Reactive Hyperemia Index Research Articles

Reactive hyperemia index is suitable for screening endothelial dysfunction especially in obese subjects with non-alcoholic hepatitis

Aim: Reactive hyperemia index (RHI) assessed by reactive hyperemia-peripheral arterial tonometry (RH-PAT), is associated with flow mediated dilatation (FMD). Recent studies suggested that the RHI may be predictable for mortality in subjects at high risks for cardiovascular events. On the other hand, carotid intima-media thickness (IMT), pulse wave velocity (PWV) and/or Cardio ankle vascular index (CAVI) are known to be used for screening vascular disorders. Since obesity and metabolic syndrome are at risks of cardiovascular events, we aimed to examine the association of the RHI, CAVI, and plaque score (PS) in carotid arteries with body mass index (BMI).

Reactive Hyperemia is Decreased in Black Subjects with Heart Failure Despite Equal Prescription of Guideline-Directed Medical Therapy

Background Impaired vascular function in Black Americans contributes to a higher risk of heart failure compared to other race/ethnicities. Augmentation of digital pulse volume amplitude (PVA) in response to hyperemia is a novel measure of microvascular function that is partially nitric oxide dependent, and is related to adverse cardiovascular events. We sought to examine augmentation of digital PVA in blacks and whites with heart failure to determine if guideline-directed medical therapy (GDMT) ameliorates racial differences in vascular function. Methods We assessed vascular function in 139 subjects with heart failure with reduced ejection fraction. Using digital pulse amplitude tonometry (EndoPAT), we estimated the reactive hyperemia index (RHI). Generalized linear models were used to determine if race was predictive of the RHI after adjustment for age, sex, blood pressure, diabetes, body mass index, lipid profile, serum creatinine, and number of vasodilator drugs as GDMT. Results Compared with whites, blacks were younger (51 ± 4 vs. 59 ± 11 years, P Figure ). Conclusion Black race is associated with impaired microvascular vasodilatory function, despite equal prescription of GDMT. Whether the vascular impairment seen in Blacks is associated with increased risk for adverse clinical outcomes in HF warrants further investigation.

Cardiovascular adaptations after 10 months of intense school-based physical training for 8- to 10-year-old children.

This study examined cardiovascular adaptations in 8- to 10-year-old schoolchildren after 10months (a full school year) of 3×40minute per week of small-sided ball games (SSG, including football, basketball, and/or floorball) or circuit strength training (CST). The study involved 291 Danish schoolchildren, 8-10 years old, cluster-randomized to SSG (n=93, 4 schools, 5 classes), CST (n=83, 4 schools, 4 classes), or a control group (CON, n=115, 2 schools, 5 classes). Before and after the 10-month intervention, resting heart rate and blood pressure measurements were performed as well as comprehensive transthoracic echocardiography and peripheral arterial tonometry (PAT). Analysis of baseline-to-10-months changes showed between-group differences (P<0.05) after both training interventions in diastolic blood pressure (delta scores: SSG -2.1±6.0mmHg; CST -3.0±7.1mmHg; CON 0.2±5.3mmHg). Moreover, there were between-group differences in delta scores (P<0.05) in interventricular septum thickness (SSG 0.17±0.87mm; CST 0.30±0.94mm; CON -0.15±0.68mm), left-atrial volume index (SSG 0.32±5.13mL/m2 ; CON 2.60±5.94mL/m2 ), and tricuspid annular plane systolic excursion (SSG -0.4±3.3mm; CON: 0.1±3.6mm). No significant between-group differences were observed for the PAT-derived reactive hyperemia index. In conclusion, 10months of 3×40minutes per week of SSG and CST in 8- to 10-year-old children decreased diastolic blood pressure and elicited discrete cardiac adaptations, suggesting that intense physical exercise in school classes can have effects on cardiovascular health in children.

