Flow-mediated Dilation In Response Research Articles

Effect of aerobic and resistance exercise training on endothelial function in individuals with overweight and obesity: a systematic review with meta-analysis of randomized clinical trials

The objective of this systematic review was to examine the effects of exercise training on endothelial function in individuals with overweight and obesity. Our review study included only randomized controlled trials (RCTs) involving adults (≥ 18 years of age) with body mass index (BMI) ≥ 25.0 kg/m2. Our search was conducted in the electronic bases MEDLINE (PubMed), Cochrane, LILACS and EMBASE and in the gray literature. We performed random-effects analyses for effect estimates and used 95% prediction intervals (95% PI) for estimating the uncertainty of the study results. There were selected 10 RCTs involving 14 groups (n = 400). The quality assessment of studies using Cochrane risk-of-bias 2 (RoB 2) tool identified some concerns. Exercise training resulted in improved flow-mediated dilation (FMD) in individuals with overweight and obesity (p < 0.001) compared to the no-exercise control group. This effect of training modalities on FMD was seen for aerobic training (p < 0.001) but not for resistance training (p = 0.051). There was no difference in FMD in response to exercise training by BMI classification (overweight, obesity, overweight + obesity), p = 0.793. The present results are consistent with the notion that aerobic exercise training elicits favorable adaptations in endothelial function in individuals with overweight and obesity. Our findings should be interpreted with caution because of the small number of studies included in this review.

High sodium intake differentially impacts brachial artery dilation when evaluated with reactive versus active hyperemia in salt resistant individuals.

This study sought to determine if high sodium (HS) intake in salt resistant (SR) individuals attenuates upper limb arterial dilation in response to reactive (occlusion) and active (exercise) hyperemia, two stimuli with varying vasodilatory mechanisms, and the role of oxidative stress in this response. Ten young, SR participants (9 males, 1 female) consumed a 7-day HS (6,900 mg/day) and a 7-day recommended sodium intake (RI: 2,300 mg/day) diet in a randomized order. On the last day of each diet, brachial artery (BA) function was evaluated via reactive (RH-FMD: 5 min of cuff occlusion) and active [handgrip (HG) exercise] hyperemia after consumption of both placebo (PL) and antioxidants (AO). The HS diet significantly elevated sodium excretion (P < 0.05), but mean arterial blood pressure was unchanged. During the PL condition, the HS diet significantly reduced RH-FMD when compared with RI diet (P = 0.01), but this reduction was significantly restored (P = 0.01) when supplemented with AO (HS + PL: 5.9 ± 3.4; HS + AO: 8.2 ± 2.7; RI + PL: 8.9 ± 4.7; RI + AO: 7.0 ± 2.1%). BA shear-to-dilation slopes, evaluated across all HG exercise workloads, were not significantly different across sodium intervention or AO supplementation. In SR individuals, HS intake impaired BA function when assessed via RH-FMD, but was restored with acute AO consumption suggesting oxidative stress as a contributor to this dysfunction. However, exercise-induced BA dilation was unaltered, potentially implicating an inability of HS intake to influence the mechanisms responsible for effectively maintaining skeletal muscle perfusion during exercise.NEW & NOTEWORTHY This study examined if high sodium (HS) intake in salt resistant (SR) individuals attenuates brachial artery (BA) flow-mediated dilation in response to reactive (occlusion) and active (exercise) hyperemia. In SR individuals, HS intake impaired reactive hyperemia-induced BA dilation, but not exercise-induced BA dilation. This finding suggests that although brachial artery nitric oxide bioavailability may be reduced following HS intake, the redundant mechanisms associated with adequate upper limb blood flow regulation during exercise are maintained.

Effect of the Menstrual Cycle on Vasodilatory Responses to Standard and Enhanced Flow‐ Mediated Dilation Stimuli

