Brachial Artery Endothelial Function Research Articles

The effects of prolonged sitting with a mild hypercapnic environment on vascular function in elderly adults: A pilot study

Introduction: Prolonged Sitting (PS), defined a sitting for 2+ hours at a time, has been identified as an independent risk factor for cardiovascular disease (CVD). We previously reported that an acute bout of PS can attenuate macrovascular function in healthy young adults. Additionally, we reported that PS in mild hypercapnic environments (elevated CO2 concentrations) can further exacerbate these impairments in healthy young adults, and these impairments can be partially prevented by intermittent bouts of passive and active leg movements. However, the effects of prolonged sitting with a mild hypercapnic environment in the elderly population have not been studied. Therefore, the purpose of this study was to examine the impact of prolonged sitting with a mild hypercapnic condition on macrovascular function, arterial stiffness, and leg muscle metabolism. Additionally, we have further examined the effects of passive and active movements to negate the negative effects of prolonged sitting in elderly adults. Hypothesis: We hypothesized that 1) prolonged sitting in a hypercapnic environment will attenuate vascular function and leg metabolism, 2) both passive and active leg movements will preserve endothelial function and leg metabolism. Methods: Healthy elderly adults (n=2, 2 males, 69 ± 2.83 yrs) participated in three experimental visits consisting of 2.5h of prolonged sitting in a mild hypercapnic condition (CO2 = 1500ppm): control (CON), passive (PASS, passive leg movement), and active (ACT, active leg movement). Popliteal and brachial artery endothelial function was measured using flow-mediated dilation (FMD). Peripheral and central arterial stiffness was assessed using pulse wave velocity. Leg muscle metabolism was assessed using near infrared spectroscopy and a thermal camera. All measurements were taken pre- and post-siting. Results: Popliteal FMD was reduced in the CON condition compared to both the PASS and ACT (Δ -3.559 ± 0.499 vs Δ -1.799 ± 0.824 vs Δ 0.601 ± 1.958, respectively). Brachial FMD was attenuated in the CON condition compared to both compared to both the PASS and ACT (Δ -2.368 ± 0.215 vs Δ -0.285 ± 1.578 vs Δ 1.116 ± 1.174, respectively). The CON condition showed a greater reduction in leg temperature compared to both the PASS and ACT (Δ -2.4 vs Δ -1.6 ± 0.599 vs Δ 0.1 ± 0.224, respectively). No changes in central or peripheral arterial stiffness were observed. Conclusion: This preliminary data shows that uninterrupted prolonged sitting induces impairments in both local and systemic vascular function, leg muscle metabolism, but not arterial stiffness. Additionally, intermittent bouts of passive and active movements can partially preserve leg vascular function and metabolism during PS. This research was supported by the UNO Graduate Research and Creative Activity Grant, National Institutes of Health (RO1HD106911) and the Great Plains IdeaA-CTR (U54 GM115448). 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.

Impact of Insulin-Induced Relative Hypoglycemia on Vascular Insulin Sensitivity and Central Hemodynamics in Prediabetes.

Relative hypoglycemia (RH) is linked to sympathetic responses that can alter vascular function in individuals with type 2 diabetes. However, less is known about the role of RH on hemodynamics or metabolic insulin sensitivity in prediabetes. Determine if RH alters peripheral endothelial function or central hemodynamics to a greater extent in those with prediabetes (PD) versus normoglycemia (NG). Seventy adults with obesity were classified using ADA criteria as PD (n=34 (28F); HbA1c=6.02±0.1%) or NG (n=36 (30F); HbA1c=5.4±0.0%). Brachial artery endothelial function, skeletal muscle capillary perfusion, and aortic waveforms were assessed at 0 and 120min of a euglycemic clamp (40 mU/m2/min, 90 mg/dl). Plasma nitrate/nitrite and endothelin-1 (ET-1) were measured as surrogates of nitric oxide-mediated vasodilation and vasoconstriction, respectively. RH was defined as the drop in glucose (%) from fasting to clamp steady state. There were no differences in age, weight, or VO2max between groups. PD had higher HbA1c (P<0.01) and a greater drop in glucose in response to insulin (14 vs. 8%; P=0.03). Further, heart rate (HR) increased in NG compared to PD (P<0.01), while forward wave (Pf) decreased in PD (P=0.04). Insulin also tended to reduce arterial stiffness (cfPWV) in NG versus PD (P=0.07), despite similar increases in pre-occlusion diameter (P=0.02), blood flow (P=0.02), and lower augmentation index (AIx75) (P≤0.05). Compared with NG, insulin-induced RH corresponded with a blunted rise in HR and drop in Pf during insulin infusion in adults with PD, independent of changes in peripheral endothelial function.