Arginine impairs endothelial and executive function in older subjects with cardiovascular risk

Neurovascular coupling, the relationship between cerebral blood flow and neuronal activity, is attenuated in patients with impaired executive function. We tested the hypothesis that peripheral vascular function may associate with executive function in older subjects with cardiovascular risk factors and that treatment with the antioxidant L-arginine would improve both vascular and executive function. Nineteen subjects with type 2 diabetes mellitus and/or controlled hypertension were enrolled. Subjects were treated with L-arginine or placebo for 4 days in a randomized, double-blinded, cross-over study. Brachial artery vascular function, peripheral artery tonometry, and Trail Making Test Part B testing were performed on day 1 and day 4 during each condition. L-arginine significantly reduced the digital reactive hyperemia index, and the comparison of changes against placebo was significant (P = .01). With executive function testing, we observed a significant interaction between treatment and order. Restricting the analysis to the first treatment period, subjects treated with placebo decreased their Trail Making Test Part B times by 57.3 ± 52.5 seconds from day 1 to day 4 (P = .01) while those treated with arginine had no significant change (6.4 ± 18.4 seconds worse, P = .37). In addition, L-arginine was associated with increased mean arterial pressure from 88 ± 9 mm Hg to 92 ± 11 mm Hg, which trended toward significance. L-arginine treatment worsened digital microvascular and executive function in older subjects with cardiovascular risk factors. These data further support a link between vascular and executive function.

Increased aortic wave reflection contributes to higher systolic blood pressure in adolescents born preterm.

To evaluate the wave reflection characteristics in the aortic arch and common carotid artery of ex-preterm adolescents and assess their relationship to central blood pressure in a cohort followed prospectively since birth. Central blood pressures, pulse wave velocity, augmentation index, microvascular reactive hyperemia, arterial distensibility, compliance and stiffness index, and also aortic and carotid wave intensity were measured in 18-year-olds born extremely preterm at below 28 weeks' gestation (n = 76) and term-born controls (n = 42). Compared with controls, ex-preterm adolescents had higher central systolic (111 ± 11 vs. 105 ± 10 mmHg; P < 0.001) and diastolic blood pressures (73 ± 7 vs. 67 ± 7 mmHg; P < 0.001). Although conventional measures of arterial function and biomechanics such as pulse wave velocity and augmentation index were no different between groups, wave intensity analysis revealed elevated backward compression wave area (-0.39 ± 0.21 vs. -0.29 ± 0.17 W/m/s × 10; P = 0.03), backward compression wave pressure change (9.0 ± 3.5 vs. 6.6 ± 2.5 mmHg; P = 0.001) and reflection index (0.44 ± 0.15 vs. 0.32 ± 0.08; P < 0.001) in the aorta of ex-preterm adolescents compared with controls. These changes were less pronounced in the carotid artery. On multivariable analysis, forward and backward compression wave areas were the only biomechanical variables associated with central systolic pressure. Ex-preterm adolescents demonstrate elevated wave reflection indices in the aortic arch, which correlate with central systolic pressure. Wave intensity analysis may provide a sensitive novel marker of evolving vascular dysfunction in ex-preterm survivors.

Improvement of arterial wall phenotype in subjects at moderate cardiovascular risk induced by very low-dose fluvastatin/valsartan combination: a pilot study.

