by infusion of the Nitric Oxide Synthase inhibitor Nω‐Nitro‐L‐arginine methyl ester hydrochloride (L‐NAME, 15mM), and induction of maximum vasodilation (43⁰C+28mM Sodium Nitroprusside). Sites included: control (lactated Ringer’s), ascorbic acid (10 mM), l‐arginine (10 mM), and tetrahydrobiopterin (BH4,10 mM). C‐reactive protein (CRP), a marker of systemic inflammation, was measured from fasting serum samples at both time points.ResultsVaccination (mRNA‐1273, n=3 and BNT162b2, n=6, 5men/4women, 34±2yrs) induced an increase in CRP (pre: 0.2±0.1mg/dL vs. post: 2.1±0.5mg/dL, p=0.008, r‐statistic=‐0.89), but had no effect on FMD (pre: 3.6±0.9% vs. post: 4.6±1.1%, p=0.43, Cohen’s d=0.28) or reactive hyperemia (pre: 20178±3236 AU vs. post: 28426±4573 AU, p=0.14, Cohen’s d=0.55). There was no association between the change in FMD (r=‐0.07, p=0.87) or reactive hyperemia (r=‐0.48, p=0.19) and the change in CRP. Vaccination also had no effect on microvascular nitric oxide (NO)‐dependent dilation (pre: 77.0±2.5% vs post: 77.3±2.4%, p=0.91, ηp2=0.002), nor was there an effect of microdialysis treatment on NO‐dependent dilation (p=0.74, ηp2=0.05). Following vaccination, the difference in NO‐dependent dilation relative to control was unaffected by treatment (p=0.25, η2=0.11) with no difference in the effects of BH4 (6.3±4.9%), l‐arginine (8.3±5.2%), or ascorbic acid (‐2.6±4.2%, all p&gt;0.05). The change in NO‐dependent dilation at the control site was not related to the change in CRP (r=0.32, p=0.40).ConclusionsThere was a significant inflammatory response to COVID‐19‐based mRNA vaccines ~48 hrs following the second vaccine dose. Despite this, macro‐ and micro‐vascular endothelial function and NO‐dependent dilation were preserved in healthy adults.

Objectively Measured Vigorous‐Intensity Physical Activity is Related to Endothelial Function in Midlife and Older Men but not in Estrogen‐Deficient Postmenopausal Women

BackgroundAerobic exercise training is consistently associated with enhanced vascular endothelial function via suppression of oxidative stress in midlife/older (ML/O; 50 years) men but not in estrogen‐deficient postmenopausal women (E‐PMW). It is unclear if chronic physical activity (PA) patterns assessed under free‐living conditions, including sedentary behavior and vigorous exercise, are related to endothelial function among ML/O men or E‐PMW. We investigated if objectively measured PA patterns were associated with endothelial function in ML/O adults and the potential mechanisms involved.Methods172 ML/O adults were included for analysis (67 ± 7 years; 85M/87W). Endothelium‐dependent dilation was assessed via brachial artery flow‐mediated dilation (FMDBA), a bioassay of endothelial function. PA was assessed over 3‐7 days via wrist‐worn accelerometers (GENEactiv), which measured sedentary time and light, moderate, and vigorous activity. The relations between endothelial function and PA were examined using simple and stepwise linear regression. Multiple linear regression was used to examine the correlation between endothelial function and PA when controlling for conventional cardiovascular disease risk factors. Plasma oxidized low‐density lipoprotein (OxLDL) concentrations and total antioxidant status were used as markers of oxidative stress and antioxidant defenses, respectively. Interleukin‐6, tumor necrosis factor‐α, and C‐reactive protein concentrations were examined to assess chronic low‐grade inflammation. Mediation analysis was used to determine the potential for changes in oxidative stress, antioxidant defenses, and inflammation as mechanisms mediating the relation between PA and endothelial function.ResultsIn the entire cohort of subjects, FMDBA was negatively associated with sedentary time (R2=0.04; p=0.01), not associated with light PA (R2=0.02; p=0.09), and positively associated with moderate (R2=0.03; p=0.04) and vigorous (R2=0.06; p&lt;0.01) PA. Only sedentary time (R2=0.06; p=0.02) and vigorous PA (R2=0.11; p&lt;0.01) were associated with FMDBA in ML/O men. No PA parameters were associated with FMDBA in E‐PMW (all p&gt;0.05). Stepwise linear regression revealed vigorous PA primarily mediated the effects of PA on FMDBA in ML/O men (R2=0.10; p&lt;0.01). When controlling for age, blood pressure, body mass index, triglycerides, high‐density lipoprotein, low‐density lipoprotein, and fasting glucose, vigorous PA independently predicted FMDBA in ML/O men (R2=0.05; p=0.05) but not in E‐PMW (R2=0.03; p=0.18). Plasma OxLDL concentrations mediated 13.5% of the group effect of vigorous PA on FMDBA (p&lt;0.01); no other plasma markers had a mediating effect (all p&gt;0.05).ConclusionsObjectively measured PA, primarily vigorous PA, is positively associated with endothelial function in ML/O men but not in E‐PMW. This relation is mediated, in part, by oxidative stress. These associations are consistent with findings that aerobic exercise training does not improve endothelial function in E‐PMW. Alternative strategies to improve endothelial function in E‐PMW are needed.

