Improvement In Flow-mediated Vasodilation Research Articles

Effects of Interval Cycle Training With or Without Strength Training on Vascular Reactivity in Heart Failure Patients

Background Exercise training confers beneficial effects on vascular reactivity in patients with chronic heart failure (CHF). This randomized study compares the effects of interval cycle training combined with strength training versus interval training alone on vascular reactivity in CHF patients. Methods Twenty-eight consecutive stable CHF patients (23 males, 53 ± 10 years, 28.4 ± 4.1 kg/m 2, left ventricular ejection fraction of 37 ± 12%) were randomly assigned to 3 times’ weekly training sessions for 3 months, consisting of a) 40 minutes of interval cycle training (n = 14), versus b) 20 minutes of similar interval training plus 20 minutes of strength training of the quadriceps, hamstrings, muscles of the shoulder and biceps brachialis (n = 14). The work/recovery ratio of each session was 30/60 seconds. The intensity of interval training was set at 50% of the peak workload achieved at the steep ramp test (consisted of a 25-Watt increase on a cycle ergometer every 10 seconds until exhaustion). All patients underwent maximal, symptom-limited cardiopulmonary exercise testing and ultrasound evaluation of vascular reactivity by flow-mediated vasodilation (FMD) before and after the program. Results A significant improvement in FMD was observed in the combined training group ( P = 0.002), in contrast to the interval training alone group ( P = NS); the improvement was significantly greater in the combined training than in the interval training alone group ( P < .05). Peak oxygen uptake increased significantly and similarly in both groups, in the interval training group ( P = .03), and in the combined training group ( P = .006). No significant correlation was found between FMD improvement and cardiopulmonary exercise parameters. Conclusions A combined high-intensity, interval cycle exercise with strength training induces a greater beneficial effect on vascular reactivity rather than interval exercise training alone in CHF patients.

Berberine-induced decline in circulating CD31+/CD42− microparticles is associated with improvement of endothelial function in humans

Elevated circulating endothelial microparticles (EMPs) are associated with endothelial dysfunction. This study is to investigate whether berberine-induced fall in circulating EMPs facilitates improvement of endothelial function in healthy subjects. Fourteen healthy subjects received 1-month berberine therapy (1.2 g/d) and 11 healthy subjects served as control. Circulating EMPs were measured by flow cytometric analysis before and after therapy. Brachial artery endothelium-dependent and -independent function was assessed by flow-mediated vasodilation (FMD) and sublinqual nitroglyceride-mediated vasodilation (NMD). In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated by EMPs (106/ml) with or without the presence of berberine (10 μM). Intracellular endothelial nitric oxide synthase (eNOS) protein expression was detected by flow cytometry. After berberine therapy, circulating CD31+/CD42− microparticles were reduced, which was in parallel with the improvement of flow-mediated vasodilation while nitroglyceride-mediated vasodilation kept unchanged. A robust relationship was found between drop of circulating CD31+/CD42− microparticles and increased flow-mediated vasodilation. The EMPs in vitro led to diminished eNOS protein expression in HUVECs and this EMP-mediated detrimental effect was markedly inhibited by berberine. Berberine-induced decline in circulating CD31+/CD42− microparticles contributes to upregulation of endothelial function in healthy subjects. Deceasing EMPs may be a novel therapeutic target for the improvement of endothelial dysfunction in humans.

Effects of rituximab treatment on endothelial dysfunction, carotid atherosclerosis, and lipid profile in rheumatoid arthritis

Increased cardiovascular mortality has been associated with rheumatoid arthritis (RA). There have been reports indicating that tumor necrosis factor blockers may exert favorable but transient effects on lipid profile, flow-mediated vasodilation (FMD) of the brachial artery, and common carotid intima-media thickness (ccIMT) in RA. In this study, we assessed the effects of rituximab on FMD, ccIMT, and lipid profile. Five female RA patients received two infusions of 1000 mg rituximab i.v. High-resolution B-mode ultrasound was used to assess brachial FMD and ccIMT. We also determined plasma total cholesterol (TC), HDL-C, LDL-C, and triglyceride (Tg) levels. Assessments were performed at baseline, as well as at weeks 2, 6, and 16 after the first infusion. Rituximab (RTX) treatment resulted in a rapid and sustained improvement in FMD. The mean improvement was 30%, 22%, and 81% at weeks 2, 6, and 16, respectively. RTX had little effect on atherosclerosis within this short period of time; however, we observed 10%, 9%, and 2% decreases in ccIMT at weeks 2, 6, and 16, respectively. RTX therapy resulted in 3-11% decrease in TC, as well as 14-35% increase in HDL-C levels. Two infusions of RTX exerted early and sustained favorable effects on endothelial dysfunction, as well as plasma TC and HDL-C levels. RTX may also decrease ccIMT; however, longer follow-up is needed to assess the prolonged effects of RTX on vascular function and lipid profile in RA patients.