The largest population that suffers from cardiovascular events are subjects at moderate cardiovascular risk. However, no effective and safe preventive treatment is available for this population. We investigated whether their arterial wall phenotype could be turned to a lower risk direction by low-dose fluvastatin/valsartan combination (low-flu/val). Twenty males at moderate cardiovascular risk (as classified by SCORE) were blindly randomized into the intervention group (N.=10, low-flu/val: 10 mg/20 mg) or control group (N.=10, placebo). At inclusion and after 30 days of treatment, brachial flow-mediated dilatation (FMD), β-stiffness coefficient, carotid pulse wave velocity (c-PWV), carotid-femoral PWV, Reactive Hyperemia Index, high-sensitivity C-reactive protein (hs-CRP), interleukin 6, vascular cell adhesion molecule 1, total antioxidant status and expression of several protective genes (SIRT1, mTOR, NF-κB1, NFE2L2, PRKAA1) were followed. Treatment resulted in improved FMD (from 3% to 4.2%, P=0.008), c-PWV (from 6.7 to 6.2 m/s, P=0.006), hs-CRP (from 5.39 to 3.35 mg/L, P=0.041) and SIRT1 expression (3.34-fold difference, P=0.047). No other vascular, inflammation and genetic parameters changed. The hs-CRP values after intervention correlated significantly with SIRT1 expression. The improved FMD persisted even 10 weeks after treatment discontinuation. The obtained changes were not followed by changes of lipids or blood pressure. Overall, the results revealed improvement in three different, although interrelated preventive arterial wall characteristics. This pilot study revealed that intervention with low-flu/val importantly shifts the arterial wall phenotype in a lower risk direction. This improvement could be interpolated into clinical benefits that remain to be further studied.

Association between nondipping pattern and EndoPAT signal in patients with mild obstructive sleep apnea

ObjectiveTo compare vascular endothelial function between dipping (D) and nondipping (ND) patterns in patients with and without mild obstructive sleep apnea (OSA) using EndoPAT, a test of reactive hyperemia used to assess peripheral vascular endothelial function. MethodsThe sample consisted of individuals of both genders between 18 and 65 years of age with a body mass index (BMI) of ≤35 kg/m2 and apnea/hypopnea index (AHI) of ≤15. The nondipping pattern was considered present when the dip of nocturnal blood pressure (NBP) was <10%. All of the sample underwent clinical and physical evaluation, full polysomnography, 24-hour ambulatory blood pressure monitoring, and EndoPAT evaluation. A generalized linear model was used for statistical analysis. ResultsThe sample comprised 120 individuals, 35 in the control group and 85 in the mild OSA group. Four groups were formed: Control-ND, Control-D, Mild OSA-ND, and Mild OSA-D according to nocturnal ABPM patterns. The frequency of nondipping was (34.1%) in the Mild OSA group and (17.1%) in the Control group (p = 0.07). The Mild OSA-ND group had a higher augmentation index (AIx) than the Mild OSA-D group. Regression analysis showed that male gender, higher age, and nondipping status were associated with these results, whereas oxygen desaturation index (ODI) and AHI did not. With respect to the reactive hyperemia index (RHI), the Mild OSA-D group had lower values compared to the Control-ND group, but an association with OSA was not confirmed in the regression model. ConclusionNondipping status was associated with a worse augmentation index in both groups independently of AHI or oxygen desaturation index. Male gender, higher age, and nondipping status were associated with augmentation index.ClinicalTrials.gov Identifier: NCT01461486.

Improvement of Vascular Endothelial Function at an Early Stage by the Original Stretching Exercise Designed in Our Study Group in Patients with Type 2 Diabetes Mellitus