Comparison effect of high-intensity interval training and moderate intensity continuous training on vascular function in a mouse model of lower extremity peripheral artery disease

Introduction&#x0D; Lower extremity peripheral artery disease (PAD), due to narrowing of the arteries supplying the legs, represents a major cause of physical disability. Exercise training is an important part of PAD treatment, improving functional capacity. Recent research suggests that exercise training-induced endothelial function improvement is involved in the benefits of exercise in PAD (Lee et al., 2023); however, the underlying molecular mechanisms remain unknown. In addition, the potential vascular benefits of high intensity training in PAD remain unexplored. Therefore, the aim of the study was to compare the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on endurance capacity, vascular endothelial function and expression of genes related to nitric oxide (NO) bioavailability in a mouse model of PAD.&#x0D; Methods&#x0D; PAD disease model was generated in male C57BL/6 mice by ligation of the right iliac artery. Mice with PAD were divided into 3 groups: sedentary control group (SED), MICT (40 min running at 70% of maximal aerobic speed) and HIIT (8 intervals of 2.5 minutes running at 90% of maximal aerobic speed combined with 2.5 minutes of running at 50% of maximal aerobic speed). Mice were exercised three times per week for 8 weeks. Maximal running time was determined by an incremental test until exhaustion. Vascular reactivity was assessed by measuring vasoconstrictor responses to phenylephrine as well as endothelium-dependent and -independent vasodilator responses to acetylcholine and DEA-NONOate, respectively, in isolated aortic rings. Gene expression of antioxidant enzymes (catalase and superoxide dismutase isoforms), prooxidant NADPH oxidase subunits (p22phox and p47phox), enzyme involved in NO production (endothelial NO synthase), vascular smooth muscle cell relaxation (soluble guanylate cyclase) and receptors involved in vascular tone regulation (a1 and b2 adrenergic receptors) was determined in aortic tissue by qPCR.&#x0D; Results&#x0D; Maximal running time was improved in both MICT and HIIT as compared to SED at the end of the study, but with no significant difference between the two exercise groups. Phenylephrine-induced vasoconstriction as well as vasodilator responses to acetylcholine and DEA-NONOate were significantly improved in MICT compared to SED while no significant differences were reported between HIIT and SED. There was no significant difference in gene expression among the three groups.&#x0D; Discussion/Conclusion&#x0D; MICT and HIIT were equally effective at improving endurance capacity in mice with PAD. However, only MICT improved vascular reactivity.&#x0D; References&#x0D; Lee, J., Zarezadehmehrizi, A., LaVoy, E., Markofski, M., &amp; Park, Y. (2023). Exercise training improves brachial artery endothelial function, but does not alter inflammatory biomarkers in patients with peripheral artery disease: A systematic review and meta-analysis. Journal of Cardiovascular Translational Research. Advance online publication. https://doi.org/10.1007/s12265-023-10451-0

Exercise Training Improves Brachial Artery Endothelial Function, but Does Not Alter Inflammatory Biomarkers in Patients with Peripheral Artery Disease: a Systematic Review and Meta-analysis.

The study aimed to systematically review the effects of exercise training (EX) on brachial artery flow-mediated dilation (FMD) and inflammatory biomarkers in patients with peripheral artery disease (PAD). Five electronic databases were searched: (i) patients with PAD aged ≥ 18; (ii) structured EX ≥ 2weeks; (iii) measured brachial artery FMD; and (iv) measured blood inflammatory biomarkers. Eighteen studies met the inclusion criteria. EX increased FMD but had no effect on C-reactive protein, interleukin-6, and tumor necrosis factor-α. Subgroups with moderate intensity had a greater increase in FMD than subgroups with vigorous intensity. There was no difference in effect on FMD and three inflammatory biomarkers between subgroups training for ≤ 12weeks and > 12weeks of EX, < 50min and ≥ 50min of session duration, and < 150min and ≥ 150min of weekly volume, respectively. These results suggest that EX-induced improvement in vascular function can be independent of the improvement of systemic inflammation.