Clinical Summaries

Clinical Summaries

Flow-mediated dilation in patients with coronary artery disease is enhanced by high dose atorvastatin compared to combined low dose atorvastatin and ezetimibe: Results of the CEZAR study

BackgroundEffects independent from cholesterol reduction on vascular function are considered to importantly contribute to the beneficial effects of statin therapy in cardiovascular disease. We aimed to evaluate the effect of high versus low dose atorvastatin on endothelial dysfunction in patients with coronary artery disease (CAD) in a setting of comparable cholesterol reduction. Methods and resultsFifty-eight patients with CAD were randomly assigned to double-blind treatment for 8 weeks with atorvastatin 80mg per day (A80) or atorvastatin 10mg+ezetimibe 10mg per day (A10E10), respectively. Flow-mediated vasodilation (FMD) of the brachial artery, nitroglycerin-mediated endothelium-independent vasodilation (NMD), lipid, C-reactive protein (CRP) plasma concentrations and urinary 8-iso-prostaglandin F2alpha excretion were measured before and after treatment. Total cholesterol, triglycerides and LDL-cholesterol levels were significantly reduced with no difference between A80 and A10E10. A80 caused significantly stronger improvement of FMD compared to A10E10 (absolute change FMD: A80+2.7±3.0% (post vs. pre p<0.001), A10E10+0.6±2.9% (post vs. pre p=0.25), A80 vs. A10E10 p=0.018). NMD was improved by A80 but not by A10E10 (absolute change NMD: A80+2.7±4.6%, A10E10+0.7±3.5%, p=0.12). Both treatment groups caused a comparable reduction of CRP and did not effect urinary 8-iso-prostaglandin F2alpha excretion. There was no correlation between FMD or NMD change and LDL-cholesterol change in either treatment group. ConclusionsThe present findings clearly suggest that in the presence of comparable LDL-lowering effects of both treatment forms, LDL-cholesterol independent effects of high dose atorvastatin therapy account for the improvement of endothelium-dependent vasodilation in patients with stable CAD.

Effects of n‐3 PUFA supplementation with or without low‐calorie cranberry juice cocktail on flow‐mediated vasodilation in men

Consumption of fish as well as fruits and vegetables have been shown to have favorable effects on CVD risk. The present study was therefore undertaken in order to compare the effects of fish oil (FO) w/wo cranberry juice cocktail (CJC) supplementation on flow‐mediated vasodilation (FMD) in men. A group of 53 men was divided into 4 groups: 1) placebo, n=11, 2) 500 mL/day CJC, n=13, 3) 2.4 g/day of FO, n=15 and 4) CJC+FO, n=14. Before and after the intervention, FMD was measured by ultrasound echography of the brachial artery at 60 and 90 seconds after hyperemia. We found no difference in baseline brachial artery diameter (AD), FMD60 and FMD90 between the four groups. We noted that FMD60 (1.2 ± 1.8 %, p=0.029) and FMD90 (+2.5 ± 3.2 %, p=0.013) were significantly improved following the intervention in CJC+FO individuals only. CJC subjects showed no improvement in FMD but displayed a significantly increased resting brachial AD (+0.20 ± 0.24 mm, p=0.013) after the intervention. We also found that changes in FMD60 and FMD90 were negatively associated with brachial AD. In summary, we found that CJC+FO supplementation improved FMD in healthy overweight subjects and that drinking CJC on daily basis for 12 weeks was associated with an increase in resting brachial AD. Further studies are needed to confirm our results and verify the clinical relevance of our observations.Supported by the Canadian Institutes of Health Research (MOP‐64438)

Pharmacokinetic and pharmacodynamic properties of oral L‐citrulline and L‐arginine: impact on nitric oxide metabolism

