Flow-mediated Dilation Response Research Articles

SERUM OMENTIN-1 LEVELS AND ENDOTHELIAL DYSFUNCTION IN OBESITY.

Our aim was to investigate the relationship between serum omentin-1 levels and endothelial dysfunction in obese patients. We evaluated 50 obese patients, and age/gender matched 45 healthy non-obese subjects as controls. Oral glucose tolerance test, lipid parameters, uric acid levels, homeostatic model assessment-insulin resistance (HOMA-IR) index, serum omentin-1 levels and flow mediated dilatation (FMD) % were measured in all subjects. Body compositions were analyzed with bioelectrical impedance method using a Tanita Body Composition Analyzer and ViScan. Serum omentin-1 levels were found significantly lower in obese population compared to the control subjects. FMD response was significantly decreased in obese population. There was a significant positive correlation between serum omentin-1 levels and FMD response (r=0.359, p<0.001). Serum omentin-1 levels were negatively correlated with body mass index (BMI), waist circumference, total fat percentage, visceral fat, fasting insulin and HOMA-IR index. Lower serum omentin-1 levels and decreased FMD response may be an early marker of endothelial dysfunction in obese patients.

Consumption of energy beverage is associated with attenuation of arterial endothelial flow-mediated dilatation.

AIMTo investigate whether consumption of an energy drink will acutely impair endothelial function in young healthy adults.METHODSEnergy drinks are being consumed more and more worldwide, and have been associated with some deaths in adolescents and young adults, especially when consumed while exercising. After fasting and not smoking for at least 8 h prior, eleven medical students (9 males) received an electrocardiogram, blood pressure and pulse check, and underwent baseline testing (BL) of endothelial function using the technique of endothelium-dependent flow mediated dilatation (FMD) with high-resolution ultrasound (according to recommended guidelines of the University of Wisconsin Atherosclerosis Imaging Research Program Core Laboratory). The subjects then drank an energy beverage (EB), a 24-oz can of Monster Energy, and the above was repeated at 90 min after consumption. The relative FMD (%) was calculated as the ratio between the average post-cuff release and the baseline diameter. Each image was checked for quality control, and each artery diameter was measured from the media to media points by two experts, 3 measurements at the QRS complex, repeated on 3 separate beats, and then all were averaged.RESULTSSubjects characteristics averages (given with standard deviations) include: Age 24.5 ± 1.5 years, sex 9 male and 2 female, weight 71.0 ± 9.1 kg, height 176.4 ± 6.0 cm, BMI 22.8 ± 2.7 kg/m2. The hemodynamics were as follows, BL vs EB group respectively (mean ± SD): Heart rate 65.2 ± 11.3 vs 68.2 ± 11.8 beats per minute, systolic blood pressure 114.0 ± 10.4 mmHg vs 114.1 ± 10.4 mmHg, diastolic blood pressure 68.8 ± 9.3 mmHg vs 70.6 ± 7.1 mmHg; all were not significantly different. However after drinking the EB, a significantly attenuated peak FMD response was measured (mean ± SD): BL group 5.9% ± 4.6% vs EB group 1.9% ± 2.1%; P = 0.03). Given the increased consumption of energy beverages associated with exercise in young adults, more research is needed.CONCLUSIONEnergy beverage consumption has a negative impact on arterial endothelial function in young healthy adults.

Mediation of coffee-induced improvements in human vascular function by chlorogenic acids and its metabolites: Two randomized, controlled, crossover intervention trials.

Polyphenol intake has been linked to improvements in human vascular function, although data on hydroxycinnamates, such as chlorogenic acid (CGA) have not yet been studied. We aimed to investigate the impact of coffee intake rich in chlorogenic acid on human vascular function and whether CGAs are involved in potential effects. Two acute randomized, controlled, cross-over human intervention trials were conducted. The impact of coffee intake, matched for caffeine but differing in CGA content (89, and 310mg) on flow-mediated dilatation (FMD) was assessed in 15 healthy male subjects. In a second intervention trial conducted with 24 healthy male subjects, the impact of pure 5-caffeoylquinic acid (5-CQA), the main CGA in coffee (5-CQA; 450mg and 900mg) on FMD was also investigated. We observed a bi-phasic FMD response after low and high polyphenol, (89mg and 310mg CGA) intake, with increases at 1 (1.10±0.43% and 1.34±0.62%, respectively) and 5 (0.79%±0.32 and 1.52%±0.40, respectively) hours post coffee consumption. FMD responses to coffee intake was closely paralleled by the appearance of CGA metabolites in plasma, notably 3-, 4- and 5-feruloylquinic acid and ferulic-4'-O-sulfate at 1h and isoferulic-3'-O-glucuronide and ferulic-4'-O-sulfate at 5h. Intervention with purified 5-CQA (450mg) also led to an improvement in FMD response relative to control (0.75±1.31% at 1h post intervention, p=0.06) and concomitant appearance of plasma metabolites. Coffee intake acutely improves human vascular function, an effect, in part, mediated by 5-CQA and its physiological metabolites. The National Institutes of Health (NIH) on ClinicalTrials.govNCT01813981 and NCT01772784.