Hypoxic Preconditioning Attenuates Ischemia‐Reperfusion Injury in Older Adults

Sudden restoration of blood flow to an ischemic vessel paradoxically damages endothelial cells. In young healthy adults, ischemic preconditioning, caused by repeated periods of brief ischemia induced by local cuff inflation prior to reperfusion, attenuates endothelial dysfunction following an ischemia‐reperfusion injury. However, ischemic preconditioning does not consistently protect against ischemia‐reperfusion injury in older adults. Intermittent systemic hypoxemia, induced via brief bouts of breathing low levels of oxygen, attenuates endothelial dysfunction following an ischemia‐reperfusion injury in young healthy adults. Therefore, the aim of the present study was to determine whether intermittent hypoxia protects against ischemia‐reperfusion injury in older adults. Eleven older adults (4 women, age: 57±9 years, height: 173±8 cm, body weight: 76±13 kg) visited the laboratory on two separate occasions. Endothelium‐dependent vasodilation was assessed by brachial artery flow‐mediated dilation using a semiautomated diagnostic ultrasound system before and after 20 minutes of blood flow occlusion to induce an ischemia‐reperfusion injury. Blood flow occlusion was preceded by either intermittent hypoxia (IH), consisting of three 4‐min hypoxic cycles at a targeted arterial oxygen saturation of 80% interspersed with 4‐min room air cycles, or intermittent normoxia (IN), consisting of three 4‐min normoxic cycles separated by 4‐min room air cycles. Intermittent hypoxia resulted in an arterial oxygen saturation of 80±2%, which corresponded to oxygen levels of 11.6±1.0%. When preceded by intermittent normoxia, blood flow occlusion reduced flow‐mediated dilation by 4.0±2.6% (6.4±1.7 to 2.4±1.8%). In contrast, flow‐mediated dilation was reduced by 1.8±1.5% when blood flow occlusion was preceded by intermittent hypoxia (5.6±1.8 to 3.7±2.4%: p=0.05). Intermittent hypoxia increased cardiac output (5.2±1.5 to 5.7±1.8 L·min‐1, p=0.03) mainly due to an increase in heart rate (61±12 to 69±10 bpm, p&lt;0.01). In conclusion, hypoxic preconditioning attenuated the reduction in flow‐mediated dilation induced by blood flow occlusion in older adults. Thus, exposure to intermittent hypoxia represents a potential strategy to protect against ischemia‐reperfusion injury in populations at risk for ischemic events.