Flow‐mediated dilation (FMD) is a clinical index of endothelial health that has not revealed consistent differences between the sexes or the phases of the menstrual cycle, both of which are known to affect endothelial function. Since estradiol varies with the menstrual cycle and up‐regulates nitric oxide, a primary mediator of the FMD response, it is surprising that past studies have not revealed consistent associations between FMD and menstrual cycle phase. It may be that the standard FMD is not sensitive enough to reflect the subtle changes in endothelial function which occur across the menstrual cycle. Recent data suggest that enhanced FMD stimuli provide a potential means for detecting subtle changes in endothelial function that are not observed using the standard FMD. We hypothesized that an enhanced FMD stimulus, as elicited by 3 min of forearm occlusion concomitant with isometric handgrip exercise at 30% of maximal voluntary contraction (IEFMD), will be more responsive to menstrual cycle‐induced changes in estradiol (and therefore vasodilatory responsiveness) than the standard 5‐min FMD in young healthy women. We compared reactive hyperemic responses (%FMD) between FMD protocols (i.e. standard FMD vs. IEFMD) in eumenorrheic women (n: 4; age: 21±1.4 yrs, range: 19–22 yrs, BMI: 23.3±3.2 kg/m2, range: 20.5–26.4 kg/m2, cycle length: 29.8±1.7 days, range: 28–32 days) during the low‐estradiol early follicular phase of the menstrual cycle (EF; days 1–5) and the high‐estradiol late follicular phase (LF; days 10–14). As expected, we observed a greater %FMD in response to the IEFMD relative to the standard FMD in the EF phase (19.4±4.6% vs. 9.0±1.6% respectively, p&lt;0.05). Similarly, in the LF phase we observed a trend toward a greater %FMD in the IEFMD versus the standard FMD (13.5±5.8% vs. 7.0±0.04%, p=0.1). However, a two‐way ANOVA demonstrated no main effect of menstrual cycle phase (p=0.5), or FMD stimulus (p=0.7) on %FMD (phase x stimulus interaction: p=0.9). Therefore, these preliminary data do not support our hypothesis that an enhanced FMD stimulus involving isometric handgrip exercise is more sensitive than the standard FMD in detecting changes in endothelial function across menstrual cycle phases in young healthy women.Support or Funding InformationThis project was supported by a Natural Sciences and Engineering Research Council Discovery Grant (CWU). TEA &amp; YC were supported by the McGill Department of Kinesiology and Physical Education Graduate Excellence Fellowship.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients

BackgroundThis pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes.Methods and resultsRadial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation. Moreover, plasma levels of EET regioisomers increased during heating in healthy subjects, did not change in hypertensive patients and decreased in diabetic patients. Correlation analysis showed in the overall population that the less NO and EETs bioavailability increases during heating, the more flow-mediated dilatation is reduced. The expression and activity of sEH, measured in isolated peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated dilatation in healthy subjects and this was associated with an altered EETs release during heating.ConclusionsThese results demonstrate that an increased EETs degradation by sEH and altered NO bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hypertensive status. The hyperinsulinemic and hyperglycemic state in these patients may contribute to these alterations.Trial registration NCT02311075. Registered December 8, 2014.

Thirty minutes of handgrip exercise potentiates flow-mediated dilatation in response to sustained and transient shear stress stimuli to a similar extent.

What is the central question of this study? This study sought to determine whether enhancement of brachial artery flow-mediated dilatation (FMD) after acute exposure to a sustained elevation in shear stress is greater when the shear stress stimulus for FMD is also sustained. What is the main finding and its importance? Brachial artery FMD in response to a sustained (handgrip exercise) and transient (reactive hyperaemia) shear stress stimulus was enhanced to a similar extent 10min after a 30min handgrip exercise intervention. This suggests that prior exposure to a sustained elevation in shear stress results in a similar acute augmentation of the ability of the endothelium to transduce sustained and transient shear stress stimuli. Brief (30min) exposure of the brachial artery (BA) to a sustained elevation in shear stress has been shown to potentiate subsequent BA flow-mediated dilatation (FMD) in response to a transient shear stress stimulus [reactive hyperaemia (RH) FMD]. It is unknown whether matching the sustained shear stress exposure to a subsequent sustained shear stress stimulus for FMD [via handgrip exercise (SS-FMD)] might enhance the potentiation of FMD. The purpose of the study, therefore, was to assess the impact of a 30min handgrip exercise intervention-induced elevation in shear stress on subsequent BA SS-FMD versus RH-FMD. Nineteen healthy men (22±3years) preformed a 30min rhythmic handgrip exercise intervention on two experimental days. BA-FMD was assessed using either an RH or a 6min sustained shear stress stimulus created via handgrip exercise (order of visits counterbalanced) at three time points: pre-intervention and 10 and 60min post-intervention. The FMD was assessed using duplex ultrasound. Shear stress was estimated as shear rate (SR=BA blood velocity/BA diameter). Data are mean±SD. Both SS and RH-FMD increased from pre-intervention to 10min post-intervention [SS-FMD (6min average), from 0.11±0.05 to 0.16±0.08mm; P=0.008; Cohen's d = 0.66; and RH-FMD, from 0.25±0.1 to 0.32±0.11mm; P=0.013; Cohen's d = 0.68]. The magnitude of enhancement in RH and SS-FMD did not differ (change in RH versus SS-FMD pre- versus 10min post-intervention, P=0.344). These findings suggest that exposure to elevated shear stress via 30min of handgrip exercise potentiates subsequent FMD in response to sustained and transient elevations in shear stress to a similar extent.

