Change In Flow-mediated Dilation Research Articles

Calcium Channel Blockers in Restoration of Endothelial Function: Systematic Review and Meta-Analysis of Randomized Controlled Trials

Clinical evaluation of the Endothelial Function (EF) is becoming an essential step in the quality assessment of cardiovascular risk prevention and rational pharmacotherapy of cardiovascular disorders. The existing pieces of evidence suggested that Calcium Channel Blockers (CCB) can induce positive effects on impaired EF. To evaluate the effects of CCB on EF, we performed a meta-analysis of available data from randomized and placebo-controlled or other treatment-controlled clinical studies encompassing effects of CCB on EF, as measured by Flow-Mediated Dilation (FMD) of the brachial artery. The relevant clinical studies were searched by systematic exploration of the appropriate databases until November 30, 2017. A random-effect model was conducted. The primary outcome was the percentage change in FMD between the baseline and the final levels in response to investigated drugs. Fifteen randomized clinical studies with 33 arms were identified. CCB improved FMD more pronounced than thiazide diuretics - TD (3 studies, 157 participants, WMD=2.08%, 95% CI=0.35-3.80%; P=0.02). Oppositely, ACE Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) notably improved FMD if compared to CCB (CCB vs. ACEI: 5 studies, 533 participants, WMD = -1.62%, 95% CI = -2.74% to -0.50%; P=0.005; and CCB vs. ARB: 9 studies, 669 participants, WMD = -1.52%, 95% CI = -2.22% to -0.81%; P=0.0001). CCB effects on EF were similar to those evoked by beta blockers or placebo. CCB improved EF to a more prominent extent only if paralleled to TD, while inversely; ACEI and ARB were more effective in augmenting FMD.

P6205Increase in EPA/AA Ratio Predicts Improvement in Endothelial Function in Purified Eicosapentaenoic Acid-Treated Patients

Abstract Background Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are well-known for preventing cardiovascular disease. Among n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) play key roles in preventing cardiovascular diseases. However, the effects of n-3 PUFAs have been examined under conditions of simultaneous administration of EPA and DHA in the majority of clinical investigations and the effect of purified EPA is still controversial. EPA has been reported to improve endothelial dysfunction. Although several mechanisms underlying the effects of EPA on endothelial function have been demonstrated such as the modulation of lipid metabolism including increases in high-density lipoprotein (HDL) and/or decreases in triglyceride (TG) levels, decreases in cytokine production, and inhibition of inflammatory processes, the main mechanisms ameliorating endothelial function have not been fully determined. Purpose We sought to clarify the main factors associated with EPA administration that led to improved endothelial function. Methods Fifty-one consecutive patients with hypertriglyceridemia (mean ± SD age, 60±13 years) with no evidence of coronary artery disease (CAD) were prospectively enrolled and administered purified EPA (1800 mg/day). Forty-eight patients who were not administered EPA were enrolled as age- and sex-matched controls. Clinical variables such as body mass index, HbA1c, fasting glucose level, HDL, low-density lipoprotein, TG, systolic blood pressure, diastolic blood pressure, heart rate, interleukin-6, baseline diameter of the brachial artery, intima-media thickness of the brachial artery, and flow-mediated dilation (FMD) were examined before and after 6 months of treatment. Univariate and multivariate regression analyses were performed to examine the associations between FMD changes and clinical variables. Results FMD was significantly improved from 4.16% ± 1.88% to 6.30% ± 2.24% (p<0.0001) in the EPA group. The change in FMD was positively correlated with the change in EPA/arachidonic acid (AA) ratio (r=0.34, p=0.014). The multivariate regression analysis showed that the change in EPA/AA ratio alone was significantly associated with the change in FMD (p=0.010). Conclusions EPA treatment improves endothelial dysfunction in patients with hypertriglyceridemia without evidence of CAD. The change in FMD was associated with the change in EPA/AA ratio alone. These finding suggest that a direct effect of EPA on the endothelium may be the predominant factor ameliorating endothelial function. Acknowledgement/Funding This study was supported, in part, by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (15K08649).