Differential vascular reactivity responses acutely following ingestion of a nitrate rich red spinach extract.

Inorganic nitrate ingestion has been posited to affect arterial blood pressure and vascular function. We sought to determine the acute effect of a red spinach extract (RSE) high in inorganic nitrate on vascular reactivity 1-h after ingestion in peripheral conduit and resistance arteries. Fifteen (n=15; males 8, females 7) apparently healthy subjects (aged 23.1±3.3years; BMI 27.2±3.7kg/m2) participated in this crossover design, double-blinded study. Subjects reported to the lab ≥2-h post-prandial and consumed RSE (1000mg dose; ~90mg nitrate) or placebo (PBO). Venipuncture was performed on three occasions: baseline, 30-min post-ingestion and between 65 to 75-min post-ingestion. Baseline vascular measurements [i.e., calf venous occlusion plethysmography, brachial artery flow-mediated dilation (FMD)], 30-min of continuous blood pressure (BP) and heart rate (HR) analysis, and follow-up vascular measurements beginning at 40-min post-ingestion were also performed. Humoral nitrate following RSE ingestion was significantly higher at 30- (+54%; P=0.039) and 65 to 75-min post-ingestion compared to baseline (+255%, P<0.001) and PBO at the same time points (P<0.05). No significant changes in BP or HR occurred in either condition. Peak reactive hyperemia (RH) calf blood flow increased significantly (+13.7%; P=0.016) following RSE ingestion, whereas it decreased (-14.0%; P=0.008) following PBO ingestion. No significant differential FMD responses were detected (P>0.05), though RH was decreased following the baseline measure in both conditions. RSE significantly increased plasma nitrate 30-min post-ingestion, but acute microvascular (i.e., resistance vasculature) reactivity increases were isolated to the lower limb and no appreciable change in brachial artery FMD was observed.

Aging, not age-associated inflammation, determines blood pressure and endothelial responses to acute inflammation.

Aging is characterized by a state of chronic, low-grade inflammation that impairs vascular function. Acute inflammation causes additional decrements in vascular function, but these responses are not uniform in older compared with younger adults. We sought to determine if older adults with low levels of baseline inflammation respond to acute inflammation in a manner similar to younger adults. We hypothesized age-related differences in the vascular responses to acute inflammation, but that older adults with low baseline inflammation would respond similarly to younger adults. Inflammation was induced with an influenza vaccine in 96 participants [older = 67 total, 38 with baseline C-reactive protein (CRP) > 1.5 mg/l and 29 with CRP < 1.5 mg/l; younger = 29]; serum inflammatory markers IL-6 and CRP, blood pressure and flow-mediated dilation (FMD) were measured 24 and 48 h later. Younger adults increased IL-6 and CRP more than the collective older adult group and increased pulse pressure, whereas older adults decreased SBP and reduced pulse pressure. The entire cohort decreased FMD from 11.3 ± 0.8 to 8.3 ± 0.7 to 8.7 ± 0.7% in younger and from 5.8 ± 0.3 to 5.0 ± 0.4 to 4.7 ± 0.4% in older adults, P less than 0.05 for main effect. Older adult groups with differing baseline CRP had the same IL-6, blood pressure, and FMD response to acute inflammation, P less than 0.05 for all interactions, but the low-CRP group increased CRP at 24 and 48 h (from 0.5 ± 0.1 to 1.4 ± 0.2 to 1.7 ± 0.3 mg/l), whereas the high-CRP group did not (from 4.8 ± 0.5 to 5.4 ± 0.5 to 5.4 ± 0.6 mg/l), P less than 0.001 for interaction. Aging, not age-related chronic, low-grade inflammation, determines the vascular responses to acute inflammation.