The impact of menstrual phase on brachial artery flow-mediated dilatation during handgrip exercise in healthy premenopausal women.

What is the central question of this study? The aim of this study was to determine the influence of menstrual phase on flow-mediated dilatation in response to sustained, exercise-induced increases in shear stress. What is the main finding and its importance? We showed, for the first time, that in healthy, premenopausal women the flow-mediated dilatation stimulated by exercise-induced increases in shear stress did not fluctuate across two phases of the menstrual cycle, despite significant fluctuations in oestrogen. This suggests that endothelial function is not consistently augmented in the high-oestrogen phase. Flow-mediated dilatation (FMD) in response to a sustained shear-stress stimulus (e.g. via handgrip exercise; HGEX) is emerging as a useful tool for assessing endothelial function; however, the impact of menstrual phase on HGEX-FMD is unknown. The purpose of this study was to determine whether HGEX-FMD fluctuates with cyclical changes in oestrogen concentrations over two discrete phases (low and high oestrogen) of the menstrual cycle. Brachial artery (BA) diameter and blood velocity were assessed with two-dimesional and Doppler ultrasound, respectively. Shear stress was estimated using shear rate (SR=BA blood velocity/BA diameter). Participants (12 healthy, regularly cycling women, 21±2years of age) completed two experimental visits: (i) low oestrogen (early follicular, EF); and (ii) high oestrogen (late follicular, LF). Reactive hyperaemia-stimulated FMD (RH-FMD) and HGEX-FMD (6min of handgrip exercise) were assessed during each visit. Results are mean values±SD. Oestrogen increased from the EF to LF phase (EF, 33±9pgml-1 ; LF, 161±113pgml-1 , P=0.003). However, neither the SR stimuli (HGEX, P=0.501; RH, P=0.173) nor the FMD responses differed between phases (EF versus LF: HGEX-FMD, 4.8±2.8 versus 4.6±2.2%, P=0.601; RH-FMD, 7.9±4.3 versus 6.4±3.1%, P=0.071). These results extend existing RH-FMD findings indicating that not all women experience fluctuations in FMD with the menstrual cycle. Further research is needed to investigate the mechanisms that underlie variability in the impact of menstrual phase on FMD.

Physiological role of endothelin-1 in flow-mediated vasodilatation in humans and impact of cardiovascular risk factors.

The current study addressed the hypothesis that the local decrease in endothelin-1 (ET-1) bioavailability during sustained flow increases contributes to endothelium-dependent, flow-mediated dilatation (FMD) of conduit arteries and is altered in presence of cardiovascular risk factors. In nine young healthy individuals, the decrease in local ET-1 plasma levels and radial artery FMD in response to hand skin heating (from 34 to 44 °C) was not affected by endothelin type A (ETA) receptor blockade, achieved using the brachial infusion of BQ-123 (100 nmol/min per l of forearm), as compared with physiological saline (0.9% NaCl) infusion. In contrast, endothelin type B (ETB) receptor blockade with BQ-788 (10 nmol/min per l) suppressed the decrease in plasma ET-1 during heating and reduced FMD, without altering nitric oxide release. The coinfusion of BQ-123 did not affect the inhibitory effect of ETB receptor blockade on the decrease in ET-1 plasma levels during heating but prevented the reduction in FMD. Basal radial artery parameters, systemic hemodynamics, and endothelium-independent dilatation to glyceryl trinitrate were not modified by ETA and/or ETB blockade. In a general population of 40 participants without treatment or major cardiovascular diseases, including the nine healthy individuals, the reduction in endothelin-1 level during heating was correlated with FMD (r = -0.55, P < 0.001) and decreased with increased age (r = 0.49, P = 0.001), mean arterial blood pressure (r = 0.48, P = 0.002), and total cholesterol level (r = 0.37, P = 0.024). The uptake of endothelin-1 by ETB receptors contributes to conduit artery FMD, preventing its vasoconstrictor action mediated by ETA receptors. The alteration of this mechanism by cardiovascular risk factors may contribute to endothelial dysfunction.