P1573Chemotherapy-induced vasotoxicity in patients undergoing therapy for breast cancer

Abstract Background Cardiotoxicity is a well-known adverse effect of anthracycline and HER-2 monoclonal antibodies, however the vascular effects of these agents remain less-well studied. Purpose To explore the effects of breast chemotherapy on vascular function. Methods A total of 57 female patients undergoing breast diagnosed with breast cancer and scheduled for anthracycline-based and HER-2 chemotherapy were included in this study. At baseline, at 3, 6 and 12 months, patients underwent assessment of cardiac function by transthoracic echocardiography, endothelial function assessment by brachial flow mediated dilation (FMD) and assessment of arterial stiffness by carotid-radial pulse wave velocity (PWV) and augmentation index (Aix). Results There was a significant decrease in left ventricular ejection fraction (LVEF) overtime compared to baseline (A). This was paralleled by a significant decrease in brachial FMD at 6 months (B) and a significant increase in PWV compared to baseline (C). There was no significant change in Aix compared to baseline levels (D). Chemotherapy-induced cardiotoxicity (expressed by the change in LVEF) was not associated with either the change in FMD or PWV at 6 months. Conclusions Breast chemotherapy-induced cardiotoxicity is paralleled by vasotoxicity, which is manifested as endothelial dysfunction and increased arterial stiffness. Systemic vasotoxicity is not directly related to cardiotoxicity, suggesting that monitoring of both cardiac and vascular function could be useful in identifying early signs of cardiovascular toxicity.

Impact of Acipimox Therapy on Free Fatty Acid Efflux and Endothelial Function in the Metabolic Syndrome: A Randomized Trial.

Insulin resistance is associated with increased lipolysis and elevated concentrations of free fatty acids (FFA), which in turn contribute to impaired vascular function. It was hypothesized that lowering FFA with acipimox, a nicotinic acid derivative that impairs FFA efflux, would improve endothelial function, measured by flow-mediated dilation (FMD), in individuals with metabolic syndrome. A total of 18 participants with metabolic syndrome and 17 healthy controls were enrolled and treated with acipimox 250 mg orally every 6 hours or placebo for 7 days in a randomized, double-blind, crossover trial. Acipimox reduced FFA concentrations among individuals with metabolic syndrome to near normal levels (P=0.01), but there was no change among healthy controls (P=0.17). Acipimox did not improve endothelial-dependent FMD in either group (metabolic syndrome: P = 0.42; healthy controls: P = 0.16), although endothelial-independent nitroglycerin-mediated dilation among those with metabolic syndrome tended to increase (20.3%, P = 0.06). There were no changes in blood lipids or markers of inflammation following therapy. There was minimal correlation between change in FMD and baseline measures of BMI ( ρ = -0.09) or waist circumference ( ρ = -0.15). In groups with normal or elevated baseline FFA, short-term reductions do not improve endothelial function assessed by FMD.

The effects of moderate and high-intensity exercise on circulating markers of endothelial integrity and activation in young, healthy men.

Endothelial function typically exhibits a hormetic response to exercise. It is unknown whether endothelial damage occurs in response to acute exercise and could be a contributing mechanism. We sought to determine the effects of acute exercise on endothelial-derived circulating factors proposed to reflect endothelial integrity and activation. Young, healthy men (n = 10) underwent 30-min moderate continuous (MOD) and high-intensity interval (HII) cycling exercise bouts. Venous blood samples were taken immediately before and after exercise for quantification of circulating endothelial cells (CECs), circulating angiogenic cells (CACs), apoptotic and activated endothelial microvesicles (EMVs), thrombomodulin (TM), von Willebrand factor (vWF), syndecan-1, and circulating microRNAs (ci-miRs) 126-3p and 126-5p. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery before, 10 min after, and 60 min after exercise. Numbers of CECs and EMVs were unchanged by either exercise bout (P > 0.05). Numbers of all measured CAC subtypes decreased in response to MOD (21%-34%, P < 0.05), whereas only CD31+/34+/45dim/- CACs decreased following HII (21%, P < 0.05). TM and syndecan-1 increased with both exercise intensities (both ~20%, P < 0.05). HII, but not MOD, increased vWF (88%, P < 0.001), ci-miR-126-3p (92%, P = 0.009) and ci-miR-126-5p (110%, P = 0.01). The changes in several circulating factors correlated with changes in FMD following either one or both intensities. Changes in circulating factors do not support the concept of exercise-induced endothelial cell denudation, apoptosis, or activation, though slight disruption of endothelial glycocalyx and membrane integrity may occur. A related loss of mechanotransduction along with mechanisms underlying endothelial activation and ci-miR-126 secretion may relate to changes in endothelial function.NEW & NOTEWORTHY Using circulating endothelial-derived factors, we show that endothelial denudation, apoptosis, and activation do not appear to increase, whereas disrupted endothelial glycocalyx and membrane integrity may occur during both high-intensity interval and moderate intensity cycling. Increases in factors nonspecific to endothelial damage, including von Willebrand factor and microRNA-126, occurred only after high-intensity interval exercise. These results shed light on the hypothesis that disrupted endothelial integrity contributes to the endothelial function response to exercise.

