Endothelial Function In Humans Research Articles

Fluctuation in shear rate, with unaltered mean shear rate, improves brachial artery flow-mediated dilation in healthy, young men.

Increase in mean shear stress represents an important and potent hemodynamic stimulus to improve conduit artery endothelial function in humans. No previous study has examined whether fluctuations in shear rate patterns, without altering mean shear stress, impacts conduit artery endothelial function. This study examined the hypothesis that 30-min exposure to fluctuations in shear rate patterns, in the presence of unaltered mean shear rate, improves brachial artery flow-mediated dilation. Fifteen healthy men (27.3 ± 5.0 yr) completed the study. Bilateral brachial artery flow-mediated dilation was assessed before and after unilateral exposure to 30 min of intermittent negative pressure (10 s, -40mmHg; 7 s, 0 mmHg) to induce fluctuation in shear rate, while the contralateral arm was exposed to a resting period. Negative pressure significantly increased shear rate, followed by a decrease in shear rate upon pressure release (both P < 0.001). Across the 30-min intervention, mean shear rate was not different compared with baseline (P = 0.458). A linear mixed model revealed a significant effect of time observed for flow-mediated dilation (P = 0.029), with exploratory post hoc analysis showing an increase in the intervention arm (∆FMD +2.0%, P = 0.008), but not in the contralateral control arm (∆FMD +0.5%, P = 0.664). However, there was no effect for arm (P = 0.619) or interaction effect (P = 0.096). In conclusion, we found that fluctuations in shear patterns, with unaltered mean shear, improves brachial artery flow-mediated dilation. These novel data suggest that fluctuations in shear pattern, even in the absence of altered mean shear, represent a stimulus to acute change in endothelial function in healthy individuals. NEW & NOTEWORTHY Intermittent negative pressure applied to the forearm induced significant fluctuations in antegrade and retrograde shear rate, while mean shear was preserved relative to baseline. Our exploratory study revealed that brachial artery flow-mediated dilation was significantly improved following 30-min exposure to intermittent negative pressure. Fluctuations in blood flow or shear rate, with unaltered mean shear, may have important implications for vascular health; however, further research is required to identify the underlying mechanisms and potential long-term health benefits.

Examining the acute effects of retrograde versus low mean shear rate on flow-mediated dilation.

Arterial endothelial function is acutely and chronically regulated by blood flow-associated shear stress. An acute intervention employing modest forearm cuff occlusion to simultaneously increase retrograde and decrease mean brachial artery shear rate for 30 min evokes transient impairments in flow-mediated dilation (FMD). However, the independent influence of the low mean versus the retrograde shear stress components is unclear. Healthy young adults [n = 24 (12 women, 12 men); 22 ± 2 yr, body mass index = 25 ± 2 kg/m2 (mean ± SD)] completed three laboratory visits within 1 wk. Visits consisted of 45 min of supine rest followed by a brachial artery FMD test (duplex ultrasound) before and after a 30-min intervention: control (shear rate unchanged), cuff (mean shear rate decreased, retrograde shear rate increased), or arterial compression (mean shear rate decreased, no increase in retrograde shear rate). The mean shear rate on the compression visit was targeted to match that achieved on the cuff visit. Cuff and compression trials decreased mean shear rate to a similar extent (cuff: 43 ± 22 s-1, compression: 43 ± 21 s-1; P = 0.850) compared with control (65 ± 21 s-1; both P < 0.001), with the retrograde component elevated only in the former (cuff: -83 ± 30 s-1, compression: -7 ± 5 s-1; P < 0.001). FMD decreased by 29 ± 30% (P < 0.001) after the cuff intervention and 32 ± 24% (P < 0.001) after the compression trial but was unchanged on the control visit (-0.3 ± 18%; P = 0.754). This was not altered by accounting for the shear rate stimulus. An increased retrograde shear stress does not appear to be obligatory for the transient reduction in FMD achieved after a 30-min exposure to low mean shear stress. These findings provide novel mechanistic insight on the regulation of endothelial function in vivo. NEW & NOTEWORTHY Low mean and retrograde shear stress are considered atherogenic; however, their relative contribution to the acute regulation of endothelial function in humans is unclear. Matched reductions in mean shear stress (30 min), with and without increases in retrograde shear stress, elicited equivalent reductions in flow-mediated dilation in men and women. These findings afford novel insight regarding the shear stress components governing the acute (dys)regulation of conduit artery endothelial function in vivo.