Vascular function assessed by passive leg movement and flow-mediated dilation: initial evidence of construct validity

The vasodilatory response to passive leg movement (PLM) appears to provide a novel, noninvasive assessment of vascular function. However, PLM has yet to be compared with the established noninvasive assessment of vascular health, flow-mediated dilation (FMD). Therefore, as an initial evaluation of the construct validity of PLM and upright seated and supine PLM as well as brachial (BA) and superficial femoral (SFA) artery FMDs were performed in 10 young (22 ± 1) and 30 old (73 ± 2) subjects. During upright seated PLM, the peak change in leg blood flow (ΔLBF) and leg vascular conductance (ΔLVC) was significantly correlated with BA (r = 0.57 and r = 0.66) and SFA (r = 0.44 and r = 0.41, ΔLBF and ΔLVC, respectively) FMD. Furthermore, although the relationships were not as strong, the supine PLM response was also significantly correlated with BA (r = 0.38 and r = 0.35) and SFA (r = 0.39 and r = 0.35, ΔLBF and ΔLVC, respectively) FMD. Examination of the young and old separately, however, revealed that significant relationships persisted in both groups only for the upright seated PLM response and BA FMD (young: r = 0.73 and r = 0.77; old: r = 0.35 and r = 0.45, ΔLBF and ΔLVC, respectively). Normalizing FMD for shear rate during PLM abrogated all significant relationships between the PLM and FMD response, suggesting a role for nitric oxide (NO) in these associations. Collectively, these data indicate that PLM, particularly upright seated PLM, likely provides an index of vascular health analogous to the traditional FMD test. Given the relative ease of PLM implementation, these data have important positive implications for PLM as a clinical vascular health assessment.

Abstract P157: Assessment of Vascular Endothelial Function in Postural Tachycardia Syndrome and Healthy Controls

Postural tachycardia syndrome (POTS) is a heterogeneous disorder characterized by an excessive rise in HR and symptoms consistent with cerebral hypoperfusion while upright. Increased sympathetic activity may contribute to this condition and may also impair nitric oxide (NO)-function. We evaluated NO function using flow-mediated dilation (FMD) and Peripheral Artery Tonometry (PAT) in POTS patients and age-matched controls. We studied 16 POTS patients (30±2 years, BMI 22.3±1 kg/m 2 ) and 7 healthy control subjects (HC; 31±2 years, BMI 22.1±1 kg/m 2 ). Medications affecting BP, blood volume, the immune system, and autonomic function, were withheld for ≥5 half-lives. All subjects followed the same low-monoamine, caffeine-free diet for ≥3 days before testing. Endothelial function was measured as the percentage change in FMD (%FMD) and using the reactive hyperemic index (RHI) for PAT. We also measured autonomic function, plasma levels of catecholamines, renin activity (PRA) and aldosterone. We found that POTS patients had a significantly blunted FMD (6.11±0.8 vs. 9.67±1.6 %, P=0.049, figure), compared to healthy controls. This blunted FMD response was similar as what our group has reported in obese hypertensive females (N=13, 5.7±0.9%, figure). Also, as expected they had higher upright HR (121±6 vs. 90±6 bpm, for POTS and HC, P=0.020). There were no differences in PAT (2.08±0.12, vs. 1.8±0.13 RHI, for POTS and HC, P=0.168). There were no differences in norepinephrine (765±150 vs. 545±39 pg/mL, P=0.955), renin activity (5.3±1.3 vs. 5.2±1.6 ng/mL/hr, P=0.735) or aldosterone (19.6±3.8 vs. 15.9±5.5 ng/dL, P=0.129).

High‐flow‐mediated constriction in adults is not influenced by biomarkers of cardiovascular and metabolic risk

During reactive hyperemia, the brachial artery in some individuals constricts prior to dilation. Our aim was to describe the frequency of high-flow-mediated constriction (H-FMC) in adults, and its relationship to body composition and biomarkers of cardiovascular and metabolic risk. Two hundred forty-six adults (124 male, 122 female; 36 ± 7 years old) were assessed for H-FMC via sonographic imaging of the brachial artery. Blood pressure, glucose, insulin, lipids, and body composition assessed via dual energy X-ray absorptiometry were collected. H-FMC was characterized as a 10-second average of maximal postocclusion constriction. Independent t test was used to compare H-FMC versus non-H-FMC individuals. H-FMC was observed in approximately 69% of adult participants (54 obese, 57 overweight, and 59 normal weight). Total body mass (82.3 ± 17.5 versus 76.3 ± 16.3 kg, p = 0.012), fat mass (27.7 ± 11.5 versus 23.8 ± 10.5 kg, p = 0.012), body mass index (27.7 ± 4.9 versus 26.1 ± 5.0 kg/m2 , p = 0.018), and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (2.41 ± 1.03 versus 2.09 ± 0.72, p = 0.007) were higher in H-FMC than in non-H-FMC individuals. Flow-mediated dilatation (FMD) (6.12 ± 3.48 versus 8.09 ± 3.02%, p < 0.001) was lower in H-FMC subjects. However, there was no difference in brachial artery dilation between groups (7.57 ± 3.69 versus 8.09 ± 3.02%, p = 0.250) when H-FMC was added to FMD. Increased body mass, fat mass, and body mass index were associated with a greater H-FMC. When H-FMC was present, the FMD response to reactive hyperemia was significantly lower. Because H-FMC has been observed to negatively affect FMD response to reactive hyperemia, we suggest that H-FMC should be noted when analyzing and interpreting FMD data. H-FMC may be an ancillary measure of endothelial health. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:35-42, 2017.