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.

Repeated-Sprint Training at 5000-m Simulated Altitude in Preparation for the World Rugby Women's Sevens Series: Too High?

The objective of this study is to investigate the effectiveness of novel repeated-sprint training in hypoxia (RSH) protocol, likely maximizing hypoxic stimulus (higher than commonly used) while preserving training quality (interset rest in normoxia). Twenty-three world-class female rugby sevens players performed four repeated-sprint training sessions (4 sets of 5 × 5-s cycle sprints-25-s intersprint recovery and 3-min interset rest) under normobaric hypoxia (RSH, exercise and interset rest at FiO 2 of 10.6% and 20.9%, respectively; n = 12) or normoxia (repeated-sprint training in normoxia; exercise and interset rest at FiO 2 of 20.9%; n = 11) during a 9-d training camp before international competition. Repeated-sprint ability (8 × 5-s treadmill sprints-25-s recovery), on-field aerobic capacity, and brachial endothelial function were assessed pre- and postintervention. Arterial oxygen saturation (pooled data: 87.0% ± 3.1% vs 96.7% ± 2.9%, P < 0.001) and peak and mean power outputs (sets 1 to 4 average decrease: -21.7% ± 7.2% vs -12.0% ± 3.8% and -24.9% ± 8.1% vs -14.9% ± 3.5%; both P < 0.001) were lower in RSH versus repeated-sprint training in normoxia. The cumulated repeated-sprint distance covered significantly increased from pre- to postintervention (+1.9% ± 3.0%, P = 0.019), irrespective of the condition ( P = 0.149). On-field aerobic capacity did not change (all P > 0.45). There was no significant interaction (all P > 0.240) or condition main effect (all P > 0.074) for any brachial artery endothelial function variable. Only peak diameter increased ( P = 0.026), whereas baseline and peak shear stress decreased ( P = 0.014 and 0.019, respectively), from pre- to postintervention. In world-class female rugby sevens players, only four additional repeated-sprint sessions before competition improve repeated-sprint ability and brachial endothelial function. However, adding severe hypoxic stress during sets of repeated sprints only did not provide supplementary benefits.

A study of the relationship between brachial artery vasodilation and platelet/lymphocyte ratio in diabetic patients with coronary atherosclerosis.

To investigate the correlation between brachial artery flow-mediated endothelium-dependent dilation (FMD) and platelet-lymphocyte ratio (PLR) in peripheral blood and coronary atherosclerosis in diabetic patients. Seventy-five diabetic patients aged 62 ± 9 years, 68% male and 32% female, who underwent brachial artery endothelial function test and coronary CT scan were collected. Coronary artery calcification (CAC) was observed to assess the presence of coronary atherosclerosis, and high-resolution extravascular ultrasound was used to detect FMD. Platelet count and lymphocyte count were recorded by routine blood tests, and PLR was calculated for each study subject. Statistical methods were used to verify the association of FMD and PLR with CAC assessed by CT, respectively. Patients with coronary atherosclerosis had decreased FMD and increased PLR compared with patients with normal coronary arteries. Univariate logistic regression analysis showed that CAC score was significantly associated with both FMD (odds ratio: 0.167; 95% confidence interval: 0.049-0.565; p = 0.002) and PLR (odds ratio: 0.127; 95% confidence interval: 0.033-0.484; p = 0.001) at FMD < 5.1% or PLR > 130. The area under the ROC curve of FMD and PLR alone was 0.760 and 0.763, respectively. In addition, combined diagnosis of FMD and PLR showed the highest area under the ROC curve (0.830). FMD combined with PLR is expected to be a precise diagnostic modality for coronary artery calcification in diabetic patients.