Changes in Gut Microbiome Composition with Healthy Aging in Humans: Links to Vascular Endothelial Function

Aging is the primary risk factor for cardiovascular diseases, primarily due to development of vascular endothelial dysfunction. The gut microbiome is a strong influencer of host physiology, but few studies have investigated how gut microbiome composition changes with primary (healthy) aging in humans, or how such changes may influence endothelial function.PURPOSETo: 1) determine changes in gut microbiome composition and their relation to endothelial function in healthy late middle‐aged to older (MA/O) vs. young (Y) adults; and 2) investigate potential mechanisms of this link.METHODS &amp; RESULTSN=14/group (MA/O: 60‐79 yrs; Y: 18‐29 yrs). Data are mean ± SE. Gut microbiome composition was assessed via fecal 16S rRNA sequencing. α‐diversity, phylogenetic diversity within each sample, was higher in MA/O vs Y adults (Faith’s PD: 22.2 ± 1.8 vs 15.5 ± 1.3, P = 0.02). β‐diversity, difference in overall composition between samples, was also altered with aging (PERMANOVA: P &lt; 0.05; unweighted UniFrac). Both α‐diversity (R = ‐0.60, P = 0.04) and β‐diversity (R = ‐0.58, P = 0.04) were inversely related to age‐related impairments in endothelial function, measured by brachial artery flow‐mediated dilation (MA/O: 4.5 ± 0.4 vs Y: 7.9 ± 1.7%, P &lt; 0.05).Potential Mechanisms: In preliminary analyses (unpaired t‐tests), changes in gut microbiome composition were accompanied by altered relative abundance of gram‐negative bacteria (e.g., Bacteroides [MA/O: 33 ± 4% vs Y: 20 ± 4%, P = 0.02]) and Enterobacteriaceae [MA/O: 1.5 ± 0.1% vs Y: 0.4 ± 0.1%, P = 0.02]), which contain pro‐inflammatory lipopolysaccharide (LPS) in their cell walls. Translocation of LPS into systemic circulation is facilitated by increased intestinal permeability, which we found was higher with aging, as measured by a lactulose‐mannitol (L:M) test (1‐hour serum L:M ratio, MA/O: 0.012 ± 0.002 vs Y: 0.007 ± 0.001, P = 0.04). As such, plasma LPS‐binding protein, a readily detectable marker of LPS in peripheral blood, was higher in MA/O vs Y adults (31.3 ± 4.1 vs 17.7 ± 2.0 ng/mL, P = 0.01). Once in circulation, LPS is recognized as a pathogen‐associated molecular pattern and can trigger an inflammatory response. Consistent with this, circulating levels of the pro‐inflammatory markers IL‐6 [MA/O: 1.56 ± 0.29 vs Y: 0.70 ± 0.13 pg/ml, P = 0.01] and CRP [MA/O: 1.65 ± 0.27 vs Y: 0.78 ± 0.11 pg/ml, P = 0.02]) were increased with aging. In biopsied venous endothelial cells from a subset of subjects (n = 4‐8/group), abundance of phosphorylated (i.e., activated) NF□B was higher in MA/O vs Y adults (0.40 ± 0.05 vs 0.31 ± 0.04 ng/ml, P = 0.24), with no difference in total NFkB, indicating potentially increased vascular inflammation.CONCLUSIONSOur findings represent initial evidence in humans that the gut microbiome changes with healthy aging and may be an important mediator of age‐related endothelial dysfunction, possibly via increasing circulating LPS and vascular inflammation.