The relationship of pro-inflammatory markers to vascular endothelial function after acute stroke

Purpose/Aim: Data from chronic stroke studies have reported reduced blood flow and vascular endothelial function in the stroke-affected limb. It is unclear whether these differences are present early after stroke. First, we investigated whether vascular endothelial function in the stroke-affected limb would be different from healthy adults. Second, we examined whether between-limb differences in vascular endothelial function existed in the stroke-affected arm compared to the non-affected arm. Last, we tested whether reduced vascular endothelial function was related to pro-inflammatory markers that are present early after stroke. Materials and Methods: Vascular endothelial function was assessed by flow-mediated dilation (FMD) in the brachial artery within 72 h post-stroke. All participants withheld medications from midnight until after the procedure. Ultrasound scans and blood draws for pro-inflammatory markers occurred on the same day between 7:30 am and 9:00 am. Results: People with acute stroke had significantly lower FMD (4.2% ± 4.6%) than control participants (8.5% ± 5.2%, p = 0.037). Stroke participants had between-limb differences in FMD (4.2% ± 4.6% stroke-affected vs. 5.3% ± 4.4% non-affected, p = 0.02), whereas, the control participants did not. Of the pro-inflammatory markers, only vascular cell adhesion molecule-1(VCAM-1) had a significant relationship to FMD (stroke-affected limb, r = −0.62, p = 0.03; non-affected limb, r = −0.75, p = 0.005), but not tumor necrosis factor alpha nor interleukin-6. Conclusions: Vascular endothelial function is reduced starting in the early stage of stroke recovery. People with higher levels of VCAM-1 had a lower FMD response.

Reactivity to low-flow as a potential determinant for brachial artery flow-mediated vasodilatation.

Previous studies have reported a vasoconstrictor response in the radial artery during a cuff‐induced low‐flow condition, but a similar low‐flow condition in the brachial artery results in nonuniform reactivity. This variable reactivity to low‐flow influences the subsequent flow‐mediated dilatation (FMD) response following cuff‐release. However, it is uncertain whether reactivity to low‐flow is important in data interpretation in clinical populations and older adults. This study aimed to determine the influence of reactivity to low‐flow on the magnitude of brachial artery FMD response in middle‐aged and older individuals with diverse cardiovascular risk profiles. Data were analyzed from 165 individuals, divided into increased cardiovascular risk (CVR: n = 115, 85M, 67.0 ± 8.8 years) and healthy control (CTRL: n = 50, 30M, 63.2 ± 7.2 years) groups. Brachial artery diameter and blood velocity data obtained from Doppler ultrasound were used to calculate FMD, reactivity to low‐flow and estimated shear rate (SR) using semiautomated edge‐detection software. There was a significant association between reactivity to low‐flow and FMD in overall (r = 0.261), CTRL (r = 0.410) and CVR (r = 0.189, all P < 0.05) groups. Multivariate regression analysis found that reactivity to low‐flow, peak SR, and baseline diameter independently contributed to FMD along with sex, the presence of diabetes, and smoking (total R 2 = 0.450). There was a significant association between reactivity to low‐flow and the subsequent FMD response in the overall dataset, and reactivity to low‐flow independently contributed to FMD. These findings suggest that reactivity to low‐flow plays a key role in the subsequent brachial artery FMD response and is important in the interpretation of FMD data.