Background and Aims: Vascular endothelial cells play an important role in protecting and repairing vessels. It is little known that exercise therapy could ameliorate the vascular endothelial function in diabetic patients. In 2015, in collaboration with Tobu Sports Ltd. (Japan), we created the original exercise program including 12 kinds of body-stretching and converted the program to a DVD. The main aim in the present study is whether the exercise therapy using our original DVD would improve the vascular endothelial function in type 2 diabetic patients. Subjects and Methods: Ten patients with type 2 diabetic mellitus (M/F: 8/2, Age: 58.2±12.7 years) strictly performed the exercise program using the DVD for 12 weeks. Vascular endothelial function was estimated as a reactive hyperemia index (RHI) measured with Endo PAT (Nihon-Koden Ltd. Japan). Body compositions in patients were measured with MC-780 (Tanita Ltd. Japan). We evaluated CAVI or ABI as marker of arteriosclerosis. Various biomedical parameters were assayed in the study. Results: There was a significant increase in RHI before and after intervention (initiation: 1.63±0.3, after: 2.02±0.5, p&amp;lt;0.01). A marked increase in RHI was shown in 90% of patients (9/10). A single patient who showed a reduction in RHI was observed going up of HbA1c levels on a background of irregularity of diet therapy. Any significant alterations were obtained in neither metabolic markers including HbA1c, FPG and body compositions, nor CAVI and ABI during the study. Conclusions: The present study suggests that the intervention of exercise composed by various stretching actions could lead to improvement of vascular endothelial function at an early stage, different from alterations of other metabolic markers in diabetic patients. Thereby, we speculate that vascular endothelial function might be relatively sensitive against a stretching-exercise. Disclosure K. Hara: None. H. Shinozaki: None. M. Yamauchi: None. R. Naruse: None. M. Suetsugu: None. T. Tsuchiya: None. K. Takebayashi: None. T. Inukai: None.

Elevated Fibroblast Growth Factor-21 Protect Endothelial Function in Type 2 Diabetes Patients

Background: Fibroblast growth factor 21 (FGF-21) is a metabolic regulator with multiple effects on improving glucose metabolism and energy utilization. Recent researches pointed that FGF-21 protect endothelial function against high glucose induced cell damage. Our research tried to detect the relationship of FGF-21 and endothelial dysfunction in newly diagnosed type 2 diabetes (T2D) patients. Methods: Fifty newly diagnosed T2D patients and fifty healthy controls were recruited in the research. Clinical and biological data, FGF-21 were measured. Endothelial function was tested by reactive hyperaemia index (RHI) approved by American Food and Drug Administration. Results: T2DM patients had higher FGF-21 levels (155.57±85.3 vs. 117.39±68.9ug/l,P&amp;lt;0.05) and more serious endothelial dysfunction (1.73±0.51 vs. 2.05±0.52,P&amp;lt;0.05) than controls. RHI was negatively related with low density lipoprotein cholesterol (LDL-C) (r=-0.322, P&amp;lt;0.05) and positively with FGF-21 (r=0.543, P&amp;lt;0.01). In the multivariate linear analysis, FGF-21 (β=0.551,P&amp;lt;0.01) and LDL-C (β=-0.188,P&amp;lt;0.01) were independently predictors of RHI. FGF-21 was the protective factor of endothelial function in the T2D patients. Conclusions: T2D patients had endothelial dysfunction even in the early period. Elevated FGF-21 might protect endothelial dysfunction. Disclosure Y. Hu: None. Y. Xu: None. G. Wang: None.

The Effect of Liraglutide on 24-Hour Ambulatory Blood Pressure in Patients with T2DM—A Pilot Study