Influence of dietary inorganic nitrate on blood pressure and vascular function in hypertension: prospective implications for adjunctive treatment.

Dietary inorganic nitrate (nitrate) is a promising adjunctive treatment to reduce blood pressure and improve vascular function in hypertension. However, it remains unknown if the efficacy of nitrate is dependent upon an elevated blood pressure or altered by medication in patients with hypertension. Therefore, blood pressure and vascular function, measured by passive leg movement (PLM) and flow-mediated dilation (FMD), were assessed following 3 days of placebo (nitrate-free beetroot juice) and nitrate (nitrate-rich beetroot juice) administration in 13 patients (age: 53 ± 12 yr) with hypertension taking antihypertensive medications (study 1) and in 14 patients (49 ± 13 yr) with hypertension not taking antihypertensive medications (study 2). In study 1, plasma nitrite concentration was greater for nitrate than placebo (341 ± 118 vs. 308 ± 123 nmol/L, P < 0.05), yet blood pressure and vascular function were unaltered. In study 2, plasma nitrite concentration was greater for nitrate than placebo (340 ± 102 vs. 295 ± 93 nmol/L, P < 0.01). Systolic (136 ± 16 vs. 141 ± 19 mmHg), diastolic (84 ± 13 vs. 88 ± 12 mmHg), and mean (101 ± 12 vs. 106 ± 13 mmHg) blood pressures were lower (P < 0.05), whereas the PLM change in leg vascular conductance (6.0 ± 3.0 vs. 5.1 ± 2.6 mL·min-1·mmHg-1) and FMD (6.1 ± 2.4% vs. 4.1 ± 2.7%) were greater (P < 0.05) for nitrate than placebo. The changes in systolic blood pressure (r = -0.60) and FMD (r = -0.48) induced by nitrate were inversely correlated (P < 0.05) to the respective baseline values obtained in the placebo condition. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive medication status, per se.NEW & NOTEWORTHY Dietary nitrate (nitrate) is a promising intervention to improve blood pressure and vascular function in hypertension. We demonstrate that these beneficial effects of nitrate are inversely related to the baseline value in a continuous manner with no distinction between antihypertensive medication status. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive mediation status.

Direct-acting antivirals improve endothelial function in patients with chronic hepatitis: a prospective cohort study.

Hepatitis C virus (HCV) infection is associated with increased cardiovascular risk. We evaluated effects of direct-acting antiviral agents (DAAs) on flow-mediated dilation (FMD), a recognized marker of cardiovascular risk. We evaluated FMD and post-ischemic hyperemia (PIH) in consecutive HCV out-patients before starting DAAs, at the end of treatment (Teot) and 12weeks thereafter. In 22 HCV subjects (age 64.0years), baseline FMD was 4.52% ± 1.90 and PIH of 5814.4 (IQR 3786.9-7861.9). At (Teot), all patients showed undetectable levels of HCV-RNA and FMD changed from 4.52% ± 1.90 to 9.39% ± 4.06 (p < 0.001), with a direct correlation between changes in FMD and baseline HCV-RNA levels (r = 0.494, p = 0.020). In parallel, PIH increased from 5814.4 (IQR 3786.9-7861.9) to 7277.6 (IQR 4579.8-10388.8) (p = 0.019). Twelve weeks after Teot, all patients had persistently negative HCV-RNA, FMD was 10.9% ± 4.65 and PIH was 10930.3 (IQR 6254.6-18248.2) suggesting a further significant improvement in these parameters. Results remained significant regardless of the presence of cardiovascular risk factors, whereas FMD changes were not statistically significant in subjects with cirrhosis. A persistent and significant improvement in endothelial function is observed in HCV patients obtaining viral eradication with DAAs treatment. This might suggest a beneficial effect of DAAs treatment on cardiovascular risk profile of HCV patients.