Abstract 13635: Blunted Vascular Endothelial Function in Black Females: Examining the Impact of Psychosocial Stress Exposure versus Internalization and Coping

Introduction: Among females in the United States, Black females suffer from the highest rates of hypertension, coronary artery disease, and total cardiovascular disease (CVD) mortality. Vascular endothelial dysfunction precedes overt CVD and predicts CVD risk and has been reported in this population, but this is not always a consistent finding. Although psychosocial stress from numerous sources likely contributes to this disparity, the precise pathways and mechanisms remain incompletely understood. A growing literature suggests that internalization and coping may be more important than exposure to stressors alone. Therefore, we examined the relationship between endothelial function (brachial artery flow-mediated dilation, FMD) and psychosocial stress exposure (adverse childhood experiences, ACEs; past week discrimination, PWD) versus internalization/coping (John Henryism Active Coping Scale, JHAC12; Giscombe Superwoman Schema Questionnaire, G-SWS-Q). We hypothesized that 1) FMD would be blunted in Black relative to White females and 2) among Black females, internalization and maladaptive coping would exhibit a stronger negative relationship with FMD than exposure to stressful experiences alone. Methods: Twelve Black (21 ± 3 yr) and 8 White (25 ± 6 yr) healthy females underwent standard FMD testing. Black participants completed the ACEs, PWD, JHAC12, and G-SWS-Q inventories. Higher scores indicated greater stressor exposure or endorsement of the internalization/coping constructs. Results: Brachial artery FMD was lower in Black relative to White females (4.93 ± 3.10 vs 8.58 ± 1.62%; p &lt; .01). Neither ACEs ( r = -.10, p = .75) nor PWD ( r = -.24, p = .45) were associated with FMD. JHAC12 scores were ( r = -.61, p = .02) and SWS scores tended to be ( r = -.39, p = .11) negatively associated with FMD. Among the SWS subscales, SWS-Resistance to Being Vulnerable ( r = -.51, p = .04) and SWS-Intense Motivation to Succeed ( r = -.54, p = .04) were negatively associated with FMD. Conclusion: These preliminary data indicate that 1) brachial artery endothelial function is blunted in young Black females and 2) reduced vascular function in Black females may be due more to internalization and maladaptive coping than exposure to stressful experiences alone.

Upper-body Rowing Increases Cardiorespiratory Fitness But Not Flow-mediated Dilation In Individuals With Spinal Cord Injury

Spinal cord injury (SCI) is often associated with low cardiorespiratory fitness (VO2peak). Traditional upper-body exercise training for individuals with SCI (e.g. arm crank exercise and wheelchair propulsion) elicits positive effects on VO2peak, while the effects on vascular health are less clear. Upper-body rowing may prove to be an effective exercise modality for improving VO2peak and vascular health, as it involves repeated contractions of a relatively large muscle mass. PURPOSE: To determine the effects of exercise training performed on a rowing ergometer modified for wheelchair users on VO2peak, resting diameter of brachial artery and flow-mediated dilation (FMD). METHODS: Fifteen participants with SCI (8 males, 7 females; level of injury: C4-L3; ASIA Impairment Scale (AIS): A-C) were randomized to a control (CON, n = 7) or exercise (EXR, n = 8) group. VO2peak, resting brachial artery lumen diameter (mm) and FMD (%) were assessed before, and after six (6 W) and 12 weeks (12 W) of three weekly sessions of moderate-to-vigorous intensity exercise. VO2peak (ml/kg/min) was determined using an incremental arm crank test until exhaustion. FMD (%) was calculated as the relative increase in brachial artery diameter (determined by high-resolution ultrasound) after five minutes of cuff occlusion. Changes in diameter were analyzed off-line using semi-automated edge-detecting software. Main effects of group and time and group-by-time interactions were examined using linear-mixed models. RESULTS: There was an interaction effect for VO2peak and resting brachial artery diameter (p < .001 and p = .016, respectively). VO2peak increased from baseline (15.1 ± 5.0 ml/kg/min) to 6 W (16.6 ± 5.3 ml/kg/min, p = .007) and 12 W (17.8 ± 6.1 ml/kg/min, p < .001) in EXR, but not in CON. Resting brachial artery diameter increased from baseline (4.8 ± 0.7 mm) to 12 W (5.1 ± 0.9 mm, p = .005) in EXR, with no changes at 6 W (5.0 ± 0.9 mm), and no changes in CON. There were no main effects or interaction effect observed for FMD. CONCLUSION: These data indicate that rowing is efficient for improving VO2peak in individuals with SCI. While resting lumen diameter increases with training, 12 weeks of rowing does not increase brachial artery endothelial function.

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.