The GLP-1 receptor agonists have been shown to decrease blood pressure (BP) in clinical trials using office BP measurements. However, the effect of GLP-1 agonist liraglutide on 24-hour ambulatory blood pressure and on the nocturnal BP decrease (dipping) have not been adequately assessed in large trials. To better characterize the effect of GLP-1 agonists on 24-hour ambulatory BP in subjects with T2DM we conducted a randomized controlled trial comparing the effects of liraglutide to placebo. Eleven subjects with T2DM (mean age 58.6±7.4 years, female 63.7%, African-American 72.7%) were randomized to 8 weeks of treatment with liraglutide (n=6) or placebo (n=5). ABPM and EndoPAT (Peripheral Arterial Tone) for assessment of endothelial dysfunction were done at baseline, 4 weeks and 8 weeks of therapy. Mixed models with repeated measures was used to estimate the treatment effect over time. Treatment with liraglutide was found to increase the nighttime SBP (LSM±SE): 135.3±4.3 vs. 102.1±4.5 (mmHg), p=0.0015), diastolic BP (DBP) (74.7±6.1 vs. 57.5±5.6 (mmHg), p=0.047) and increase daytime heart rate (109.5±9.2 vs. 77.1±7.9 (mmHg), p=0.021) after adjusting for age, race, history of hypertension, current use of ACE-I/ARBs and Reactive Hyperemia Index (RHI). There was no significant change in BMI between baseline and 8 weeks (1.5±2.4 vs. 1.0±2.5 (kg/m2), p=0.65). After adjustment for treatment and other covariates, abnormal RHI (≤ 1.67) was associated with decreased nighttime SBP (110.6±3.4 vs. 126.8±3.4 (mmHg), p=0.0003), and increased nighttime DBP (69.1±5.0 vs. 63.2±5.1 (mmHg), p=0.16) although lack of power to detect the statistical significance. In conclusion, our study showed that treatment with liraglutide over 8 weeks was unable to correct the abnormal elevation in nocturnal BP known to occur in patients with T2DM. ABPM also confirmed the known side effect of increase in heart rate previously seen in other liraglutide trials. Abnormal RHI tended to be associated with all patients with high DBP. Disclosure D. Lovre: None. B. Katalenich: None. C. Carrion Olmeda: None. S.B. Camitta: None. A.N. Khan: None. V. Fonseca: Consultant; Self; Abbott. Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Eli Lilly and Company. Stock/Shareholder; Self; Amgen Inc.. Consultant; Self; Asahi Kasei Corporation, AstraZeneca, Novo Nordisk Inc., ADOCIA, Intarcia Therapeutics, Inc., Sanofi-Aventis. T.K. Thethi: None.

Fourteen-Day Study of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in Patients with Diabetes and Hypertension

Background: Praliciguat (IW-1973), a soluble guanylate cyclase stimulator, has been shown to augment nitric oxide (NO) signaling and reduce fasting plasma glucose and proteinuria in an animal model of diabetic nephropathy. In healthy adults, repeated oral doses of 15-40 mg were tolerated and lowered blood pressure (BP). Methods: This Phase 2a, double-blind, placebo (PBO)-controlled study assessed the effects of oral praliciguat in 26 patients with type 2 diabetes mellitus (T2DM) and hypertension on stable glycemic and BP-lowering therapy. Most (69%) were also on statins. Two praliciguat regimens were tested: (1) 40 mg QD for days 1-14 (N=10), and (2) 20 mg BID for days 1-7 then 40 mg QD for days 8-14 (N=10). Assessments included serum chemistry, fasting plasma glucose, BP and heart rate, platelet function, reactive hyperemia index (RHI), plasma biomarkers, and adverse events (AEs). Results: Results were similar for both praliciguat regimens and are here combined. After 14 days of treatment, praliciguat-treated patients had notable differences in least squares mean change from baseline (95% CI) relative to PBO in 24-hour mean arterial pressure [-4.7 mmHg (-10, 0.8)], heart rate [2.9 bpm (-0.7, 6.5)], fasting glucose [-13 mg/dL (-32, 7)], HOMA-IR [-26 (-58, 7)], total serum cholesterol [-26 mg/dL (-44, -7)], and LDL cholesterol [-20 mg/dL (-37, -3)]. Praliciguat had no effect on platelet function or RHI. Among the exploratory biomarkers tested, levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine were lower in praliciguat vs. PBO recipients. Both praliciguat dose regimens were generally well tolerated. Except for one serious AE of upper gastrointestinal hemorrhage, AEs in praliciguat-treated patients were mild. Conclusion: In this initial trial, praliciguat had beneficial effects on BP and metabolic parameters in T2DM patients with hypertension on standard therapies. Further clinical investigation of praliciguat in T2DM patients is warranted. Disclosure J.P. Hanrahan: Employee; Self; Ironwood. J.D. Wakefield: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. P.J. Wilson: None. P. Miller: None. J. Chickering: None. L. Morrow: Stock/Shareholder; Self; ProSciento. Employee; Spouse/Partner; Eli Lilly and Company. M.L. Hall: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G. Milne: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. Employee; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. A.T. Profy: Other Relationship; Self; Ironwood Pharmaceuticals.