Examining Endothelial Function and Platelet Reactivity in Patients with Depression before and after SSRI Therapy.

Although it is recognized that patients with major depressive disorder (MDD) are at increased risk of developing cardiovascular disease (CVD) the mechanisms responsible remain unknown. Endothelial dysfunction is one of the first signs of CVD. Using two techniques, flow-mediated dilatation in response to reactive hyperemia and laser Doppler velocimetry with iontophoresis, we examined endothelial function in the forearm before and after serotonin-specific reuptake inhibitor (SSRI) treatment in 31 patients with MDD. Measurement of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, soluble P-selectin, and noradrenaline in plasma was also performed. Prior to treatment, markers of endothelial and vascular function and platelet reactivity were within the normal range. Following SSRI therapy (95 ± 5 days) symptoms of depression were reduced (paired difference between pre- and post-treatment Hamilton rating −18 ± 1, P < 0.001) with 19 patients recovered and 4 remitted. There occurred no significant change in markers of endothelial or vascular function following SSRI therapy. The improvement in Hamilton depression rating in response to therapy could be independently predicted by the baseline arterial plasma noradrenaline concentration (r2 = 0.36, P = 0.003). In this cohort of patients with MDD, SSRI therapy did not influence endothelial function or markers of vascular or platelet reactivity. Patient response to SSRI therapy could be predicted by the initial circulating level of noradrenaline, with noradrenaline levels being lower in responders.

Mineralocorticoid receptors modulate vascular endothelial function in human obesity

Obesity increases linearly with age and is associated with impaired vascular endothelial function and increased risk of cardiovascular disease. MRs (mineralocorticoid receptors) contribute to impaired vascular endothelial function in cardiovascular disease; however, their role in uncomplicated human obesity is unknown. Because plasma aldosterone levels are elevated in obesity and adipocytes may be a source of aldosterone, we hypothesized that MRs modulate vascular endothelial function in older adults in an adiposity-dependent manner. To test this hypothesis, we administered MR blockade (eplerenone; 100 mg/day) for 1 month in a balanced randomized double-blind placebo-controlled cross-over study to 22 older adults (ten men, 55-79 years) varying widely in adiposity [BMI (body mass index): 20-45 kg/m²], but who were free from overt cardiovascular disease. We evaluated vascular endothelial function [brachial artery FMD (flow-mediated dilation)] via ultrasonography) and oxidative stress (plasma F2-isoprostanes and vascular endothelial cell protein expression of nitrotyrosine and NADPH oxidase p47phox) during placebo and MR blockade. In the whole group, oxidative stress (P>0.05) and FMD did not change with MR blockade (6.39 ± 0.67 compared with 6.23 ± 0.73%; P=0.7). However, individual improvements in FMD in response to eplerenone were associated with higher total body fat (BMI: r=0.45, P=0.02; and dual-energy X-ray absorptiometry-derived percentage body fat: r=0.50, P=0.009) and abdominal fat (total: r=0.61, P=0.005; visceral: r=0.67, P=0.002; and subcutaneous: r=0.48, P=0.03). In addition, greater improvements in FMD with eplerenone were related to higher baseline fasting glucose (r=0.53, P=0.01). MRs influence vascular endothelial function in an adiposity-dependent manner in healthy older adults.

Response to Effect of Fenofibrate on Vascular Endothelial Function: Statistical Appraisal and its Validity

We recently published an original research article reporting that short-term fenofibrate improves flow-mediated dilation (FMD) in healthy normolipidemic older adults.1 By assessing the response to vitamin C infusion before and after fenofibrate treatment, we determined that the mechanism for the improvements in FMD was reduced oxidative stress. We also assessed the influence of changes in clinical characteristics on the improvements in FMD. On the basis of these analyses, we concluded that oxidative stress was the primary mechanism for the improvements in FMD in response to fenofibrate. In a letter to the editor, Dr Kawada2 recently stated concerns about our statistical analyses. Specifically, there was a concern that the distributions for circulating factors may not be normal. In …