Novel Characterisation of In-Exercise Vascular Shear Rate

PURPOSE: Exercise induced changes in vascular shear stress act as the stimulus for improvements in endothelial function. Similar improvements in endothelial function have been found with interval (IT) compared to continuous (CON) exercise. This study aimed to distinguish the differing patterns of shear produced by these protocols and determine whether these patterns differentially influence acute changes in endothelial function. METHODS: 9 healthy (23 ± 3 yrs, 23.9 ± 2.1 kg/m2, 7 male vs. 2 female) participants completed a ramp incremental test on a supine ergometer. Participants then completed 4 different intensity and duration matched protocols consisting of 24 min at work rates (WR) equivalent to 125% lactate threshold (LT): (i) continuous exercise (CON), (ii) 180s of work interspersed with 180s of active recovery (10 W: LONG IT), (iii) 60s of work with 60s active recovery (SHORT IT) and (iv) 180s second work with 180s recovery at WR equivalent to 70% LT (LONG IT 70). During each protocol heart rate and breath by breath gas exchange was measured in addition to Doppler ultrasound assessment of shear rate in the brachial artery. Flow Mediated Dilation (FMD) using ultrasound was used as an index of endothelial function pre and 15 min post each protocol. Data were assessed via two-way repeated measures ANOVA for protocol and time. RESULTS: Anterograde shear increased continuously during CON and SHORT IT but mirrored changes in WR during both LONG protocols. Retrograde shear remained low in CON and oscillated with WR during IT. Peak retrograde shear was greater in IT than in CON (P<0.05) but did not differ between IT protocols. However, total volumes of anterograde and retrograde shear (all protocol mean respectively: 557113 ± 180159 s−1 and 180074 ± 80960 s−1) and the oscillatory shear index (0.26 ± 0.07) were similar across all protocols (P>0.05). FMD increased by an average of 2.45 ± 3.83 % (P<0.05) following exercise with no difference between protocols (P>0.05). CONCLUSION: When exercise sessions are matched for intensity and duration, variable shear rate patterns during IT and CON protocols do not differentially affect acute FMD responses. IT exercises of varying duty cycle length are equally as effective at improving endothelial function as traditional CON exercise.

Novel Form of Curcumin Improves Endothelial Function in Young, Healthy Individuals

It is known that endothelial dysfunction (ED) may increase the risk of cardiovascular disease (CVD). ED can be measured as a decreased flow‐mediated dilation (FMD) response, using occlusion and subsequent dilation response of the brachial artery. Increased levels of inflammatory molecules contribute to ED, and increase CVD. Curcumin, a highly pleiotropic molecule, interacts with multiple inflammatory pathways primarily by inhibiting the IκB Kinase (IKK) signaling complex thereby preventing the activation of nuclear factor‐kappa B (NF‐κB). However, poor solubility and rapid metabolism may limit benefits. CurcuWIN®, a novel curcumin formulation containing 20% curcuminoids (CUR), resulted in 45.9 fold greater absorption over standard curcumin. This current study sought to examine the effect of differing doses of a novel form of curcumin on FMD. Fifty‐nine moderately trained men (n=30; 21±2 years; 173.8±20.0 cm; 79.4±11.0 kg) and women (n=29; 21±2 years; 164.9±6.5 cm; 60.1±8.0 kg) were randomly assigned to ingest 50 mg CUR (in the form of 250 mg CurcuWIN®), 200 mg CUR (in the form of 1000 mg CurcuWIN®), or placebo (PLA) for eight weeks in a double‐blind, randomized, placebo controlled parallel design. ANOVA and paired t‐tests were used to examine differences followed by magnitude based inference. Subsequently, a subset analyses was performed on subjects with a baseline FMD ≤7%. An improvement of magnitude (Effect size [ES] = 0.67) of FMD was observed in those receiving 200mg CUR (Pre, 7.6±3.2%; Post, ↑10.4±3.5%; p=0.011). FMD improvement (↑2.8±3.3%) was beneficial compared to PLA (↓−0.8±5.4%; p=0.020). No change was observed in those receiving 50MG CUR (Pre, 8.2±3.3%; Post, ↑9.1±2.7%; p=0.405). Twenty‐five (PLA, n=8; 50MG, n=7; 200MG, n=10) had baseline FMD &lt;7%. Supplementation resulted in improvement of very large magnitude (ES &gt; 2.0) in those receiving 50MG (Pre, 4.9±1.4%; Post, 8.1±1.6%; p=0.029) and 200MG (Pre, 5.2±1.1%; Post, ↑8.9±3.5%; p=0.005). These data demonstrate 200mg CUR improves FMD (endothelial function) in healthy young subjects. Further, in those with baseline FMD ≤7% FMD (at risk) 50mg CUR and 200mg CUR improves endothelial function. Given every 1% increase in FMD reduces cardiovascular disease risk by 9–17%; further research in clinical populations is recommended to clarify the true nature of the effect and potential mechanism(s).Support or Funding InformationOmniActive Health Technologies Ltd. Mumbai, India

Mitochondrial DNA damage and vascular function in patients with diabetes mellitus and atherosclerotic cardiovascular disease.