In vivo assessment of endothelial function in small animals using an infrared pulse detector.

Objective:Endothelial dysfunction is the earliest change in atherosclerosis. Flow-mediated dilatation (FMD) is used to assess endothelial function in humans. However, this assessment is not easy in small animals. This study demonstrated the reliability and reproducibility of a proposed instrument for in vivo assessment of FMD in a rodent model using infrared pulse sensors.Materials and Methods:We used 24 adult male Wistar Kyoto rats randomly divided into three groups. FMD was measured under continuous infusion of normal saline followed by intra-arterial infusion of acetylcholine (Ach; n = 8), sodium nitroprusside (SNP; n = 8), or Nω-nitro-L-arginine methyl ester (L-NAME; n = 8).Results:The dilatation indices (DIs) of all three groups were similar before application of the vasoactive agents (1.82 ± 0.46, 1.81 ± 0.44, and 1.93 ± 0.40, P = 0.877, by one-way analysis of variance). The DI was significantly increased during infusion of Ach (2.97 ± 1.03 vs. 1.82 ± 0.46, P = 0.015), unchanged during infusion of SNP (1.81 ± 0.44 vs. 1.98 ± 0.40, P = 0.574), and attenuated during infusion of L-NAME (1.91 ± 0.40 vs. 1.42 ± 0.35; P = 0.028).Conclusion:The results of this study correlated well with those of human studies, suggesting that this method can be used for in vivo evaluation of endothelial function in small animals.

Dose–response relationship between cocoa flavanols and human endothelial function: a systematic review and meta-analysis of randomized trials

Several intervention studies have investigated the relationship between cocoa flavanols and endothelial function. However, the shape of the association and the type of compounds responsible for the effects are largely unknown. To examine the dose-response association between the consumption of cocoa flavanols and endothelial function, measured by flow-mediated dilation (FMD). Two investigators searched Scopus® for the relevant human intervention studies, which were pooled and meta-analysed. Heterogeneity in the findings was explored with various subgroup analyses. Fifteen published articles with 18 intervention arms met the inclusion criteria. Participants in these intervention groups received 80 to 1248 mg (mean: 704 mg) more flavanols than control groups. A significant improvement of FMD by 1.17% (95% CI: 0.76% to 1.57%) was calculated, with strong evidence of a non-linear association (inverted U-shape) between cocoa flavanols and FMD. This meta-analysis provides evidence that cocoa flavanols could significantly improve endothelial function, with an optimal effect observed with 710 mg total flavanols, 95 mg (-)-epicatechin or 25 mg (+)-catechin. However, there was substantial variation in the results that could not be explained by the characteristics that we explored, and there were significant risk-of-bias concerns with a large majority of the studies.

The Effects of Flavonoids on Cardiovascular Health: A Review of Human Intervention Trials and Implications for Cerebrovascular Function.

Research has suggested a number of beneficial effects arising from the consumption of dietary flavonoids, found in foods such as cocoa, apples, tea, citrus fruits and berries on cardiovascular risk factors such as high blood pressure and endothelial dysfunction. These effects are thought to have a significant impact upon both vascular and cerebrovascular health, ultimately with the potential to prevent cardiovascular and potentially neurodegenerative disease with a vascular component, for example vascular dementia. This review explores the current evidence for the effects of flavonoid supplementation on human endothelial function and both peripheral and cerebral blood flow (CBF). Evidence presented includes their potential to reduce blood pressure in hypertensive individuals, as well as increasing peripheral blood perfusion and promoting CBF in both healthy and at-risk populations. However, there is great variation in the literature due to the heterogeneous nature of the randomised controlled trials conducted. As such, there is a clear need for further research and understanding within this area in order to maximise potential health benefits.