Effect of hawthorn standardized extract on flow mediated dilation in prehypertensive and mildly hypertensive adults: a randomized, controlled cross-over trial

BackgroundHawthorn extract has been used for cardiovascular diseases for centuries. Recent trials have demonstrated its efficacy for the treatment of heart failure, and the results of several small trials suggest it may lower blood pressure. However, there is little published evidence to guide its dosing. The blood pressure lowering effect of hawthorn has been linked to nitric oxide-mediated vasodilation. The aim of this study was to investigate the relationship between hawthorn extract dose and brachial artery flow mediated dilation (FMD), an indirect measure of nitric oxide release.MethodsWe used a four-period cross-over design to evaluate brachial artery FMD in response to placebo or hawthorn extract (standardized to 50 mg oligomeric procyanidin per 250 mg extract). Randomly sequenced doses of hawthorn extract (1000 mg, 1500 mg, and 2500 mg) and placebo were assigned to each participant. Doses were taken twice daily for 3 1/2 days followed by FMD and a 4-day washout before proceeding to the next dosing period.ResultsTwenty-one prehypertensive or mildly hypertensive adults completed the study. There was no evidence of a dose-response effect for our main outcome (FMD percent) or any of our secondary outcomes (absolute change in brachial artery diameter and blood pressure). Most participants indicated that if given evidence that hawthorn could lower their blood pressure, they would be likely to use it either in conjunction with or instead of lifestyle modification or anti-hypertensive medications.ConclusionWe found no evidence of a dose-response effect of hawthorn extract on FMD. If hawthorn has a blood pressure lowering effect, it is likely to be mediated via an NO-independent mechanism.Trial RegistrationThis trial has been registered with ClinicalTrials.gov, a service of the U.S. National Institutes of Health: NCT01331486.

Epoxyeicosatrienoic Acids Contribute With Altered Nitric Oxide and Endothelin-1 Pathways to Conduit Artery Endothelial Dysfunction in Essential Hypertension

We sought to clarify, using functional and biological approaches, the role of epoxyeicosatrienoic acids, nitric oxide (NO)/reactive oxygen species balance, and endothelin-1 in conduit artery endothelial dysfunction during essential hypertension. Radial artery diameter and mean wall shear stress were determined in 28 untreated patients with essential hypertension and 30 normotensive control subjects during endothelium-dependent flow-mediated dilatation induced by hand skin heating. The role of epoxyeicosatrienoic acids and NO was assessed with the brachial infusion of inhibitors of cytochrome P450 epoxygenases (fluconazole) and NO synthase (N(G)-monomethyl-l-arginine [L-NMMA]). Compared with controls, hypertensive patients exhibited a decreased flow-mediated dilatation in response to postischemic hyperemia as well as to heating, as shown by the lesser slope of their diameter-shear stress relationship. In controls, heating-induced flow-mediated dilatation was reduced by fluconazole, L-NMMA, and, to a larger extent, by L-NMMA+fluconazole. In patients, flow-mediated dilatation was not affected by fluconazole and was reduced by L-NMMA and L-NMMA+fluconazole to a lesser extent than in controls. Furthermore, local plasma epoxyeicosatrienoic acids increased during heating in controls (an effect diminished by fluconazole) but not in patients. Plasma nitrite, an indicator of NO availability, increased during heating in controls (an effect abolished by L-NMMA) and, to a lesser extent, in patients, whereas, inversely, reactive oxygen species increased more in patients (an effect diminished by L-NMMA). Plasma endothelin-1 decreased during heating in controls but not in patients. These results show that an impaired role of epoxyeicosatrienoic acids contributes, together with an alteration in NO/reactive oxygen species balance and endothelin-1 pathway, to conduit artery endothelial dysfunction in essential hypertension. https://www.eudract.ema.europa.eu. Unique identifier: RCB2007-A001-10-53.