ObjectivePrior studies demonstrate mitochondrial dysfunction with increased reactive oxygen species generation in peripheral blood mononuclear cells in diabetes mellitus. Oxidative stress-mediated damage to mitochondrial DNA promotes atherosclerosis in animal models. Thus, we evaluated the relation of mitochondrial DNA damage in peripheral blood mononuclear cells s with vascular function in patients with diabetes mellitus and with atherosclerotic cardiovascular disease.Approach and resultsWe assessed non-invasive vascular function and mitochondrial DNA damage in 275 patients (age 57 ± 9 years, 60 % women) with atherosclerotic cardiovascular disease alone (N = 55), diabetes mellitus alone (N = 74), combined atherosclerotic cardiovascular disease and diabetes mellitus (N = 48), and controls age >45 without diabetes mellitus or atherosclerotic cardiovascular disease (N = 98). Mitochondrial DNA damage measured by quantitative PCR in peripheral blood mononuclear cells was higher with clinical atherosclerosis alone (0.55 ± 0.65), diabetes mellitus alone (0.65 ± 1.0), and combined clinical atherosclerosis and diabetes mellitus (0.89 ± 1.32) as compared to control subjects (0.23 ± 0.64, P < 0.0001). In multivariable models adjusting for age, sex, and relevant cardiovascular risk factors, clinical atherosclerosis and diabetes mellitus remained associated with higher mitochondrial DNA damage levels (β = 0.14 ± 0.13, P = 0.04 and β = 0.21 ± 0.13, P = 0.002, respectively). Higher mitochondrial DNA damage was associated with higher baseline pulse amplitude, a measure of arterial pulsatility, but not with flow-mediated dilation or hyperemic response, measures of vasodilator function.ConclusionsWe found greater mitochondrial DNA damage in patients with diabetes mellitus and clinical atherosclerosis. The association of mitochondrial DNA damage and baseline pulse amplitude may suggest a link between mitochondrial dysfunction and excessive small artery pulsatility with potentially adverse microvascular impact.

Impaired handgrip exercise-induced brachial artery flow-mediated dilation in young obese males.

Flow mediated dilation (FMD) stimulated by different shear stress stimulus profiles may recruit distinct transduction mechanisms, and provide distinct information regarding endothelial function. The purpose of this study was to determine whether obesity influences brachial artery FMD differently depending on the shear stress profile used for FMD assessment. The FMD response to a brief, intermediate, and sustained shear stress profile was assessed in obese (n = 9) and lean (n = 19) young men as follows: brief stimulus, standard reactive hyperemia (RH) following a 5 min forearm occlusion (5 min RH); intermediate stimulus, RH following a 15 min forearm occlusion (15 min RH); sustained stimulus, 10 min of handgrip exercise (HGEX). Brachial artery diameter and mean shear stress were assessed using echo and Doppler ultrasound, respectively, during each FMD test. There was no group difference in HGEX shear stress (p = 0.390); however, the obese group had a lower HGEX-FMD (5.2 ± 3.0% versus 11.5 ± 4.4%, p < 0.001). There was no group difference in 5 min RH-FMD (p = 0.466) or 15 min RH-FMD (p = 0.181); however, the shear stress stimulus was larger in the obese group. After normalization to the stimulus the 15 min RH-FMD (p = 0.002), but not the 5 min RH-FMD (p = 0.118) was lower in the obese group. These data suggest that obesity may have a more pronounced impact on the endothelium's ability to respond to prolonged increases in shear stress.

Single Low-Density Lipoprotein Apheresis Does Not Improve Vascular Endothelial Function in Chronically Treated Hypercholesterolemic Patients.