Slow-Speed Low-Intensity but Not Normal-Speed High-Intensity Resistance Exercise Maintains Endothelial Function

ABSTRACT Purpose: High-intensity resistance exercise two or three times a week has been considered optimal for muscle hypertrophy, although it can remarkably elevate blood pressure (BP). In contrast, slow-speed resistance exercise with low intensity and tonic force generation (slow-low) can induce muscle hypertrophy without elevating BP. However, it is unclear how endothelial function changes after slow-low. Therefore, this study examined whether slow-low would maintain brachial artery endothelial function in comparison with normal-speed with high intensity resistance exercise (normal-high) and normal-speed with low-intensity resistance exercise (normal-low). Methods: Eleven healthy young men performed leg-extensions with slow-low (3 sets of 8 repetitions at 50% of 1RM), normal-high (3 sets of 8 repetitions at 80% of 1RM), and normal-low (3 sets of 8 repetitions at 50% of 1RM). Flow-mediated dilation (FMD) in the brachial artery was evaluated at pre-exercise and at 10, 30, and 60 min after exercise. Result: The results showed that normal-high caused significant impairment of FMD at 30 (3.7 ± 2.7%) and 60 (3.7 ± 2.8%) min after exercise (P < .05). In contrast, slow-low and normal-low showed no significant difference from baseline. FMD was significantly lower in normal-high compared with slow-low and normal-low at 30 and 60 min after exercise (P < .05). Additionally, systolic BP was significantly higher during normal-high compared with slow-low and normal-low (P < .05). Conclusion: We concluded that slow-low did not impair brachial artery FMD concomitant with lower systolic BP, and may therefore be a useful mode of exercise training to improve muscle hypertrophy without provoking transient endothelial dysfunction.

Curcumin Enhances Fed-State Muscle Microvascular Perfusion but Not Leg Glucose Uptake in Older Adults.

Therapeutic interventions aimed at enhancing blood flow may combat the postprandial vascular and metabolic dysfunction that manifests with chronological ageing. We compared the effects of acute curcumin (1000 mg) coupled with an oral nutritional supplement (ONS, 7.5 g protein, 24 g carbohydrate and 6 g fat) versus a placebo and ONS (control) on cerebral and leg macrovascular blood flow, leg muscle microvascular blood flow, brachial artery endothelial function, and leg insulin and glucose responses in healthy older adults (n = 12, 50% male, 73 ± 1 year). Curcumin enhanced m. tibialis anterior microvascular blood volume (MBV) at 180 and 240 min following the ONS (baseline: 1.0 vs. 180 min: 1.08 ± 0.02, p = 0.01 vs. 240 min: 1.08 ± 0.03, p = 0.01), and MBV was significantly higher compared with the control at both time points (p < 0.05). MBV increased from baseline in the m. vastus lateralis at 240 min after the ONS in both groups (p < 0.05), and there were no significant differences between groups. Following the ONS, leg blood flow and leg vascular conductance increased, and leg vascular resistance decreased similarly in both conditions (p < 0.05). Brachial artery flow-mediated dilation and middle cerebral artery blood flow were unchanged in both conditions (p > 0.05). Similarly, the curcumin and control groups demonstrated comparable increases in glucose uptake and insulin in response to the ONS. Thus, acute curcumin supplementation enhanced ONS-induced increases in m. tibialis anterior MBV without potentiating m. vastus lateralis MBV, muscle glucose uptake, or systemic endothelial or macrovascular function in healthy older adults.

Metformin improves skeletal muscle microvascular insulin resistance in metabolic syndrome.