Effects of aronia berry (poly)phenols on vascular function and gut microbiota: a double-blind randomized controlled trial in adult men

Aronia melanocarpa is a rich source of (poly)phenols. Previous research has demonstrated that these berries may provide cardiovascular health benefits in high-risk populations. However, very few studies have investigated the effects of daily consumption of dietary achievable amounts of the berries in healthy subjects. The aim of this study was to investigate the effects of aronia berries on vascular function and gut microbiota composition in a healthy population. A double-blind, placebo-controlled, parallel designed study was conducted in 66 healthy men randomly allocated to consume a (poly)phenol-rich extract (116 mg, 75 g berries), a whole fruit powder (12 mg, 10 g berries), or placebo (maltodextrin) for 12 wk. Flow-mediated dilation (FMD), arterial stiffness, blood pressure, heart rate, and serum biochemistry were assessed. Plasma (poly)phenol metabolites were analyzed by LC-MS. Gut microbiota composition was determined via 16S rRNA sequencing in stool samples. Consumption of aronia whole fruit and extract powder for 12 wk led to a significant increase in FMD over control of 0.9%±0.4% (95% CI: 0.13%, 1.72%) and 1.2%±0.4% (95% CI: 0.36%, 1.97%), respectively. Acute improvements in FMD were also observed 2 h after consumption of aronia extract on day 1 (1.1%±0.3%, P=0.003) and 12 wk later (1.5%±0.4%, P=0.0001). Circulating plasma phenolic metabolites increased upon consumption of the aronia treatments. Although no changes were found in gut microbiota diversity, consumption of aronia extract increased the growth of Anaerostipes (+10.6%, P=0.01), whereas aronia whole fruit showed significant increases in Bacteroides (+193%, P=0.01). Correlation analysis identified significant associations between changes in FMD, aronia-derived phenolic metabolites, and specific gut microbial genera. In healthy men, consumption of aronia berry (poly)phenols improved endothelial function and modulated gut microbiota composition, indicating that regular aronia consumption has the potential to maintain cardiovascular health in individuals at low risk of cardiovascular disease. This trial was registered at CLINICALTRIALs.gov as NCT03041961.

Curcumin supplementation attenuates the decrease in endothelial function following eccentric exercise

[Purpose]Eccentric exercise induces a decrease in vascular endothelial function. Curcumin, a major component of turmeric, has potent antioxidant and anti-inflammatory properties that are associated with vascular protective effects. The present study examined the effect of acute supplementation of curcumin on eccentric exercise-induced endothelial dysfunction in healthy young men.[Methods]Fourteen healthy sedentary young men (range, 21–29 years) were assigned to either the curcumin (n = 6) or placebo (n = 8) group. All subjects consumed either curcumin or placebo before exercise, and eccentric exercise of the elbow flexors was performed with their nondominant arm. Before and 60 min after exercise, brachial artery flow-mediated dilation (FMD), as an indicator of endothelial function, was measured in the non-exercised arm.[Results]Brachial artery FMD significantly decreased following eccentric exercise (p < 0.05) in the placebo group, but acute supplementation with curcumin before exercise nullified this change. The change in FMD before and after eccentric exercise between the placebo and curcumin groups was significantly different (p < 0.05).[Conclusion]The present study found that acute curcumin supplementation could attenuate the decrease in endothelial function, as measured by FMD, following eccentric exercise in healthy young men.

Flow-mediated dilation shows impaired endothelial function in patients with mastocytosis

Mastocytosis is a rare disease characterized by clonal proliferation of mast cells (MCs) in different organs. Clinical manifestations of mastocytosis are mostly due to release of mediators from MCs and, in many cases, such as urticaria, flushing, angioedema, and anaphylaxis, are an expression of the biological effects of mediators on endothelial cells. Chronic secretion of mediators in patients with mastocytosis can lead to alteration of endothelial function. We sought to investigate endothelial function in patients with mastocytosis using a noninvasive technique of flow-mediated dilation (FMD). Twenty-five adult patients with indolent and advanced forms of mastocytosis and 20 healthy control subjects were enrolled in the study. Ultrasound assessment of FMD was performed by measuring changes in the diameter of the brachial artery after 5minutes of arterial occlusion. Changes in FMD were correlated with clinical parameters and serum tryptase levels. Patients with mastocytosis had lower FMD compared with healthy control subjects (P<.001). Advanced and smoldering forms showed a lower FMD compared with indolent forms (P<.001). FMD inversely correlated with age and serum tryptase levels and directly with median arterial pressure and recurrent flushing episodes. No correlation was found between FMD and osteoporosis, recurrent anaphylaxis, presence of skin lesions, and long-term antihistamine treatment. Endothelial dysfunction, as demonstrated by FMD reduction, is detectable in patients with mastocytosis and is more severe in patients with high tryptase levels and advanced disease. Endothelial function appears to be negatively influenced by MC proliferation rather than by the severity of mediator-related symptoms.