Objective. To investigate vascular endothelial function (VEF) responses to a single low-density lipoprotein (LDL) apheresis session in hypercholesterolemic patients undergoing chronic treatment. Methods. We measured brachial artery flow-mediated dilation (FMD), plasma lipids, vitamin E (α- and γ-tocopherol), markers of oxidative/nitrative stress (malondialdehyde (MDA) and nitro-γ-tocopherol (NGT)), and regulators of NO metabolism (arginine (ARG) and asymmetric dimethylarginine (ADMA)) prior to (Pre) and immediately following (Post) LDL apheresis and at 1, 3, 7, and 14 d Post in 5 hypercholesterolemic patients (52 ± 11 y). Results. Relative to Pre, total cholesterol (7.8 ± 1.5 mmol/L) and LDL-cholesterol (6.2 ± 1.2 mmol/L) were 61% and 70% lower (P < 0.01), respectively, at Post and returned to Pre levels at 14 d. Brachial FMD responses (6.9 ± 3.6%) and plasma MDA, ARG, and ADMA concentrations were unaffected by LDL apheresis. Plasma α-tocopherol, γ-tocopherol, and NGT concentrations were 52–69% lower at Post (P < 0.01), and α-tocopherol remained 36% lower at 1 d whereas NGT remained 41% lower at d 3. Conclusions. Acute cholesterol reduction by LDL apheresis does not alter VEF, oxidative stress, or NO homeostasis in patients treated chronically for hypercholesterolemia.

Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study

Background: The beneficial cardiovascular effects of vegetables may be underpinned by their high inorganic nitrate content.Objective: We sought to examine the effects of a 6-wk once-daily intake of dietary nitrate (nitrate-rich beetroot juice) compared with placebo intake (nitrate-depleted beetroot juice) on vascular and platelet function in untreated hypercholesterolemics.Design: A total of 69 subjects were recruited in this randomized, double-blind, placebo-controlled parallel study. The primary endpoint was the change in vascular function determined with the use of ultrasound flow-mediated dilatation (FMD).Results: Baseline characteristics were similar between the groups, with primary outcome data available for 67 patients. Dietary nitrate resulted in an absolute increase in the FMD response of 1.1% (an ∼24% improvement from baseline) with a worsening of 0.3% in the placebo group (P < 0.001). A small improvement in the aortic pulse wave velocity (i.e., a decrease of 0.22 m/s; 95% CI: −0.4, −0.3 m/s) was evident in the nitrate group, showing a trend (P = 0.06) to improvement in comparison with the placebo group. Dietary nitrate also caused a small but significant reduction (7.6%) in platelet-monocyte aggregates compared with an increase of 10.1% in the placebo group (P = 0.004), with statistically significant reductions in stimulated (ex vivo) P-selectin expression compared with the placebo group (P < 0.05) but no significant changes in unstimulated expression. No adverse effects of dietary nitrate were detected. The composition of the salivary microbiome was altered after the nitrate treatment but not after the placebo treatment (P < 0.01). The proportions of 78 bacterial taxa were different after the nitrate treatment; of those taxa present, 2 taxa were responsible for >1% of this change, with the proportions of Rothia mucilaginosa trending to increase and Neisseria flavescens (P < 0.01) increased after nitrate treatment relative to after placebo treatment.Conclusions: Sustained dietary nitrate ingestion improves vascular function in hypercholesterolemic patients. These changes are associated with alterations in the oral microbiome and, in particular, nitrate-reducing genera. Our findings provide additional support for the assessment of the potential of dietary nitrate as a preventative strategy against atherogenesis in larger cohorts. This trial was registered at clinicaltrials.gov as NCT01493752.

Peak shear and peak flow mediated dilation: a time-course relationship.

To explore the temporal relationship between brachial artery peak shear stress (Shear) and flow-mediated dilation (FMD) in children and adults. Shear and brachial artery diameter were tracked following reactive hyperemia in 122 children and 350 adults using sonographic imaging. Peak Shear, Shear area under the curve (Shear(AUC)), and Peak FMD were significantly larger in children than in adults. The time to peak Shear (Shear(TTP)) and time to peak FMD (FMD(TTP)) were significantly lower in children, while there was no significant difference in time from Shear(TTP) to FMD(TTP) between children and adults. Children have a lower shear stimulus and FMD response than adults, but the time interval separating these events is similar. These differences could be due to changes in vascular dynamics with age, including reduced smooth muscle cell responsiveness and other factors. Despite differences in timing, the interval from peak Shear to peak FMD was similar in children and adults.

Vascular responsiveness determined by near-infrared spectroscopy measures of oxygen saturation.