Microvascular insulin resistance is present in metabolic syndrome and may contribute to increased cardiovascular disease risk and the impaired metabolic response to insulin observed. Metformin improves metabolic insulin resistance in humans. Its effects on macro and microvascular insulin resistance have not been defined. Eleven subjects with nondiabetic metabolic syndrome were studied four times (before and after 12 wk of treatment with placebo or metformin) using a crossover design, with an 8-wk washout interval between treatments. On each occasion, we measured three indices of large artery function [pulse wave velocity (PWV), radial pulse wave separation analysis (PWSA), brachial artery endothelial function (flow-mediated dilation-FMD)] as well as muscle microvascular perfusion [contrast-enhanced ultrasound (CEU)] before and at 120 min into a 150 min, 1 mU/min/kg euglycemic insulin clamp. Metformin decreased body mass index (BMI), fat weight, and % body fat (P < 0.05, each), however, placebo had no effect. Metformin (not placebo) improved metabolic insulin sensitivity, (clamp glucose infusion rate, P < 0.01), PWV, and FMD after insulin were unaffected by metformin treatment. PWSA improved with insulin only after metformin P < 0.01). Insulin decreased muscle microvascular blood volume measured by contrast ultrasound both before and after placebo and before metformin (P < 0.02 for each) but not after metformin. Short-term metformin treatment improves both metabolic and muscle microvascular response to insulin. Metformin's effect on microvascular insulin responsiveness may contribute to its beneficial metabolic effects. Metformin did not improve aortic stiffness or brachial artery endothelial function, but enhanced radial pulse wave properties consistent with relaxation of smaller arterioles.NEW & NOTEWORTHY Metformin, a first-line treatment for type 2 diabetes, is often used in patients with insulin resistance and metabolic syndrome. Here, we provide the first evidence for metformin improving muscle microvascular insulin sensitivity in insulin-resistant humans. Simultaneously, metformin improved muscle glucose disposal, supporting a close relationship between insulin's microvascular and its metabolic actions in muscle. Whether enhanced microvascular insulin sensitivity contributes to metformin's ability to decrease microvascular complications in diabetes remains to be resolved.

Relationship between the volume of perivascular adipose tissue and the vascular wall lesion

Aim. To study the relationship between the volume of perivascular adipose tissue (PVAT) and the vascular wall lesion.Material and methods. The study included 318 patients without cardiovascular disease (mean age, 63,5±13,7 years). Hypertension was detected in 268 (84,3%) patients. All patients underwent assessment of anthropometric characteristics, lipid profile, arterial wall stiffness with the estimation of cardio-ankle vascular index, intima-media thickness, brachial artery endothelial vasomotor function. Chest computed tomography was performed with the estimation of the volumes of PVAT and pericardial adipose tissue (PAT).Results. The volume of PVAT, on average, was 0,3 [0,2; 0,4] cm3 . The VAT volume was significantly higher in obese individuals when compared with patients with normal body weight: 0,4 [0,3; 0,5] vs 0,25 [0,2; 0,4] cm3 (p=0,0007). The VAT volume was higher in individuals with an increased CAVI level when compared with patients with normal CAVI values: 0,4 [0,3; 0,5] vs 0,3 [0,25; 0,3] (p=0,02). A significant correlation was found between the VAT volume and body mass index (r=0,27, p&lt;0,005), waist circumference (r=0,41, p&lt;0,005), CAVI (r=0,49, p&lt;0,05), impaired endothelium-dependent brachial artery vasodilation (r=0,38, p&lt;0,05). When performing multiple linear regression, a significant relationship of CAVI was found with age (β±SE, 0,51±0,15; p=0,002) and volume of PVAT (β±SE, 0,41±0,13; p=0,005).Conclusion. The results indicate the relationship of PVAT with visceral obesity and vascular wall stiffness parameters.

Improvement of retinal microvascular function after initiation of lipid-lowering therapy with PCSK9 inhibitors – an observational study