Quantitative measurement of selected protein biomarkers of endothelial dysfunction in plasma by micro-liquid chromatography-tandem mass spectrometry based on stable isotope dilution method

The aim of this study was to develop and validate the novel microLC/MS-MRM method for the simultaneous quantification of six proteins: angiopoietin 2 (Angpt-2), soluble form of fms-like tyrosine kinase 1 (sFLT-1), plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (t-PA), endocan (ESM-1), soluble form of E-selectin (sE-sel), and one peptide: adrenomedullin (ADM) in mouse plasma. Two approaches were compared: a stable isotope dilution (SID) method- used as a reference and a modified SID (mSID) procedure. In SID strategy the calibration curves were used, whereas in mSID the ratio between the chromatogram peak area of endogenous tryptic peptides at unknown concentration to chromatogram peak area of exogenous, stable isotope-labelled internal standards (SISs) added to the sample at known concentration was calculated. The microLC/MS-MRM method in the SID approach was linear from 0.250 pmol/mL to 250 pmol/mL for Angpt-2; 5 pmol/mL to 5000 pmol/mL for sFLT-1; 2.5 pmol/mL to 5000 pmol/mL for PAI-1; 0.375 pmol/mL to 250 pmol/mL for t-PA; 0.375 pmol/mL to 187.5 pmol/mL for ESM-1; 2.5 pmol/mL to 5000 pmol/mL for sE-sel and 0.375 pmol/mL to 250 pmol/mL for ADM. LPS-induced changes in plasma assessed based on SID and mSID approaches gave comparable quantitative results and featured LPS-induced dysregulation of endothelial permeability (Angpt-2, sFLT-1), glycocalyx injury (SDC-1) accompanied by a pro-thrombotic response (PAI-1). In addition, we applied microLC/MS-MRM method with mSID strategy to analyze human plasma samples from patients with chronic myeloid leukemia (CML) and obstructive sleep apnoea (OSA) and demonstrated usefulness of the method to characterize endothelial function in humans. In conclusion, the microLC/MS-MRM method with mSID strategy applied for simultaneous quantification of protein biomarkers of endothelial function in plasma represents a novel targeted proteomic platform for the comprehensive evaluation of endothelial function in mice and humans.

Blue light exposure decreases systolic blood pressure, arterial stiffness, and improves endothelial function in humans.

Previous studies have shown that ultraviolet light can lead to the release of nitric oxide from the skin and decrease blood pressure. In contrast to visible light the local application of ultraviolet light bears a cancerogenic risk. Here, we investigated whether whole body exposure to visible blue light can also decrease blood pressure and increase endothelial function in healthy subjects. In a randomised crossover study, 14 healthy male subjects were exposed on 2 days to monochromatic blue light or blue light with a filter foil (control light) over 30 minutes. We measured blood pressure (primary endpoint), heart rate, forearm vascular resistance, forearm blood flow, endothelial function (flow-mediated dilation), pulse wave velocity and plasma nitric oxide species, nitrite and nitroso compounds (secondary endpoints) during and up to 2 hours after exposure. Blue light exposure significantly decreased systolic blood pressure and increased heart rate as compared to control. In parallel, blue light significantly increased forearm blood flow, flow-mediated dilation, circulating nitric oxide species and nitroso compounds while it decreased forearm vascular resistance and pulse wave velocity. Whole body irradiation with visible blue light at real world doses improves blood pressure, endothelial function and arterial stiffness by nitric oxide released from photolabile intracutanous nitric oxide metabolites into circulating blood.

Measurement of flow-mediated dilation of mouse femoral artery in vivo by optical coherence tomography.

Flow-mediated vasodilation (FMD) is used for assessment of vascular endothelial function in humans as a predictor of cardiovascular events. It has been challenging to carry it on preclinical murine models due to the diminutive size of the femoral artery. Here, we present a new approach to accurately measure the blood velocity and femoral artery diameters of mice by acquiring Doppler optical coherence tomography and optical coherence tomography angiography continuously within 1 single experimental scanning protocol. Using the 3-dimensional imaging and new velocity algorithm, the measurement precision of diameter, blood flow, velocity and wall shear stress are improved to 0.91%, 11.0%, 10.7% and 14.0%, respectively. FMD of healthy mouse femoral artery measured by this method was 11.96% ± 0.98%, which was blunted to 5.69% ± 0.4% by intravenous administration of endothelial nitric oxide synthase inhibitor (L-NG -Nitroarginine methyl ester), in agreement with that reported in the literature.