A Longitudinal Investigation On The Effect Of Age And Sex On Flow-mediated Dilation In Children

Flow-mediated dilation (FMD) is a non-invasive assessment of arterial endothelial function. Previous cross-sectional analysis suggests resting arterial diameter and FMD increase throughout childhood, with no sex-based differences in FMD until girls exceed that of boys at 17-18 years old. No previous investigations included longitudinal examinations of the change in FMD over time, between boys and girls. PURPOSE: To assess the effects of age and sex on arterial diameters and FMD in school-aged children annually over a 3-year period. We hypothesized that resting arterial diameters will be larger in boys compared to girls at every time point and will increase each year, in both sexes. We also hypothesized that there would be no difference in FMD in girls versus boys over all 3 years as all of the children were tested younger than 17-18 years. METHODS: This observational study assessed 100 participants initially aged 8.5±1.1 years, (range 6-10 years, 53 boys) annually for 3 years from the School-age Kids’ health from early Investment in Physical activity (SKIP) study. The primary outcome was brachial artery FMD, which was measured using ultrasound technology. RESULTS: One-way repeated measures ANOVA was followed up with paired-sample t-test to compare mean differences between years. Two-way repeated measures ANOVA with sex as the between subjects’ factor was used to determine interaction effects. Resting arterial diameter was largest across the cohort at year 3 (2.8±0.28mm) compared to year 1 (2.7±0.30mm, p<0.001) and year 2 (2.7±0.30mm, p<0.001). Contrary to our hypothesis, allometrically scaled FMD for boys was larger than girls (boys: 6.4±3.09, girls: 6.2±3.17mm, p=0.002) and no time differences were observed between years 1, 2 and 3 (year 1: 6.2±3.11, year 2: 6.2±3.14, year 3: 6.35±3.15%, p=0.67). On average, boys had a larger resting arterial diameter compared to girls (boys: 2.8±0.3, girls: 2.6±0.24, p=0.001). CONCLUSION: Differences observed in resting arterial diameter are driven by year 3 data and allometrically scaled FMD was larger in boys compared to girls, which may be explained by boys having larger resting arterial diameters compared to girls, and may also be accounted for by rapidly changing growth patterns in children. Funded by CIHR.

7-OR: Effect of Dapagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, on Vascular Function in Patients with Type 2 Diabetes Compared with Gliclazide

Objective: Recent studies showed that sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce the risk of cardiovascular events and mortality in patients with type 2 diabetes (T2D). However, the mechanisms underlying this effect remain unclear. We compared the effects of dapagliflozin, a SGLT2 inhibitor, with those of gliclazide on vascular function in patients with T2D. Research Design and Methods: This was a prospective, randomized, blinded-endpoint, comparative clinical trial. In 2016−2017, T2D patients treated with ≥750 mg of metformin (HbA1c, 7.5%−10.0%; n = 32) were enrolled and randomized to receive either gliclazide (30 mg/day) with uptitration, or dapagliflozin (10 mg/day) for 24 weeks. The primary endpoint was a change in flow-mediated dilation (FMD) from baseline to the end of the study. The secondary outcomes included changes in pulse wave velocity (PWV), microvascular reactivity, ankle-brachial index (ABI), and carotid intima-medial thickness (IMT). Biochemical parameters related to glucose homeostasis, atherogenic dyslipidemia, oxidative stress, and adverse events, were evaluated. Results: Glycated hemoglobin and fasting glucose levels decreased significantly in both groups. The FMD, PWV, microvascular reactivity, and ABI improved significantly in the dapagliflozin group, but not in the gliclazide group. Lipoprotein(a), oxidized LDL, and thiobarbituric acid reactive substance levels decreased, whereas LDL particle sizes increased, in the dapagliflozin group exclusively. Hypoglycemia was more common in the gliclazide group. Conclusions: Dapagliflozin therapy for 24 weeks improved vascular function, alleviated atherogenic dyslipidemia, and decreased oxidative stress in patients with T2D. Glucose independent changes in cardiometabolic risk factors may contribute to the cardiovascular benefits observed in clinical trials with SGLT2 inhibitors. Disclosure S. Lim: None. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi.