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

ObjectiveThe reactivity of conduit vessels such as the brachial artery is important in influencing arterial diameter, and subsequently, blood flow. Flow‐mediated dilation (FMD) measures vessel reactivity. The increase in shear stimuli from transient arterial occlusion enhances arterial diameter in an endothelial‐dependent manner, and this is thought to be impaired in individuals with congenital heart disease (CHD). Isometric handgrip (IHG) exercise is a proposed intervention to improve vessel reactivity by optimizing the shear stimuli to provoke changes in arterial diameter. Indeed, IHG training has been found to improve FMD in healthy adults and children. Whether IHG training improves endothelial dysfunction in CHD remains unknown. Improving vessel reactivity in the young becomes increasingly important in optimizing vascular health into adulthood. The effects of acute IHG exercise on the brachial artery were examined in children with CHD.HypothesisWe tested the hypothesis that acute IHG exercise would increase FMD in children with CHD.MethodsFour subjects with CHD (mean, 13 ± 1 year, 3 female) completed a single session of 4 × 2 mins of acute IHG (30% maximum voluntary contraction using the right hand) with 1‐min rest intervals between bouts. Before and after IHG exercise, the right brachial artery was imaged with Duplex ultrasound using a 1‐min baseline, 5 mins of forearm circulatory occlusion, followed by 3 mins of cuff deflation. Blood pressure and heart rate were measured continuously.ResultsPre‐FMD (baseline) mean arterial pressure (pre: 102 ± 17 mmHg vs. post: 110 ± 16 mmHg, p = 0.496) and heart rate (pre: 75 ± 13 bpm vs. post: 66 ± 5 bpm, p = 0.253) were not different. Baseline brachial artery diameter increased following acute IHG in 3 of 4 subjects (pre: 3.11 ± 0.45 mm vs. post: 3.23 ± 0.39 mm, Cohen’s d = 0.3). Peak shear rate was greater post‐IHG in 3 of 4 subjects (pre: 995 ± 346 sec‐1vs. post: 1158 ± 501 sec‐1, Cohen’s d = 0.4). FMD% (4.7% vs. 6.3% and 8.2% vs. 10.5%) and FMD% normalized to shear rate area under the curve (AUC) ratio (2.2E‐5 vs. 7.4E‐5 a.u. and 3.1E‐5 vs. 4.3E‐5 a.u., Cohen’s d = 2.0) increased post‐IHG in 2 of 4 subjects. When brachial artery diameter increased, peak shear rate, FMD%, and FMD% normalized to shear rate AUC improved post‐IHG in 2/3 subjects whereas subject four showed a decrease in brachial artery diameter, FMD% and FMD% normalized to shear rate AUC, with the exception of peak shear rate post‐IHG.ConclusionFavorable changes in brachial artery diameter, peak shear rate, FMD% and FMD% normalized to shear rate AUC following acute IHG may be a promising intervention for improving vascular tone and endothelial function in children with CHD.

Conduit Artery and Forearm Microvascular Reactivity in Black and White Females: Examining the Role of Greater Superwoman Schema Endorsement

Among females in the United States, Black females suffer from the highest rates of hypertension, stroke, coronary artery disease, heart failure, and total cardiovascular disease (CVD) mortality. Importantly, vascular dysfunction precedes overt CVD and predicts CVD risk. In this regard, a recent study reported that upper limb microvascular but not macrovascular function was blunted in Black relative to White women. However, this is not always a consistent finding and such investigations have not incorporated psychosocial measures, which are known to contribute to race/ethnicity‐related disparities in cardiovascular health. Given the strong relationship between psychosocial stress and health, Woods‐Giscombe, et al. recently developed the Giscombe Superwoman Schema Questionnaire (G‐SWS‐Q), which operationalizes the Superwoman Schema (SWS) Conceptual Framework to quantify psychological stress processes specifically associated with being a Black woman. Accordingly, we tested the hypothesis that Black females would have blunted post‐occlusive upper limb microvascular and macrovascular vasodilation relative to White females and that greater SWS endorsement by Black females would be associated with blunted vascular responses.METHODSSeven Black (age: 22 ± 1 yr; BMI: 27.5 ± 1.6 kg/m2) and 6 White (age: 23 ± 1 yr; BMI: 25.9 ± 1.3 kg/m2) females participated. Post‐occlusive brachial artery flow‐mediated dilation (FMD) and forearm reactive hyperemia were assessed via well‐established procedures. Briefly, brachial artery diameter and blood velocity were measured continuously and recorded via Doppler ultrasound and a video capture system throughout a 2 min baseline, 5 min suprasystolic forearm cuff occlusion, and 3 min recovery. Offline analysis was performed via a continuous edge detection and blood velocity tracking software. Black participants also completed the G‐SWS‐Q, which is a 35‐item instrument designed to measure the cognitive, affective, and behavioral underpinnings associated with being a “Strong Black Woman” in the United States.RESULTSBrachial artery FMD was lower in Black relative to White females (3.99 ± 1.15 vs. 7.34 ± 1.10%; p = 0.03); however, after correcting for post‐occlusive shear rate AUC via ANCOVA, group differences in FMD were less apparent (p = 0.07). Post‐occlusive peak blood velocity and blood flow AUC were not different between groups (p = 0.43 and p = 0.42, respectively). A moderate negative correlation was observed between overall SWS and FMD (r = ‐0.58, p = 0.09). Among the SWS subscales, a strong negative correlation was observed between “Obligation to Present an Image of Strength” and FMD (r = ‐0.70, p = 0.04), whereas “Intense Motivation to Succeed” was moderately negatively correlated with FMD (r = ‐0.64, p = 0.06).CONCLUSIONThese preliminary data indicate that 1) upper limb macrovascular but not microvascular function may be blunted in young Black females and 2) stronger SWS endorsement may be associated with blunted vascular reactivity. Therefore, blunted conduit artery endothelial function in Black females may be partially attributable to greater SWS internalization.