Effects of Ticagrelor, Prasugrel, or Clopidogrel on Endothelial Function and Other Vascular Biomarkers: A Randomized Crossover Study

ObjectivesThe study sought to assess whether treatment with ticagrelor, as compared with prasugrel and clopidogrel, improves endothelium-dependent dilation throughout the course of the treatment and other vascular biomarkers, including systemic adenosine plasma levels. BackgroundThe in vivo off-target effects of ticagrelor in post–acute coronary syndrome (ACS) patients remain poorly characterized. MethodsFifty-four stable post-ACS patients were sequentially exposed to each of the 3 oral P2Y12 inhibitors following a 3-period balanced Latin square crossover design with 4 weeks per treatment in 5 European centers. The primary endpoint was the assessment of endothelial function with pulse amplitude tonometry and expressed as reactive hyperemia index at treatment steady state. Secondary endpoints included reactive hyperemia index after loading or before maintenance regimen, systemic adenosine plasma levels, a wide set of vascular biomarkers, and ticagrelor or AR-C124910XX plasma levels throughout each ticagrelor period. In 9 patients, the evaluation of endothelial function was performed simultaneously by pulse amplitude tonometry and flow-mediated dilation. ResultsReactive hyperemia index did not differ after ticagrelor (1.970 ± 0.535) as compared with prasugrel (2.007 ± 0.640; p = 0.557) or clopidogrel (2.072 ± 0.646; p = 0.685), nor did systemic adenosine plasma levels or vascular biomarkers at any time points. P2Y12 platelet reactivity units were lower after ticagrelor as compared with clopidogrel at all time points and after maintenance dose as compared with prasugrel. Flow-mediated dilation did not differ after the maintenance dose of ticagrelor as compared with clopidogrel and prasugrel. ConclusionsTicagrelor did not improve endothelial function or increased systemic adenosine plasma levels as compared with prasugrel and clopidogrel in stabilized patients who suffered from an ACS. (Hunting for the Off-Target Properties of Ticagrelor on Endothelial Function in Humans [HI-TECH]; NCT02587260).

UBC-Nepal Expedition: imposed oscillatory shear stress does not further attenuate flow-mediated dilation during acute and sustained hypoxia.

Experimentally induced oscillatory shear stress (OSS) and hypoxia reduce endothelial function in humans. Acute and sustained hypoxia may cause increases in resting OSS; however, whether this influences endothelial susceptibility to further increases in OSS is unknown. Healthy lowlanders ( n = 15, 30 ± 6 yr; means ± SD) participated in three OSS interventions: two interventions at sea level [normoxia and after 20 min of normobaric hypoxia (acute hypoxia, 11% O2)] and one intervention 5-7 days after a 9-day ascent to 5,050 m (sustained hypoxia). OSS was provoked in the brachial artery using a 30-min distal cuff inflation (75 mmHg). Endothelial function was assessed before and after each intervention by reactive hyperemia flow-mediated dilation (FMD). Shear stress magnitude and patterns were obtained via Duplex ultrasound. Baseline retrograde shear stress and OSS were greater in acute hypoxia versus normoxia ( P < 0.001), and OSS was elevated in sustained hypoxia versus normoxia ( P = 0.011). The intervention further augmented OSS during each condition. Preintervention FMD was decreased by 29 ± 48% in acute hypoxia and by 25 ± 31% in sustained hypoxia compared with normoxia ( P = 0.001 and 0.026); these changes correlated with changes in baseline mean and antegrade shear stress. After the intervention, FMD decreased during normoxia (-41 ± 26%, P < 0.001) and was unaltered during acute or sustained hypoxia. Therefore, a 30-min exposure to OSS reduced FMD during normoxia, a condition with an unchallenged, healthy endothelium; however, imposed OSS did not appear to worsen endothelial function during acute or sustained hypoxia. Exposure to an altered magnitude and pattern of shear stress at baseline in hypoxia may contribute to the insensitivity to further acute augmentation of OSS. NEW & NOTEWORTHY We investigated whether the endothelium remains sensitive to experimental increases in oscillatory shear stress in acute (11% O2) and sustained (2 wk at 5,050 m) hypoxia. Hypoxia altered baseline shear stress and decreased endothelial function (flow-mediated dilation); however, exposure to experimentally induced oscillatory shear stress only impaired flow-mediated dilation in normoxia.

Performing under pressure: hypertension and the regulation of cerebral oxygen delivery.

Performing under pressure: hypertension and the regulation of cerebral oxygen delivery.