Oxygen Desaturation in Sleep Apnea is Inversely Associated with Vascular Changes Following Exercise Training

PURPOSE: Obstructive sleep apnea (OSA) is characterized by reductions in nocturnal mean O2 saturation (meanSpO2) that may increase cardiovascular disease morbidity. The extent to which exercise confers cardioprotection in overweight adults with different meanSpO2 profiles is not known. The purpose of this study was to examine the association of meanSpO2 with vascular function changes following exercise training in adults with and without OSA. METHODS: At baseline, participants underwent overnight polysomnography to determine the presence and severity of OSA. Tertile-based cut-off points were used to categorize meanSpO2 and apnea hypopnea index (AHI). Body fat was analyzed using dual energy X-ray absorptiometry. Vasoreactivity of the brachial artery was measured using flow-mediated dilation (FMD), while microcirculatory function was assessed via the total shear stress area under the curve (SSAUC) response during FMD. Body fat and vascular measures were repeated upon completion of a 6 week (3 sessions/wk; 1 hr/session) exercise training program. RESULTS: Thirty (age: 49+9 years; BMI: 32.0+3.8 kg/m2; 18 men: 12 women) adults with and without OSA completed the study. At baseline, adults in the highest tertile of meanSpO2 were younger than those in the lowest tertile (43+9 yrs vs. 53+7 yrs, p=0.017), yet no differences in vascular measures, AHI or total body fat percentage were observed across the tertiles. No changes in brachial artery diameter or FMD were observed across tertiles following exercise. However, the change in SSAUC in the highest tertile of meanSpO2 was greater, compared to the lowest tertile (13,636+15898 A.U. vs. -186+10879 A.U., p=0.041). Forward stepwise linear regression revealed that the highest tertile of meanSpO2 was a significant (F=5.15, p=0.036) determinant of the increased SSAUC with exercise, independent of age and baseline SSAUC. CONCLUSIONS: Severe oxygen desaturation during sleep was inversely associated with improvements in microcirculatory function following exercise training.

Peripheral artery endothelial function responses to altered shear stress patterns in humans.

What is the central question of this study? What is the effect of altered shear stress pattern, with or without concurrent neurohumoral and metabolic activation, on the acute endothelial function response assessed via brachial artery flow-mediated dilatation? What is the main finding and its importance? Despite generating distinctive shear stress patterns (i.e. increases in anterograde only, anterograde only with neurohumoral and metabolic activation, and both anterograde and retrograde), similar acute improvements were observed in the brachial artery flow-mediated dilatation response in all conditions, indicating that anterograde and/or turbulent shear stress might be the essential element to induce acute increases in endothelial function. Endothelial function is influenced by both the direction and the magnitude of shear stress. Acute improvements in endothelial function have mostly been attributed to increased anterograde shear, whereas results from many interventional models in humans suggest that enhancing shear stress in an oscillatory manner (anterograde and retrograde) might be optimal. Here, we determined the acute brachial artery shear stress (SS) and flow-mediated dilatation (FMD) responses to three shear-altering interventions [passive heat stress (HEAT), mechanical forearm compression (CUFF) and handgrip exercise (HGEX)] and examined the relationship between changes in oscillatory shear index (OSI) and changes in FMD. During separate visits, 10 young healthy men (22±3years old) underwent 10min of HEAT, CUFF or HGEX in their left forearm. Anterograde and retrograde SS, Reynolds number, OSI and FMD were assessed at rest and during/after each intervention. Anterograde SS increased during all interventions in a stepwise manner (P<0.05 between interventions), with the change in HGEX (∆37.7±12.2dyncm-2 , P<0.05)>CUFF (∆25.1±11.9dyncm-2 , P<0.05)>HEAT (∆14.5±7.9dyncm-2 , P<0.05). Retrograde SS increased during CUFF (∆-19.6±4.3dyncm-2 , P<0.05). Anterograde blood flow was turbulent (i.e. Reynolds number≥|2000|) during all interventions (P<0.05). The relative FMD improved after all interventions (P=0.01), and there was no relationship between ∆OSI and ∆FMD. We elicited changes in SS profiles including increased anterograde SS (HEAT and HGEX) and both increased anterograde and retrograde SS (CUFF); regardless of the SS pattern, FMD improved to the same extent. These findings suggest that the presence of anterograde and/or turbulent SS might be the key to optimizing endothelial function in acute assessment protocols.

Abstract 60: Ischemic Conditioning Improves Brachial Artery Flow Mediated Dilation in Chronic Stroke Survivors