The Association between Flow-Mediated Dilation and Oxidative Stress in Response to Acute Exercise

A single bout of exercise has been used experimentally to investigate flow-mediated dilation (FMD) in response to acute physiological stress. We have previously observed the contribution of chronic physical activity (PA) in modulating the post exercise FMD response; however, the influence of oxidative stress has not been determined. Moreover, independent of PA status, some individuals exhibited a transient improvement in FMD (responder) while attenuation in FMD was observed in others (non-responder). PURPOSE: We sought to identify the association between oxidative stress and FMD in response to acute exercise in overweight men grouped by 1) PA status and 2) responders or non-responders. METHODS: FMD and TBARS were assessed in 14 overweight men at baseline and 1 hour following a single bout of moderate intensity (50% VO2peak) treadmill walking for 45 minutes. Of the 14 men, 7 were sedentary and 7 were active; 8 were non-responders and 6 were responders. RESULTS: No differences (p>0.05) in baseline FMD (8.2±1.2 vs. 6.1±1.2) or TBARS (17.4±2.5 vs. 17.8±3.1) was observed between the sedentary and active groups, respectively. Similar findings were observed between the responders and non-responders. An improvement in FMD following acute exercise was observed in both the active and responders groups, whereas a decrease in FMD was observed in the sedentary and non-responding groups. Controlling for baseline FMD, no differences in the TBARS response to acute exercise was observed between the sedentary (-1.2±1.0) and active group (-0.8±2.1); however, a significant (p=0.011) group × time interaction was observed such that the responders exhibited a reduction in TBARS (18.1±2.8 to 14.6±3.3), whereas an increase in TBARS (16.9±2.6 to 18.5±3.1) was observed in the non-responders. CONCLUSION: Oxidative stress in response to acute exercise does not appear to contribute to the FMD response in overweight active and sedentary men; however, when stratifying the same subjects into responders and non-responders, the FMD response appears to be associated with changes in oxidative stress. Supported in part by Gatorade Sports Science Institute and Indiana University HPER Research Grants.

Endothelial Function, Carotid–Femoral Stiffness, and Plasma Matrix Metalloproteinase-2 in Men With Bicuspid Aortic Valve and Dilated Aorta

This study sought to examine the relationship between proximal aortic dilation and systemic vascular function in men with bicuspid aortic valve (BAV). Proximal aortic dilation in subjects with BAV is associated with structural and functional abnormalities in the ascending aorta. We studied 32 men (median age 31 years [range 28 to 32 years]) with nonstenotic BAV categorized into 2 subgroups according to proximal ascending aorta dimensions (nondilated <or=35 mm and dilated >or=40 mm, respectively). Sixteen healthy men were studied as control subjects. Flow-mediated dilation in response to hyperemia (a marker of endothelial dysfunction) and carotid-femoral pulse wave velocity (an index of aortic stiffness) were assessed, and peripheral blood was sampled for matrix metalloproteinases (MMP-2 and -9) and their tissue inhibitors (TIMP-1 and -2), respectively. Cardiac chamber and aortic dimensions were assessed by echocardiography and cardiac magnetic resonance imaging, respectively. Despite the similar severity of aortic stenosis, left ventricular mass, and function, men with dilated aortas had blunted brachial flow-mediated vasodilation to hyperemia (5% [interquartile range (IQR) 4% to 6%] vs. 8% [IQR 7% to 9%] change, p = 0.001), higher carotid-femoral pulse wave velocity (9.3 cm/s [IQR 9 to 10 cm/s] vs. 7 cm/s [IQR 6.9 to 7.4 cm/s], p = 0.001), and significantly higher plasma levels of MMP-2 (1,523 [IQR 1,460 to 1,674] vs. 1,036 [IQR 962 to 1,167], p = 0.001) compared with men with BAV and nondilated aorta. Values for MMP-9, TIMP-1 and -2 levels, and nitroglycerin-induced (endothelium-independent) vasodilation were similar in all 3 groups. Young men with BAV and dilated proximal aortas manifest systemic endothelial dysfunction, increased carotid-femoral pulse wave velocity, and higher plasma levels of MMP-2. These observations could introduce new targets for screening and perhaps for therapeutic intervention.

Nitric oxide is not obligatory for radial artery flow-mediated dilation following release of 5 or 10 min distal occlusion