The Effects of Space and Terrestrial Weather Factors on Arterial Stiffness and Endothelial Function in Humans

A differential evolution algorithm was used to detect the biotropic influence of geomagnetic activity on several parameters of human vascular tone. Studies of the characteristics of vascular tone in healthy volunteers showed that arterial stiffness and endothelial function, as well as blood pressure and heart rate, depend on the geomagnetic and, in most cases, weather conditions. The pulse wave velocity (PWV) was measured to characterize the arterial stiffness and was found to be the most sensitive to the effects of space weather parameters. The strength of the effect of geomagnetic activity was for the first time observed to depend on the configuration of terrestrial weather parameters. A linear correlation between the K index of geomagnetic activity and PWV was estimated at r =–0.44 (p = 0.0003), although the relationship was detectable exclusively in the case of certain terrestrial weather parameters. Endothelial dysfunction and the pulse-rate response to variations in geomagnetic activity implicated nitrogen monoxide in body adaptation to variations in geomagnetic activity.

MiR-29 contributes to normal endothelial function and can restore it in cardiometabolic disorders.

We investigated the role of microRNAs (miRNA) in endothelial dysfunction in the setting of cardiometabolic disorders represented by type 2 diabetes mellitus (T2DM). miR‐29 was dysregulated in resistance arterioles obtained by biopsy in T2DM patients. Intraluminal delivery of miR‐29a‐3p or miR‐29b‐3p mimics restored normal endothelium‐dependent vasodilation (EDVD) in T2DM arterioles that otherwise exhibited impaired EDVD. Intraluminal delivery of anti‐miR‐29b‐3p in arterioles from non‐DM human subjects or rats or targeted mutation of Mir29b‐1/a gene in rats led to impaired EDVD and exacerbation of hypertension in the rats. miR‐29b‐3p mimic increased, while anti‐miR‐29b‐3p or Mir29b‐1/a gene mutation decreased, nitric oxide levels in arterioles. The mutation of Mir29b‐1/a gene led to preferential differential expression of genes related to nitric oxide including Lypla1. Lypla1 was a direct target of miR‐29 and could abrogate the effect of miR‐29 in promoting nitric oxide production. Treatment with Lypla1 siRNA improved EDVD in arterioles obtained from T2DM patients or Mir29b‐1/a mutant rats or treated with anti‐miR‐29b‐3p. These findings indicate miR‐29 is required for normal endothelial function in humans and animal models and has therapeutic potential for cardiometabolic disorders.

Reproducibility and agreement of different non-invasive methods of endothelial function assessment

Flow-mediated dilatation (FMD) is an established, but investigator-demanding method, used to non-invasively determine nitric oxide (NO)-dependent endothelial function in humans. Local thermal hyperemia (LTH) or post-occlusive reactive hyperemia (PORH) of the skin measured with a laser Doppler flow imager may be a less demanding alternative of FMD. We investigated the reproducibility of the different measures of vascular function, their interrelationship and the NO-dependency of LTH. Measurements were performed twice in 27 healthy men (8 smokers), one week apart. Local application of NG-monomethyl-l-arginine (L-NMMA) by means of iontophoresis was used to determine the NO-dependency of LTH. Using L-NMMA, the peak and plateau responses of LTH were reduced by 31% (p < .001) and 65% (<0.001), respectively. For all measurements the coefficient of variation (CV) was higher in smokers than in non-smokers. For non-smokers the CV of FMD was 12%, of LTH peak response 17%, of LTH plateau response 12%, of PORH peak response 14% and of PORH area under the curve response 11%. FMD correlated weakly with the PORH peak and area under the curve response (r = 0.39 and 0.43, p < .05), whereas the LTH-plateau response correlated with the PORH peak response (r = 0.68, p < .01) in non-smokers, but FMD and LTH peak or plateau responses were unrelated. In conclusion, the LTH plateau response is for two-third NO-dependent, but unrelated to FMD. Furthermore, despite easy to perform the LTH responses are not more reproducible than FMD. Given the weak associations, the different methods of vascular function assessment are not interchangeable.