Introduction: Brachial artery flow mediated dilation (FMD) is a well-established measure of vascular endothelial health and is pathologically low in chronic stroke survivors. Ischemic conditioning (IC) is a cardioprotective stimulus and has been shown to improve FMD and enhance motor function in healthy humans. We recently showed that IC can improve paretic muscle strength and increase self-selected walking speed in stroke survivors. These improvements could be, in part, mediated by improved peripheral vascular function and increased blood flow to the exercising muscle. The effects of IC on vascular endothelial function post-stroke have not been investigated. Hypothesis: Two weeks of IC on the paretic leg of chronic stroke survivors will improve FMD in the non-paretic brachial artery. Methods: This was a prospective, randomized, blinded and controlled pilot study. Twenty chronic stroke survivors (&gt;1-year post-stroke) received either IC (cuff inflation on the paretic leg for five minutes to 225 mmHg) or Sham IC (cuff inflation to 10 mmHg) every other day for two weeks (five on-off cycles per session). Brachial artery FMD was assessed using ultrasonography within 48 hours of the beginning and end of the intervention period. Results: Eight men and twelve women participated in this study. The mean age was 59 ± 16 years and the mean time post-stroke was 9 ± 9 years. Brachial artery FMD increased in the IC group from 6.2 ± 4.9% to 8.9 ± 3.9% (n=10; p=0.023, 2-way Repeated Measures ANOVA) while no change was observed in the Sham IC group (pre- vs. post = 3.8 ± 3.9% vs. 2.7 ± 3.1%, respectively; p=0.32, n=10). Expressed as the mean change in FMD, IC increased FMD by 2.8 ± 3.7% while no change was observed in the Sham IC group (delta FMD = -1.1 ± 3.4%; p=0.024 IC vs. IC Sham, unpaired t-test). Conclusions: Two weeks of IC increases brachial artery FMD in chronic stroke survivors. Taken together with our previous work that shows IC increases paretic muscle strength and walking speed in chronic stroke survivors, IC has the potential to improve both motor and cardiovascular function post-stroke. Future larger studies are needed to evaluate the efficacy of IC to improve stroke recovery and to identify the pathways involved which confer benefit to both the nervous and cardiovascular systems.

Association between vitamin B group supplementation with changes in % flow-mediated dilatation and plasma homocysteine levels: a randomized controlled trial.

There is limited evidence examining the association between B vitamin supplementation and improved endothelial function via lowering plasma homocysteine levels. This study investigated whether low-dose B vitamin supplementation improves endothelial dysfunction in Japanese adults with one or more components of metabolic syndrome. A randomized, controlled, crossover trial, without a washout period or blinding of subjects, was conducted from May-September, 2010. The subjects were 127 Japanese men and women aged 40–65 years who had at least one component of metabolic syndrome without medication. Participants took a supplement drink for two months but were divided into early intervention or later intervention groups. The flow-mediated dilatation, plasma homocysteine level, serum B-vitamins, and vitamin C levels were measured. A significant increase in serum B vitamins and vitamin C levels, and a reduction in plasma homocysteine levels were observed. The mean serum homocysteine level pre- and post-intervention was 9.8 and 8.2 µmol/L in the early intervention group and 10.8 and 7.4 µmol/L in the later intervention group (p<0.01). However, no significant changes in flow-mediated dilatation was found. Low-dose multivitamin supplementation including B vitamins is associated with a significant reduction in plasma homocysteine levels among patients with one or more components of metabolic syndrome. This study was registered at the University Hospital Medical Information Network (UMIN) centre, and has the identifier UMIN000004436.

The impact of acute mental stress on brachial artery flow-mediated dilation in women diagnosed with depression.

Endothelial function, assessed by flow-mediated dilation (FMD), may be transiently attenuated in healthy adults following acute mental stress. However, the impact of acute mental stress on endothelial function in the context of clinical depression is unknown. This study examined the impact of acute mental stress on FMD in women with a diagnosis of a depressive disorder. Forty-three otherwise healthy women (33 ± 14 years) participated. Brachial artery diameter and blood velocity were assessed with ultrasound. FMD was assessed immediately prior to and 15 min following the Trier Social Stress Test (TSST). The FMD protocol included 5 min of forearm cuff occlusion (pressure = 250 mm Hg), followed by release. Shear stress was estimated by calculating shear rate (SR = brachial artery blood velocity/diameter). Stress reactivity was assessed via changes in mean arterial pressure (MAP), heart rate (HR) and salivary cortisol. Results are mean ± SD. A significant stress response was elicited by the TSST [MAP, HR and salivary cortisol increased (p < 0.05)]. Neither the SR stimulus nor FMD response differed pre-versus post-stress (p = 0.124 and p = 0.641, respectively). There was a modest negative correlation between cortisol reactivity and change in FMD from pre- to post-stress (R = -0.392, p = 0.011). To conclude, acute mental stress did not consistently impair endothelial function in women diagnosed with a depressive disorder; however, higher cortisol reactivity may increase the likelihood of post-stress endothelial dysfunction. Further research is required to better understand the factors influencing the relationship between acute mental stress, cortisol and endothelial function in women with depression.

Is There an Association of Vascular Disease and Atherosclerosis in Children and Adolescents With Obesity and Non-alcoholic Fatty Liver Disease?