Rapid Dose Escalation Study of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in Patients with Diabetes and Hypertension

Background: Impaired nitric oxide (NO) signaling through soluble guanylate cyclase (sGC) has been associated with microvascular complications of diabetes. Praliciguat (IW-1973), an sGC stimulator that enhances NO signaling, reduced fasting plasma glucose and proteinuria in an animal model of diabetic nephropathy. In a Phase 1 clinical study in healthy adults, doses of 15-40 mg were tolerated and lowered blood pressure (BP). Methods: This Phase 2a open-label in-clinic study assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of oral praliciguat in 11 patients with type 2 diabetes mellitus (T2DM) and hypertension on stable glycemic and BP therapy. Patients received sequential 3-day dosing cycles escalating through placebo (PBO), 10, 20, 30, 40 and 50 mg praliciguat QD. Assessments included adverse events (AEs), blood chemistry, ambulatory BP and heart rate, platelet function, and reactive hyperemia index (RHI). Results: The escalating dose regimen was generally well tolerated; there were no serious or severe AEs. Escalation in 2 patients was stopped due to asymptomatic BP lowering. Overall PK showed a median Tmax of 1-3 h, low to moderate variability, and ∼2-fold accumulation supporting QD dosing. Average 12-h daytime mean arterial BP decreased by 2 to 9 mmHg relative to time-matched PBO baseline across praliciguat dose levels, while heart rate increased 4 to 7 bpm. Notable changes from PBO baseline [mean (95% CI)] at the end of treatment were seen for fasting serum glucose [-26.5 mg/dL (-43.4, -9.5], HbA1c [-0.4% (-0.8, -0.04)], cholesterol [-43 mg/dL (-67, -20)], and body weight [-3.5 kg (-4.9, -2.0)]. Praliciguat had no effect on RHI or platelet function. Conclusion: T2DM patients with hypertension on standard therapy showed improvements in hemodynamics and metabolic parameters in this small in-clinic study. These results support further evaluation of praliciguat in T2DM patients including those with complications. Disclosure J.P. Hanrahan: Employee; Self; Ironwood. J.D. Wakefield: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. P.J. Wilson: None. D.P. Zimmer: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. M. Mihova: None. J. Chickering: None. D. Ruff: None. M.L. Hall: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G. Milne: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. Employee; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. A.T. Profy: Other Relationship; Self; Ironwood Pharmaceuticals.

Evaluation of Endothelial Function and Sympathetic Nervous Activity along the Glucose Continuum in Individuals with Habitual Low Sodium Intake

Objective: To assess endothelial function and sympathetic nervous activity in individuals with low sodium intake along the glucose continuum. Research Designs and Methods: In this prospective observational study, participants (n=54) with low sodium intake (single 24hour urine sodium excretion &amp;lt;150mmol/24h) were recruited and categorized based on an oral glucose tolerance test as: controls (n=10), with impaired glucose tolerance (IGT) (n=15) and with untreated (n=12) type 2 diabetes and were then compared to individuals with treated type 2 diabetes (n=17) with established cardio-metabolic risk factors. We assessed pulse amplitude tonometry (PAT) derived measures of endothelial function using the reactive hyperemic index and arterial stiffness using augmentation index; muscle sympathetic nerve activity (MSNA) using microneurography; cardiac baroreflex; heart rate; blood pressure; fasting glucose; glycosylated hemoglobin A1c (HbA1c) and lipid profile. Results: The mean (SD) sodium excretion was 110.6 (26) mmol/24hour. Compared to individuals from the other groups, the treated type 2 diabetes group had a lower PAT ratio (p=0.04), lower baroreflex (p=0.0002) and higher heart rate (p=0.02) suggestive of sympatho-vascular dysfunction. This occurred despite lower MSNA (p=0.005) and appropriate glycemic (mean +/-SD): HbA1c 7.2 (1.72)% (55mmol/mol), total cholesterol 4.2 (1.0) mmol/L, LDL 2.2 (1.0) mmol/L) and blood pressure (mean +/-SD) 136 (13) systolic and 78 (12) diastolic pressure (mmHg) control. Conclusion: In individuals with treated type 2 diabetes, despite a low sodium intake and appropriately managed cardio-metabolic risk factors, endothelial and baroreflex function were impaired. Whether sodium restriction may be associated with an attenuated sympatho-vascular response in individuals with diabetes requires further investigations. Disclosure S. Baqar: None. E.I. Ekinci: None.