Oral L-arginine supplementation has been used in several studies to improve endothelium-dependent, nitric oxide (NO)-mediated vasodilation. L-Arginine treatment is hampered by extensive presystemic elimination due to intestinal arginase activity. In contrast, L-citrulline is readily absorbed and at least in part converted to L-arginine. The aim of our study was to assess this metabolic conversion and its subsequent pharmacodynamic effects. In a double-blind, randomized, placebo-controlled cross-over study, 20 healthy volunteers received six different dosing regimes of placebo, citrulline, and arginine. Pharmacokinetic parameters (C(max), T(max), C(min), AUC) were calculated after 1 week of oral supplementation. The ratio of plasma L-arginine over asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase (arginine/ADMA ratio), urinary cyclic guanosine monophosphate (cGMP) and nitrate excretion rates, and flow-mediated vasodilation (FMD) was measured to assess pharmacodynamic effects. L-Citrulline dose-dependently increased AUC and C(max) of plasma L-arginine concentration more effectively than L-arginine (P < 0.01). The highest dose of citrulline (3 g bid) increased the C(min) of plasma L-arginine and improved the L-arginine/ADMA ratio from 186 +/- 8 (baseline) to 278 +/- 14 [P < 0.01, 95% confidence interval (CI) 66, 121]. Moreover, urinary nitrate and cGMP were increased from 92 +/- 10 to 125 +/- 15 micromol mmol(-1) creatinine (P = 0.01, 95% CI 8, 58) and from 38 +/- 3.3 to 50 +/- 6.7 nmol mmol(-1) creatinine (P = 0.04, 95% CI 0.4, 24), respectively. No treatment improved FMD over baseline. However, pooled analysis of all FMD data revealed a correlation between the increase of arginine/ADMA ratio and improvement of FMD. Our data show for the first time that oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner.

Estrogen therapy increases plasma concentrations of nitric oxide metabolites in postmenopausal women but increases flow-mediated vasodilation only in younger women

To evaluate the effect of estrogen therapy (ET) on endothelial nitric oxide (NO) production and in flow-mediated vasodilation (FMV). Randomized, crossover, double-blind, placebo-controlled study. Healthy postmenopausal women in an academic research environment. Forty postmenopausal women between 45 and 72 years of age. Women received ET or placebo during two periods of 12 weeks that were separated by 2 weeks of washout. Flow-mediated vasodilation, nitrite and nitrate, lipid profile, creatinine, and glucose were measured at weeks 12 and 24. Student's t or Wilcoxon tests were used for comparative analyses, and kappa test and limit analysis determined variability. After placebo treatment, nitrate and nitrite mean concentration was 8.28 +/- 1.17 mmol/L; it increased to 62.6 +/- 12.82 mmol/L after ET. Percentage FMV was 18.8 +/- 2.58 after the placebo period and did not change after ET (20.1 +/- 1.92) in the whole sample, but in the subgroup (n = 15) of younger women (45-50 years of age), percentage FMV increased from 13.6 +/- 3.6 after the placebo period to 22.2 +/- 3.5 after ET. An increase in plasma concentrations of nitrite and nitrate after ET was observed in all the women studied, but the improvement in FMV was observed only in the younger ones. These age-related differences in FMV in response to ET must be further investigated.

Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women

ObjectivesThe aim of the present study was to assess whether optimized antihypertensive treatment is effective in modifying endothelial function and whether an improvement in flow-mediated vasodilation (FMD) in response to treatment, as an expression of reversible endothelial dysfunction, could predict a more favorable prognosis in a population of postmenopausal women. BackgroundHypertensive postmenopausal women have been shown to have abnormal endothelium-dependent vascular function. However, FMD may change over time, according to antihypertensive treatment; the prognostic value of these changes has not been investigated. MethodsA total of 400 consecutive postmenopausal women with mild-to-moderate hypertension and impaired FMD underwent ultrasonography of the brachial artery at baseline and after six months, while optimal control of blood pressure was achieved using antihypertensive therapy. They were then followed up for a mean period of 67 months (range 57 to 78). Endothelial function was measured as FMD of the brachial artery, using high-resolution ultrasound. ResultsAfter six months of treatment, FMD had not changed (≤10% relative to baseline) in 150 (37.5%) of 400 women (group 1), whereas it had significantly improved (>10% relative to baseline) in the remaining 250 women (62.5%) (group 2). During follow-up, we noticed 32 events (3.50 per 100 person-years) in group 1 and 15 events (0.51 per 100 person-years) in group 2 (p < 0.0001). ConclusionsThis study demonstrates that a significant improvement in endothelial function may be obtained after six months of antihypertensive therapy and clearly identifies patients who possibly have a more favorable prognosis.