Chronic inhibition of lipoprotein-associated phospholipase A2 does not improve coronary endothelial function: A prospective, randomized-controlled trial

AimsLipoprotein-associated phospholipase A2 (Lp-PLA2), a novel biomarker for vascular inflammation, is associated with coronary endothelial dysfunction (CED) and independently predicts cardiovascular events. The current study aimed to determine whether darapladib, an orally administered Lp-PLA2 inhibitor, improved CED. Methods and resultsFifty-four patients with CED were enrolled in a double-blinded randomized placebo-controlled trial, and were randomized to receive oral darapladib, 160mg daily, or placebo. Coronary angiography and invasive coronary endothelial function assessment were performed at baseline and post-6months of treatment. Primary endpoints were change in coronary artery diameter and coronary blood flow in response to acetylcholine. Additionally, Lp-PLA2 activity was measured at baseline and on follow-up to evaluate for adherence and drug effect. Fifty-four patients were randomized to placebo (n=29) and darapladib (n=25). Mean age in darapladib group was 55.2.±11.7years vs. 54.0±10.5years (p=0.11). On follow-up, there was no significant difference in the percent response to acetylcholine of coronary artery diameter in treatment vs. placebo group (+3 (IQR −9, 15) vs. +3 (−12, 19); p=0.87) or coronary blood flow (−5 (IQR −24, 54) vs. 39 (IQR −26, 67); p=0.41). There was significant reduction in Lp-PLA2 activity in the treatment arm vs. placebo (−76 (IQR −113, −52) vs. −7(−21, −7); p<0.001). DiscussionLp-PLA2 inhibition with darapladib did not improve coronary endothelial function, despite significantly reduced Lp-PLA2 activity with darapladib. This study suggests endogenous Lp-PLA2 may not play a primary role in coronary endothelial function in humans. Clinicaltrials.gov IdentifierNCT01067339

Flow-mediated dilation stimulated by sustained increases in shear stress: a useful tool for assessing endothelial function in humans?

Investigations of human conduit artery endothelial function via flow-mediated vasodilation (FMD) have largely been restricted to the reactive hyperemia (RH) technique, wherein a transient increase in shear stress after the release of limb occlusion stimulates upstream conduit artery vasodilation (RH-FMD). FMD can also be assessed in response to sustained increases in shear stress [sustained stimulus (SS)-FMD], most often created with limb heating or exercise. Exercise in particular creates a physiologically relevant stimulus because shear stress increases, and FMD occurs, during typical day-to-day activity. Several studies have identified that various conditions and acute interventions have a disparate impact on RH-FMD versus SS-FMD, sometimes with only the latter demonstrating impairment. Indeed, evidence suggests that transient (RH) and sustained (SS) shear stress stimuli may be transduced via different signaling pathways, and, as such, SS-FMD and RH-FMD appear to offer unique insights regarding endothelial function. The present review describes the techniques used to assess SS-FMD and summarizes the evidence regarding 1) SS-FMD as an index of endothelial function in humans, highlighting comparisons with RH-FMD, and 2) potential differences in shear stress transduction and vasodilator production stimulated by transient versus sustained shear stress stimuli. The evidence suggests that SS-FMD is a useful tool to assess endothelial function and that further research is required to characterize the mechanisms involved and its association with long-term cardiovascular outcomes. NEW & NOTEWORTHY Sustained increases in peripheral conduit artery shear stress, created via distal skin heating or exercise, provide a physiologically relevant stimulus for flow-mediated dilation (FMD). Sustained stimulus FMD and FMD stimulated by transient, reactive hyperemia-induced increases in shear stress provide distinct assessments of conduit artery endothelial function.

The role of shear stress on cutaneous microvascular endothelial function in humans

Previous studies suggest that exercise and heat stress improve cutaneous endothelial function, caused by increases in shear stress. However, as vasodilatation in the skin is primarily a thermogenic phenomenon, we investigated if shear stress alone without increases in skin temperature that occur with exercise and heat stress increases endothelial function. We examined the hypothesis that repeated bouts of brief occlusion would improve cutaneous endothelial function via shear stress-dependent mechanisms. Eleven males underwent a shear stress intervention (forearm occlusion 5s rest 10s) for 30min, five times·week-1 for 6 weeks on one arm, the other was an untreated control. Skin blood flow was measured using laser-Doppler flowmetry, and endothelial function was assessed with and without NOS-inhibition with L-NAME in response to three levels of local heating (39, 42, and 44°C), ACh administration, and reactive hyperaemia. Data are cutaneous vascular conductance (CVC, laser-Doppler/blood pressure). There were no changes in the control arm (all d ≤ 0.2, p > 0.05). In the experimental arm, CVC to 39°C was increased after 3 and 6 weeks (d = 0.6; p ≤ 0.01). Nitric oxide contribution was increased after 6 weeks compared to baseline (d = 0.85, p < 0.001). Following skin heating to 42°C and 44°C, CVC was not different at weeks 3 or 6 (d ≤ 0.8, p > 0.05). For both 42 and 44°C, nitric oxide contribution was increased after weeks 3 and 6 (d ≥ 0.4, p < 0.03). Peak and area-under-the-curve responses to ACh increased following 6 weeks (p < 0.001). Episodic increases in shear stress, without changes in skin or core temperature, elicit an increase in cutaneous microvascular reactivity and endothelial function.