Abstract Background Hypercholesterolemia is associated with endothelial dysfunction. While good evidence exists for the beneficial endothelial effects of first-line lipid-lowering drugs (statins), less is known on the new class of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. This is particularly true for the differential effects on micro- and macrovascular endothelial function and arterial stiffness. Purpose The goal of this study was to study the change in retinal microvascular dysfunction, brachial artery endothelial function and arterial stiffness in high-risk cardiovascular risk patients before and after initiation of PCSK9 inhibitor therapy with alirocumab or evolocumab. Methods In this prospective observational study, cardiovascular high-risk patients with a clinical indication for PCSK9 inhibitors were included for the measurement of retinal microvascular function (flicker light-induced dilatation of retinal arterioles and venules, FIDart and FIDven respectively; retinal arteriovenous ratio, AVR), brachial artery flow-mediated dilatation (FMD) and arterial stiffness (pulse wave velocity, PWV; augmentation index, AI). Measurements were performed at baseline, after 3 months and after 12 months of PCSK9 inhibitor therapy. The primary endpoint was the change in FIDart after 12 months of therapy compared to baseline. Results We recruited 48 patients (mean age 57±11 years, 27% female, 81% coronary artery disease) which began treatment with alirocumab or evolocumab in our lipid outpatient clinic. 6 patients were excluded from the analysis (n=3 stopped due to side effects, n=1 stopped due to new metastatic cancer, n=1 moved abroad, n=1 no retinal vessel analysis possible). LDL cholesterol was reduced from 3.8±1.2 to 1.5±0.8 and 1.8±0.9 mmol/L at 3 and 12 months respectively (all p&amp;lt;0.001). There was no significant change in systolic blood pressure during therapy. The primary endpoint FIDart was significantly increased after 12 months of PCSK9 inhibitor therapy compared to baseline (3.4±2.3 vs. 2.6±1.6%, p=0.01). Among the secondary endpoints, augmentation index improved at 12 months vs. baseline (21±12 vs. 24±9%, p=0.03). No significant change was seen for FIDven, AVR, FMD and PWV after 3 and 12 months of therapy. Conclusion In cardiovascular high-risk patients, PCSK9 inhibition is associated with an improvement of retinal microvascular function and augmentation index after one year of therapy. No effects were seen for macrovascular parameters such as FMD or PWV in our cohort. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): University Hospital Zurich, AGLA Grant (sponsored by Amgen)

1244Associations of endothelial function, arterial elasticity, and arterial stiffness with adiponectin and skeletal muscle mass

Abstract Background A temporal association where better arterial function and structure predicts adiponectin level and skeletal muscle mass during childhood remains uninvestigated. Methods We studied 5566 children and adolescents (51% girls) aged 9-11 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, Bristol, UK. Brachial artery endothelial function was determined using flow-mediated dilation (FMD), expressed as the percentage change in diameter from baseline after reactive hyperemia; arterial elasticity as distensibility coefficient (DC) expressed in mean percentage change in cross-sectional area relative to blood pressure (BP); and arterial stiffness by carotid to radial pulse wave velocity (crPWV). Skeletal muscle mass and total fat mass were assessed by dual-energy Xray absorptiometry. We conducted multivariable linear regressions with Sidak correction and adjusted for age, sex, total fat mass, cardiorespiratory fitness, pubertal status, brachial artery diameter, systolic BP, low-density lipoprotein cholesterol, mother’s social-economic class, and time (years) between the measurement of predictors and outcomes. Results FMD (β [95% CI]) = (0.027 [0.007 to 0.047]; P = 0.009) and DC (0.229 [0.088 to 0.369]; P = 0.001) were directly associated with skeletal muscle mass. FMD had a borderline inverse association with adiponectin (-0.004 [-0.008 to &amp;lt; 0.0001]; P = 0.056). crPWV was unrelated to adiponectin and skeletal muscle mass, while DC was not associated with adiponectin. Conclusions Better endothelial function and arterial elasticity were associated with higher skeletal muscle mass while arterial stiffness was unrelated to adiponectin and lean mass. Key message Healthy arterial function and structure may enhance muscle growth in children.

Effects of Arm-cranking Training with Electrical Muscle Stimulation on Vessel Function.

This study aimed to determine whether arm-cranking training with electrical muscle stimulation (EMS) results in a greater improvement in vessel function than performing the same exercise without EMS. First, nine healthy young men performed two 20-min arm-cranking trials at 50% V˙O2max with and without EMS applied to the lower limbs. The flow-mediated vasodilation (FMD) of the right brachial artery was measured using a high-resolution ultrasound device. Both FMD and normalized FMD were increased significantly after the arm-cranking with EMS trial, and significant differences were observed between the two trials. Second, 16 healthy adult men were randomly assigned to either the arm-cranking exercise training (A) group or arm-cranking training with EMS (A+EMS) group. The subjects were engaged in 20 min of arm-cranking at 50% V˙O2max twice a week for 8 weeks with/without EMS applied to the lower limbs. The FMD increased significantly after A+EMS training session and the FMD in A+EMS group was significantly higher than that in the A group. These results indicate that acute/chronic endurance arm-cranking with EMS applied to the lower limbs improves the brachial artery endothelial function more markedly than the same exercise without EMS.

The vascular response to acute hyperglycaemia: What is the role of exercise capacity?

The vascular response to acute hyperglycaemia: What is the role of exercise capacity?