Carotid intima media thickness (cIMT) and brachial flow-mediated dilation (FMD) evaluated by ultrasound are non-invasive markers of atherosclerosis. Increased cIMT in adults has been correlated to early vascular damage. Several studies show similar correlations of elevated cIMT in children with obesity, hyperlipidemia, and metabolic syndrome. Additionally, several articles have correlated non-alcoholic fatty liver disease (NAFLD) with elevated cIMT, indicating early atherosclerosis. It is alarming that these vascular changes may be seen in children as young as 10 years of age. Children with NAFLD may also have an increased pulse wave velocity that correlates to increased arterial stiffness and increased left ventricular dimension, mass, and diastolic dysfunction. These articles are persuasive, indicating a correlation of Pediatric NAFLD and early vascular disease. However, study limitations include the use of elevated alanine aminotransferase (ALT) and echogenic changes on ultrasound that may have low accuracy to identify NAFLD. Ultrasound has low sensitivities and specificities for detection of NAFLD and therefore is not recommended for diagnosis. In comparison, studies that used liver biopsy or proton magnetic resonance spectroscopy to identify NAFLD did not find a correlation with elevated cIMT or reduction in FMD. Due to these conflicting findings, more studies looking at cIMT and FMD changes in children with NAFLD are needed with more accurate diagnostic methods for steatosis to identify if there truly is a correlation of increased liver steatosis to early atherosclerosis.

Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis.

Cystic fibrosis (CF) is a genetic disorder associated with vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function, and tetrahydrobiopterin (BH4) is a critical determinant of NO bioavailability. Thus the purpose of this study was to investigate the effects of oral administration of BH4 on endothelial function in patients with CF. Twenty-nine patients with CF (18 ± 8 yr old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received a 5 mg/kg dose of oral BH4 (BH4-5; n = 17) or a 20 mg/kg dose of oral BH4 (BH4-20; n = 12). On a separate visit, a subset of patients from each group was retested following a placebo (PLC; n = 9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function, and a plasma sample was obtained before and 3 h after treatment. Cultured endothelial cells were treated with plasma to assess NO bioavailability. Baseline FMD was lower in patients compared with controls (5.7 ± 3.4 vs. 8.4 ± 3.5%, respectively, P = 0.005). No change in FMD was observed following PLC or BH4-5 (∆FMD: -0.8 ± 1.9% and -0.5 ± 2.5%; P = 0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in significant improvements in FMD (∆FMD: 1.1 ± 1.4%) compared with BH4-5 ( P = 0.023) and PLC ( P = 0.017). Moreover, BH4-20 significantly decreased endothelial cell superoxide production and increased NO production. These data suggest that a single oral dose of BH4 at 20 mg/kg improves vascular endothelial function in patients with CF, likely via increased endothelial NO synthase coupling. These findings support the hypothesis that loss of BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF. NEW & NOTEWORTHY For the first time, the present study documents that a single dose of oral BH4 can improve vascular endothelial function in patients with cystic fibrosis (CF), and our in vitro data suggest this is via decreasing uncoupled nitric oxide. These data provide insight into the important role of BH4 bioactivity in vascular dysfunction and provide the foundation for further investigation into the chronic effects of BH4 treatment in patients with CF.

The association between near-infrared spectroscopy-derived and flow-mediated dilation assessment of vascular responsiveness in the arm

IntroductionFollowing a period of blood flow occlusion, the near-infrared spectroscopy (NIRS)-derived reperfusion slope of the oxygen saturation signal (StO2) is a measure of microvascular responsiveness that has been shown to be positively correlated with flow-mediated dilation (FMD) assessment of conduit artery function in the lower limb vasculature. Given that previously established differences in structure and function of the vessels in the upper compared to the lower limbs may change this relationship, investigating whether this correlation between the reperfusion slope of the StO2 and the FMD response is maintained in upper limbs is important. Accordingly, this study investigated the correlation between the reperfusion slope of the StO2 and FMD in the arm vasculature. Methods18 physically active individuals were submitted to a vascular occlusion test (VOT). Microvascular responsiveness was calculated as the NIRS-derived reperfusion slope assessed in a forearm muscle. Macrovascular responsiveness was assessed at the brachial artery and calculated as a percent of change in FMD (%FMD). ResultsA statistically significant correlation (r = 0.66; P = 0.001) was found between the reperfusion slope and %FMD response. ConclusionThe significant correlation between the reperfusion slope in the forearm muscle and %FMD in the brachial artery, reinforces the relationship between downstream and upstream vascular reactivity in healthy human limbs.