Association of dietary nitrate with atherosclerotic vascular disease mortality: a prospective cohort study of older adult women

Background: Nitrate-rich vegetables lower blood pressure and improve endothelial function in humans. It is not known, however, whether increased consumption of nitrate-rich vegetables translates to a lower risk of atherosclerotic vascular disease (ASVD) mortality.Objective: The objective was to investigate the association of nitrate intake from vegetables with ASVD mortality.Design: A total of 1226 Australian women aged 70-85 y without prevalent ASVD and/or diabetes were recruited in 1998 and were studied for 15 y. We assessed demographic and ASVD risk factors at baseline (1998), and we used a validated food-frequency questionnaire to evaluate dietary intake. Nitrate intake from vegetables was calculated by use of a newly developed comprehensive database. The primary outcome was any death attributed to ASVD ascertained by using linked data that were provided via the Western Australian Data Linkage system. We used Cox proportional hazards modeling to examine the association between nitrate intake and ASVD mortality before and after adjustment for lifestyle and cardiovascular disease risk factors.Results: During a follow-up period of 15,947 person-years, 238 of 1226 (19.4%) women died of ASVD-related causes. The mean ± SD vegetable nitrate intake was 67.0 ± 29.2 mg/d. Each SD higher vegetable nitrate intake was associated with a lower risk of ASVD mortality in both unadjusted [HR: 0.80 (95% CI: 0.70, 0.92), P = 0.002] and multivariable-adjusted [HR: 0.79 (95% CI: 0.68, 0.93), P = 0.004] analyses. This relation was attenuated after further adjustment for diet quality [HR: 0.85 (95% CI: 0.72, 1.01), P = 0.072]. Higher vegetable nitrate intake (per SD) also was associated with a lower risk of all-cause mortality [multivariable-adjusted HR: 0.87 (95% CI: 0.78, 0.97), P = 0.011].Conclusions: Nitrate intake from vegetables was inversely associated with ASVD mortality independent of lifestyle and cardiovascular disease risk factors in this population of older adult women without prevalent ASVD or diabetes. These results support the concept that nitrate-rich vegetables may reduce the risk of age-related ASVD mortality. This trial was registered at www.anzctr.org.au as ACTRN12617000640303.

Tea-induced improvement of endothelial function in humans: No role for epigallocatechin gallate (EGCG)

Consumption of tea is inversely associated with cardiovascular diseases. However, the active compound(s) responsible for the protective effects of tea are unknown. Although many favorable cardiovascular effects in vitro are mediated by epigallocatechin gallate (EGCG), its contribution to the beneficial effects of tea in vivo remains unresolved. In a randomised crossover study, a single dose of 200 mg EGCG was applied in three different formulas (as green tea beverage, green tea extract (GTE), and isolated EGCG) to 50 healthy men. Flow-mediated dilation (FMD) and endothelial-independent nitro-mediated dilation (NMD) was measured before and two hours after ingestion. Plasma levels of tea compounds were determined after each intervention and correlated with FMD. FMD significantly improved after consumption of green tea containing 200 mg EGCG (p < 0.01). However, GTE and EGCG had no significant effect on FMD. NMD did not significantly differ between interventions. EGCG plasma levels were highest after administration of EGCG and lowest after consumption of green tea. Plasma levels of caffeine increased after green tea consumption. The results show that EGCG is most likely not involved in improvement of flow-mediated dilation by green tea. Instead, other tea compounds, metabolites or combinations thereof may play a role.

Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy.

NCT01859793.