This study investigated the nitric oxide (NO) dependence of radial artery (RA) flow-mediated dilation (FMD) in response to three different reactive hyperemia (RH) shear stimulus profiles. Ten healthy males underwent the following three RH trials: 1) 5 min occlusion (5 trial), 2) 10 min occlusion (10 trial), and 3) 10 min occlusion with cuff reinflation at 30 s (10-30 trial). Trials were performed during saline infusion and repeated during N(G)-monomethyl-L-arginine (L-NMMA) infusion in the brachial artery. RA blood flow velocity was measured with Doppler ultrasound, and B-mode RA images were analyzed using automated edge detection software. Shear rate estimation of shear stress was calculated as the blood flow velocity/vessel diameter. L-NMMA decreased baseline vascular conductance by 35%. L-NMMA infusion did not affect the peak shear rate stimulus (P = 0.681) or the area under the curve (AUC) of shear rate to peak FMD (P = 0.088). The AUC was significantly larger in the 10 trial vs. the 10-30 or 5 trial (P < 0.001). Although percent FMD (%change in diameter) in the 10 trial was larger than that in the 5 trial (P = 0.035), there was no significant difference in %FMD between the saline and L-NMMA conditions in any trial: 5 trial, 5.62 +/- 1.48 vs. 5.63 +/- 1.27%; 10 trial, 9.07 +/- 1.16 vs. 11.22 +/- 2.21%; 10-30 trial, 6.52 +/- 1.43 vs. 7.98 +/- 1.51% for saline and L-NMMA, respectively (P = 0.158). We conclude the following: 1) RH following 10 min of occlusion results in an enhanced stimulus and %FMD compared with 5 min of occlusion. 2) When the occlusion cuff is reinflated 30 s postrelease of a 10 min occlusion, it does not result in an enhanced %FMD compared with that which results from RH following 5 min of occlusion. 3) The lack of effect of L-NMMA on FMD suggests that NO may not be obligatory for radial artery FMD in response to either 5 or 10 min of occlusion in healthy volunteers.

The effect of oral antioxidants on brachial artery flow-mediated dilation following 5 and 10 min of ischemia

In light of the current methodological developments in flow-mediated dilation (FMD) testing and the recognition that oxidative stress may play an important role in regulating this process, the present study sought to: (1) compare flow-mediated dilation (FMD) following 5 and 10 min of forearm cuff occlusion, and (2) evaluate the role of oxidative stress on vasodilation, both distal and proximal to the cuff. Of the 14 subjects studied, 6 partook solely in a validation study of the antioxidant cocktail (AOC; vitamins C, E, and alpha-lipoic acid), while the remaining 8 subjects underwent FMD assessment in response to 5 and 10 min of forearm occlusion following ingestion of AOC or placebo. Although the efficacy of the AOC was clearly documented by elevated plasma ascorbate levels (approximately 95%) and a reduced free radical concentration (approximately 65%), no effects of acute oral antioxidants were observed. FMD was significantly augmented in response to 10 min of forearm occlusion when compared to 5 min, whether expressed as % change (10.1 +/- 2 vs. 4.5 +/- 1%, respectively) or absolute change in diameter (0.035 +/- 0.005 vs. 0.018 +/- 0.005 cm, respectively). Additionally, post-occlusion shear rate (28,640 +/- 2,799 vs. 18,629 +/- 1,724/s, AUC), FMD/shear rate (approximately 50%), and time to peak dilation (68 +/- 7 vs. 53 +/- 8 s) were greater following 10 min of occlusion. In contrast to previous studies, this investigation has identified a greater brachial artery FMD in response to 10 versus 5 min of forearm ischemia, which appears to be unexplained by oxidative stress.

Effects of Carnitine Supplementation on Flow-Mediated Dilation and Vascular Inflammatory Responses to a High-Fat Meal in Healthy Young Adults

Because carnitine has been shown to decrease oxidative stress and improve endothelial cell functioning, we examined the effects of carnitine supplementation on postprandial flow-mediated dilation (FMD) and circulating biomarkers of inflammation and oxidative stress after a high-fat meal. A randomized, double-blind, placebo-controlled, crossover study design was used. Thirty men and women (age 30 +/- 8 year, body mass 72.9 +/- 17.1 kg, body fat 13.0 +/- 6.4%) participated in 2 vascular testing days, each preceded by 3 weeks of supplementation with either 2 g/day of L-Carnitine (L-Carnitine L-Tartrate) or placebo with a 3- to 5-week washout period between trials. Brachial artery FMD in response to 5 minutes of upper arm occlusion and circulating markers of oxidative stress and inflammation were measured in the fasting state and after a standardized high-fat meal. After 3 weeks of supplementation, peak FMD in the fasting state was similar between the carnitine and placebo trials, averaging 6.6%. Peak FMD during the postprandial period decreased to 5.8% at 1.5 hours during placebo and increased to 7.7% during the carnitine trial (n = 30: p = 0.043 for supplement by time interaction effect). This improvement in postprandial vascular function was most dramatic in subjects who showed a decrease in peak FMD in response to the meal (n = 15: p = 0.003 for supplement by time interaction effect). There was a significant increase in postprandial lipemia and plasma interleukin-6 but no effect of supplementation. There were no significant postprandial changes or supplement effects for plasma tumor necrosis factor-alpha and malondialdehyde. In conclusion, consistent with other work showing a beneficial effect of carnitine on vascular function, these findings indicate that carnitine supplementation in healthy individuals improves postprandial FMD after a high-fat meal.