Corrigendum: The Effect of a Simulated Commercial Flight Environment With Hypoxia and Low Humidity on Clotting, Platelet, and Endothelial Function in Participants With Type 2 Diabetes - A Cross-Over Study.

[This corrects the article on p. 26 in vol. 9, PMID: 29487564.].

Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta-Analysis.

BackgroundLow 25‐hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear.Methods and ResultsWe conducted a systematic review and individual participant meta‐analysis to examine the effect of vitamin D supplementation on flow‐mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo‐controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial‐level meta‐analysis was performed using random‐effects models; individual participant meta‐analyses used a 2‐stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial‐level meta‐analysis, and 24 trials (2051 participants) contributed to individual‐participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial‐level meta‐analysis showed no significant effect of supplementation on macrovascular measures (flow‐mediated dilatation, 0.37% [95% confidence interval, −0.23 to 0.97]; carotid‐femoral pulse wave velocity, 0.00 m/s [95% confidence interval, −0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial‐level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues.ConclusionsVitamin D supplementation had no significant effect on most markers of vascular function in this analysis.

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).

Recovery of Endothelial Function after Minor-to-Moderate Surgery Is Impaired by Diabetes Mellitus, Obesity, Hyperuricemia and Sevoflurane-Based Anesthesia.

Endothelial dysfunction is observed in several cardiovascular diseases, where endothelium-dependent vasodilation is impaired by oxidative stress. However, the time course of endothelial function during the perioperative period of a minor-to-moderate surgery, and the effects of atherosclerotic risk factors and employed general anesthetics on recovery of endothelial function, are unknown. Endothelial function of 30 patients was evaluated as the reactive hyperemia index (RHI) of reactive hyperemia peripheral arterial tonometry. RHI was measured on day before surgery (control), immediately after surgery (Day 0), day after surgery (Day 1), and day 4 after surgery (Day 4) in patients with no functional limitations who were scheduled for oral and maxillofacial surgery of around 3 hours. Sevoflurane- or propofol-based anesthesia supplemented with an opioid analgesic remifentanil was employed. The control RHI was 2.26 ± 0.64. The RHI significantly decreased to the lowest level on Day 0 (1.52 ± 0.28), recovered on Day 1 (2.07 ± 0.58), and improved further on Day 4 (2.55 ± 0.83). Multiple linear regression analysis revealed that recovery of the RHI from Day 0 to Day 4 was impaired by diabetes mellitus (P = 0.0313), obesity (BMI ≥ 25; P = 0.0166), hyperuricemia (uric acid ≥ 6.0 mg/dL; P = 0.0416) and sevoflurane-based anesthesia (P = 0.0308). These findings suggest that endothelial function as evaluated by the RHI is severely suppressed on the day of a minor-to-moderate surgery, and that it improves until the 4th postoperative day on average. Recovery of endothelial function is impaired by diabetes mellitus, obesity, hyperuricemia, and sevoflurane-based anesthesia.

Impaired Endothelial Function in Hereditary Angioedema During the Symptom-Free Period.