Vascular impairments at the macro- and microcirculatory levels are associated with increased risk for cardiovascular disease. Flow-mediated dilation (FMD) is currently the most widely used method for non-invasive assessment of vascular endothelial function. Recently, near-infrared spectroscopy (NIRS)-derived measures of tissue oxygen saturation (StO2) have been used to characterize the dynamic response of local tissue perfusion to a brief period of ischaemia. The purpose of the present study was to establish correlations between the reperfusion rate of StO2 and FMD. Ultrasound-derived FMD was quantified after 5 min of distal cuff occlusion of the popliteal artery in 20 healthy young men (26 ± 3 years old). Triplicate measurements of end-diastolic arterial diameter were made every 15 s after cuff release, and FMD response was calculated as the greatest percentage change in diameter from baseline (%FMD). The StO2 was measured using NIRS throughout the duration of each test. Two consecutive FMD tests were performed, separated by 30 min of rest, and were averaged for %FMD and StO2. The %FMD was significantly correlated with the reperfusion slope of StO2 after cuff release (slope 2 StO2; r = 0.63, P = 0.003). In conclusion, the present study established a correlation between slope 2 StO2 and %FMD in healthy young men. These data suggest that NIRS-derived slope 2 StO2 can be used as a measure of vascular endothelial function.

Comprehensive assessment of impaired peripheral and coronary artery endothelial functions in smokers using brachial artery ultrasound and oxygen-15-labeled water PET

BackgroundComprehensive evaluation of endothelium-dependent and endothelium-independent vascular functions in peripheral arteries and coronary arteries in smokers has never been performed previously. Through the use of brachial artery ultrasound and oxygen-15-labeled water positron emission tomography (PET), we sought to investigate peripheral and coronary vascular dysfunctions in smokers. Methods and resultsEight smokers and 10 healthy individuals underwent brachial artery ultrasound at rest, during reactive hyperemia [250mmHg cuff occlusion (flow-mediated dilatation (FMD)], and following sublingual nitroglycerin (NTG) administration. Myocardial blood flow (MBF) was assessed through O-15-labeled water PET at rest, during adenosine triphosphate (ATP) administration, and during a cold pressor test (CPT). Through ultrasound, smokers were shown to have significantly reduced %FMD compared to controls (6.62±2.28% vs. 11.29±2.75%, p=0.0014). As assessed by O-15-labeled water PET, smokers were shown to have a significantly lower CPT response than were controls (21.1±9.5% vs. 50.9±16.9%, p=0.0004). There was no relationship between %FMD and CPT response (r=0.40, p=0.097). Endothelium-independent vascular dilatation was similar for both groups in terms of coronary flow reserve with PET (p=0.19). Smokers tended to have lower %NTG in the brachial artery (p=0.055). ConclusionsSmokers exhibited impaired coronary endothelial function as well as peripheral brachial artery endothelial function. In addition, there was no correlation between PET and ultrasound measurements, possibly implying that while smokers may have systemic vascular endothelial dysfunction, the characteristics of that dysfunction may be different in peripheral arteries and coronary arteries.

Fenofibrate effects on arterial endothelial function in adults with type 2 diabetes mellitus: A FIELD substudy

ObjectiveDislipidaemia in type 2 diabetes mellitus contributes to arterial endothelial dysfunction and an increased risk of cardiovascular disease. Fenofibrate, a lipid-regulating peroxisome proliferator-activated receptor-α (PPARα) agonist, has been shown to reduce vascular complications in adults with type 2 diabetes. However, the mechanisms for such benefit are not well understood. We examined the effects of fenofibrate on brachial artery endothelial function in adults with type 2 diabetes. MethodsIn a prospectively designed substudy of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, we assessed arterial flow-mediated dilatation (FMD; endothelium-dependent dilatation) and dilator responses to glyceryl trinitrate (GTN, an endothelium-independent dilator) in a subset of 193 representative adults. Traditional risk factors were assessed at baseline, 4 months and 2 years after randomised treatment allocation to fenofibrate (200 mg daily) or placebo. The prespecified primary study endpoint was the difference in FMD between treatment groups at 4 months. ResultsFenofibrate was associated with a significant improvement at 4 months compared with placebo (+1.05% (absolute); P=0.03); GTN-dilator responses were unchanged (P=0.77). After 2 years, FMD was similar in both groups (P=0.46). In multivariable models, none of the fenofibrate-related changes in lipoproteins and lipids were significantly associated with improved FMD on fenofibrate at 4 months. ConclusionTreatment with fenofibrate significantly improved arterial endothelial function after 4 months. However, the effect was no longer apparent after 2 years. The long-term beneficial vascular effects of fenofibrate in type 2 diabetes are likely to be mediated via mechanisms other than improvement in endothelium-dependent dilatation of conduit arteries, and may differ for the microcirculation.