Cerivastatin and Endothelial Function in Elderly Patients With Diabetes Mellitus

To the Editor: In the recent article by Tsunekawa et al,1 3 days of therapy with the HMG Co-A reductase inhibitor cerivastatin improved flow-mediated vasodilation (FMD) of the brachial artery in a cohort of 27 older patients with diabetes mellitus (mean age 69.3±3.4 years). We found the results of this investigation puzzling for two reasons. First, we were surprised by the magnitude of the benefit of statin therapy, which in this study led to nearly a doubling in FMD and an absolute increase of approximately 4% after 3 days of therapy. The magnitude of the improvement in FMD is much higher than previously reported in larger studies with other statins using similar techniques over longer periods of time.2,3⇓ We have demonstrated that two other statins, alone and in combination with antioxidant vitamins, did not improve brachial artery FMD after 1 year of therapy in twice as …

Transdermal estrogen replacement therapy and vasomotor response.

Previous studies have shown that acute administration of estrogen improves endothelial function in postmenopausal women, but there has been little investigation of the chronic effects of transdermal estrogen replacement therapy. The present study assessed the effect of transdermal estrogen replacement therapy (0.025 mg / day for 4 weeks, the normally applied dosage in Japan) on flow-mediated endothelium-dependent vasodilation of the brachial artery (B-mode ultrasound) and forearm cutaneous blood flow (laser Doppler flowmetry), and plasma hormonal and lipid levels in 12 normolipidemic postmenopausal women. Neither resting vascular diameter, flow-mediated vasodilation, nor time to peak vasodilation, showed significant changes after the estrogen therapy. In contrast, resting forearm cutaneous blood flow decreased significantly after the estrogen therapy. The time to the peak reactive hyperemia in the forearm skin was slightly shortened, and the % change in reactive hyperemia decreased slightly after the therapy. These findings seemed to reflect the inhibition of hot-flush symptoms associated with vasomotor abnormalities in cutaneous tissue. The lack of improvement in flow-mediated vasodilation of the brachial artery despite the inhibitory effect on cutaneous vasomotor abnormalities may be related to the low plasma estradiol concentration obtained with the present transdermal therapy (42.4+/-15.2 pg / ml), a finding which supports the estrogen threshold hypothesis in hormone replacement therapy.

Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study)

OBJECTIVESTo determine the effect of angiotensin-converting enzyme (ACE) inhibition on brachial flow-mediated vasodilation.BACKGROUNDQuinapril, an ACE inhibitor with high affinity, has been shown to improve coronary endothelial dysfunction in patients with coronary artery disease. The effectiveness of different vasoactive agents to improve human endothelial function is unknown.METHODSHigh resolution ultrasound was used to assess endothelium-dependent brachial artery flow-mediated vasodilation (FMD) in patients with coronary disease. We studied 80 patients (mean age 58 ± 0.9 years) in a partial-block, cross-over design trial. Patients were randomized to one of four different drug sequences to receive quinapril 20 mg, enalapril 10 mg, losartan 50 mg or amlodipine 5 mg daily. Each patient received three drugs with a two-week washout period between treatments. The primary end point was the absolute difference in FMD after eight weeks of each study drug compared with their respective baselines analyzed in a blinded fashion.RESULTSThere was mild impairment of FMD at baseline (7.3 ± 0.6%). The change in FMD from baseline was significant only for quinapril (1.8 ± 1%, p < 0.02). No change was seen with losartan (0.8 ± 1.1%, p = 0.57), amlodipine (0.3 ± 0.9%, p = 0.97) or enalapril (−0.2 ± 0.8%, p = 0.84). No significant change in nitroglycerin-induced dilation occurred with drug therapy. The improvement in quinapril response was not seen in those with the DD ACE genotype (0.5 ± 2.1%) but was seen in those with the ID and II genotype (3.3 ± 1.2 and 3.2 ± 1.9%, respectively, p = 0.03).CONCLUSIONOnly quinapril was associated with significant improvement in FMD, and this response is related to the presence of the insertion allele of the ACE genotype.