Flow‐mediated dilatation in the superficial femoral artery is nitric oxide mediated in humans

Flow-mediated dilatation (FMD) of the brachial and radial arteries is an important research tool for assessment of endothelial function in vivo, and is nitric oxide (NO) dependent. The leg skeletal muscle vascular bed is an important territory for studies in exercise physiology. However, the role of endothelial NO in the FMD response of lower limb arteries has never been investigated. The purpose of this study was to examine the contribution of NO to FMD in the superficial femoral artery in healthy subjects. Since physical inactivity may affect endothelial function, and therefore NO availability, spinal cord-injured (SCI) individuals were included as a model of extreme deconditioning. In eight healthy men (34 +/- 13 years) and six SCI individuals (37 +/- 10 years), the 5 min FMD response in the superficial femoral artery was assessed by echo-Doppler, both during infusion of saline and during infusion of the NO synthase blocker N(G)-monomethyl-L-arginine (L-NMMA). In a subset of the controls (n = 6), the 10 min FMD response was also examined using the same procedure. The 5 min FMD response in controls (4.2 +/- 0.3%) was significantly diminished during L-NMMA infusion (1.0 +/- 0.2%, P < 0.001). In SCI, L-NMMA also significantly decreased the FMD response (from 8.2 +/- 0.4% during saline to 2.4 +/- 0.5% during L-NMMA infusion). The hyperaemic flow response during the first 45 s after cuff deflation was lower in both groups during infusion of L-NMMA, but the effect of L-NMMA on FMD persisted in both groups after correction for the shear stress stimulus. The 10 min FMD was not affected by L-NMMA (saline: 5.4 +/- 1.6%, L-NMMA: 5.6 +/- 1.5%). Superficial femoral artery FMD in response to distal arterial occlusion for a period of 5 min is predominantly mediated by NO in healthy men and in the extremely deconditioned legs of SCI individuals.

Reply to Drs. Harris and Padilla

Reply : We welcome the recent letter from Harris and Padilla ([4][1]) and are hopeful that the proposed analysis of covariance (ANCOVA) approach to normalize flow-mediated dilation (FMD) for shear stimulus might provide an advancement of importance in this area. FMD in response to a 5-min forearm

Reproducibility of the Flow-Mediated Dilation Response to Acute Exercise in Overweight Men

Flow-mediated dilation (FMD) has been established as a reliable noninvasive measurement of endothelial function. The reproducibility of FMD under resting conditions has previously been reported; however, the reproducibility of FMD in response to exercise remains to be investigated. On two separate days, we determined if flow-mediated dilation is reproducible in response to acute exercise in nine overweight men. Following pre-exercise FMD measurements, subjects were asked to walk on a treadmill for 45 min at 50% of their VO 2peak. Subsequently, FMD was measured immediately, and every hour for 3 h thereafter. Reproducibility of FMD following exercise was assessed utilizing: (1) a two-way analysis of variance (ANOVA), (2) Intraclass correlation coefficients (ICC), (3) Pearson correlations (r), and (4) coefficient of variation (CV %) and coefficient of variation prime (CV’) for FMD at each time-period. Four acceptable reproducibility assessments were required to confirm FMD reproducibility in response to acute exercise. No differences (F 1,8 = .01; p = 0.942) in FMD were observed between trials collapsing for time. All the ICC FMD fell within the reproducible criterion set and are as follows: pre-exercise 0.602, immediately post 0.840, 1 h post 0.632, 2 h post 0.724 and 3 h post 0.631. The correlation and the average CV% for FMD between trials was 0.579% and 25.2%, respectively. The FMD response to an acute bout of moderate treadmill exercise appears to be as reproducible as FMD measured during resting conditions. The findings of the present study support the use of FMD as an outcome variable in response to acute exercise. (E-mail: harrisra@indiana.edu)