Aerobic Fitness as a Predictor of Conduit, Resistance and, Microvascular Arterial Function

IntroductionVascular dysfunction increases cardiovascular disease (CVD) risk, whereas aerobic fitness (VO2peak) improves arterial function and decreases CVD risk. However, it is unclear if VO2peak has the same degree of importance across each segment of the arterial tree (e.g., conduit, resistance, and microvasculature). This is relevant given that research has not assessed these three segments in the same cohort.PurposeTo examine the relationship of VO2peak and conduit, resistance, and microvasculature arterial function.MethodsGraded exercise testing assessed VO2peak in 33 males (41±19 years, 25.6±2.6 kg/m‐2, 41.1±13.6 ml/kg‐1/min‐1) and 28 females (30±12 years, 23.3±4.3 kg/m‐2, 33.6±8.5 ml/kg‐1/min‐1). Concurrent brachial artery flow‐mediated dilation (FMD) and forearm near‐infrared spectroscopy (NIRS) examined conduit, resistance, and microvascular arterial function. FMD measured with ultrasonography to continuously record arterial diameters and Doppler velocities for 1 min baseline, 5 min forearm occlusion (250 mmHg), and 3 min recovery. The maximum percent change in diameter compared with baseline defined FMD (%) and was used to evaluate conduit arterial function. Reactive hyperemia (RH) of forearm resistance arteries was calculated as peak brachial blood flow following cuff release. Forearm tissue saturation index using NIRS during FMD was used to evaluate microvasculature function (reperfusion slope and reperfusion magnitude). Multivariate regression analysis was performed using VO2peak, age, sex, and BMI as independent variables.ResultsAge was the only predictor of FMD (β ‐0.48 [‐0.02, ‐0.01], p=0.001), sex was the only predictor of RH, females exhibited lower RH, (β ‐0.66 [‐0.30, ‐0.15], p&lt;0.001), and VO2peak only predicted reperfusion slope (β 0.56 [1.46, 4.52], p&lt; 0.001) and reperfusion magnitude (β 0.36 [3.15, 41.66], p=0.02).ConclusionIn our cohort, aerobic fitness was associated with microvascular function when age, BMI, and sex were included in the model. Only age was associated with conduit artery function, and only sex was associated with resistance arterial function. Each segment of the arterial tree was affected differently by VO2peak, age, and sex. These data show the importance of including several potentially important variables when investigating the association between VO2peak and arterial function.

On the examination of the viscous response of the brachial artery during flow-mediated dilation

In this study, mechanotransduction is investigated through a physics-based viscoelastic model describing the arterial diameter response during a brachial artery flow mediated dilation (BAFMD) test. The study is a significant extension of two earlier studies by the same group, where only the elastic response was considered. Experimental BAFMD responses were collected from 12 healthy volunteers. The arterial wall's elastic and viscous properties were treated as local variable quantities depending on the wall shear stress (WSS) sensed by mechanotransduction. The dimensionless parameters, arising from the model which serve as a quantitative assessment of the artery's physical state, were adjusted to replicate the experimental response. Among those dimensionless parameters, the viscoelastic ratio, which reflects the relative strength of the viscous response compared to its elastic counterpart, is of special relevance to this paper's main conclusion. Based on the results, it is concluded that the arterial wall's mechanical behavior is predominantly elastic, at least in the strict context of the BAFMD test. Recommendations for potential future research and applications are provided.