Prenatal exercise and cardiovascular health (PEACH) study: the remote effect of aerobic exercise training on conduit artery and resistance vessel function.

We assessed the impact of a structured lower-limb aerobic exercise training intervention during pregnancy on brachial artery endothelial function, shear rate and patterns, and forearm blood flow and reactive hyperemia. Twenty-seven pregnant women were recruited and randomized into either a control group (n= 11; 31.0± 0.7 years), or an exercise intervention group (n= 16; 32.6± 0.9 years). The exercise group completed 40minutes of aerobic exercise (50-70% heart rate reserve) 3-4 times per week, between the second and third trimester of pregnancy. Endothelial function was assessed using flow-mediated dilation (FMD, normalized for shear stress) at pre- (16-20 weeks) and post-intervention (34-36 weeks). The exercise training group experienced an attenuated increase in mean arterial pressure (MAP) relative to the control group (ΔMAP exercise: +2± 2mm Hg vs. control: +7± 3mm Hg; p= 0.044) from pre- to post-intervention. % FMD change corrected for shear stress was not different between groups (p= 0.460); however, the post-occlusion mean flow rate (exercise: 437± 32mL/min vs. control: 364± 35mL/min; p= 0.001) and post-occlusion anterograde flow rate (exercise: 438± 32mL/min vs. control: 364± 46mL/min; p= 0.001) were larger for the exercise training group compared with controls, post-intervention. Although endothelial function was not different between groups, we observed an increase in microcirculatory dilatory capacity, as suggested by the augmented reactive hyperemia in the exercise training group. Registered at ClinicalTrials.gov: NCT02948439. Novelty: Endothelial function was not altered with exercise training during pregnancy. Exercise training did contribute to improved cardiovascular outcomes, which may have been associated with augmented reactive hyperemia, indicative of increased microcirculatory dilatory capacity.

A New Protocol for Controlling and Targeting Reactive Hyperemia Shear Stress to Assess Endothelial Function

Conduit artery endothelial function is most commonly assessed via measurement of flow mediated dilation (FMD) evoked by a transient post-limb occlusion increase in shear stress [reactive hyperemia (RH)]. A limitation of RH-FMD is the uncontrolled nature of the RH shear stress stimulus which produces RH-FMD response variability that is independent of conduit artery endothelial function. The purpose of this study was to develop a protocol to create a uniform, targeted, and transient (40 second) shear stress stimulus and compare it to the standard RH-FMD approach. We hypothesize that incorporating arterial compression in the controlled targeted RH (CTRH) protocol will allow us to achieve a uniform target shear rate (estimate of shear stress) within and between participants. Young, healthy men and women (females n = 4, age = 22 ± 1 years; males n = 2, age = 25 ± 3 years) underwent one trial of RH-FMD and two trials of CTRH-FMD with duplex ultrasound assessment. The CTRH protocol incorporated three-minutes of ischemic handgrip exercise at 30% of participants’ maximum voluntary contraction during a five-minute occlusion to create a large forearm vasodilation and hyperemic reserve. Upon cuff release, the ensuing hyperemia was controlled with manual brachial artery compression at the antecubital fossa. A live velocity readout permitted compression adjustments to achieve the velocity required to maintain a target shear rate of 120 s-1. The cuff was re-inflated after 40s of cuff release. The RH-FMD trial followed the standard five-minute forearm occlusion protocol. The 40s average shear rate was 116.0 ± 8.8s-1 in the CTRH test and 102.1 ± 15.4 s-1 in the RH test. The CTRH test shear rate was significantly closer to the 120s-1 target; calculated as the absolute distance from target in 3s time bins over the 40s period: CTRH = 19.0 ± 3.9s-1; RH = 36.5 ± 6.7 s-1 p = 0.002. The between participant coefficient of variation (CV) for the RH 40s average shear rate was lower in the CTRH test (CTRH CV = 8.1%; RH CV = 15.1%). The within subject trial to trial CV for the CTRH 40s average shear rate was 3.0 ± 4.6%. FMD responses were similar between tests (CTRH-FMD% = 8.3 ± 1.6%; RH-FMD% = 7.6 ± 4.8%, p=0.717). These preliminary findings demonstrate the capacity for RH stimulus control. CTRH-FMD is minimally impacted by stimulus variability and may provide a clearer reflection of brachial artery endothelial function.