Introduction: The presence of coronary endothelial dysfunction was previously shown in Hereditary Angioedema (HAE) patients. The aim of our study was to evaluate the effect of HAE on systemic endothelial function and whether there was a relationship among endothelial function, asymmetric dimethylarginine (ADMA) -which is a strong inhibitor of nitric oxide synthesis-, and disease severity scores.Methods: Twenty-four HAE patients (18 females, aged 47.9 ± 2 years) without factors known to interfere with endothelial function were studied and compared with 24 healthy peers age- and gender-matched. Endothelial function was assessed by means of non-invasive finger plethysmography (reactive hyperaemia index: RHI) and ADMA levels by high-performance liquid chromatography. HAE severity scores have been calculated according to published literature.Results: In HAE patients RHI was lower (2.03 ± 0.46 vs. 2.82 ± 0.34, p < 0.0001) and ADMA higher (0.636 ± 7 vs. 585 ± 5 micromol/L, p < 0.01) than in controls. A statistically significant inverse correlation was revealed between RHI and patients' ADMA levels (r = −0.516, p = 0.009) as well as between RHI and patients' chronological age (r = −0.49, p = 0.015). A statistically significant correlation between RHI and ADMA was confirmed even when excluding the possible influence of cholesterol (r = −0.408, p = 0.048). No other significant correlations were found with the examined laboratory and clinical parameters (chronological age, age at disease onset, disease duration, severity scores, and gender).Conclusion: The dysfunction previously shown in HAE patients at the coronary arteries seems to involve the peripheral vessels as well, without a correlation with disease severity.

Effect of Sitagliptin on Coronary Flow Reserve Assessed by Magnetic Resonance Imaging in Type 2 Diabetic Patients With Coronary Artery Disease.

The present study was conducted to assess the cardiovascular effects of dipeptidyl peptidase-4 inhibitors (DPP4i) on coronary flow reserve (CFR), left ventricular (LV) function and endothelial function of the peripheral artery by comparison with those of α-glucosidase inhibitors (αGI) in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD).Methods and Results:We randomly assigned 30 patients with T2DM and CAD to receive either sitagliptin or voglibose, and 28 patients (age 69±9 years, 75% male, hemoglobin A1c [HbA1c] 6.62±0.48%) completed the study (14 in each group). CFR and LV function, assessed by cardiac magnetic resonance imaging, and endothelial function, assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT), were measured at baseline and 24 weeks after treatment. Clinical and laboratory parameters, including HbA1c level, plasma active glucagon-like peptide-1 concentrations, and biomarkers of inflammation, were unchanged in both groups after 24 weeks of treatment. CFR were unchanged in both the αGI group (3.01±0.98 at baseline and 3.06±0.8 after treatment, P=NS) and the DPP4i group (4.29±2.04 at baseline and 3.63±1.31 after treatment, P=NS), with no interaction effect. LV functional parameters and the reactive hyperemia index also remained unchanged after the 24-week treatment. DPP4i did not improve CFR, LV function or endothelial function of the peripheral artery in patients with relatively well-controlled T2DM and CAD.

Curcumin Supplementation Decreases Homocysteine and Increases HDL in Young, Obese Men

Obesity increases cardiovascular disease risk and is associated with generalized metabolic dysfunction that may contribute to vascular endothelial dysfunction. Curcumin, an active component of the Asian-Indian spice turmeric, is known to improve vascular function in various populations, but the effects of this constituent are largely unknown in young, obese individuals. PURPOSE: To determine if 12 weeks of curcumin supplementation in young, apparently-healthy obese men would improve resting serum homocysteine, cholesterol, glucose, and insulin values that would be associated with improvements in endothelial function. METHODS: Twenty-two young (26.27 ± 4.18 years), obese (BMI = 33.20 ± 3.42 kg/m2) men were matched based on BMI and randomized into the intervention (curcumin formulated with fenugreek soluble dietary fiber) or placebo (fenugreek soluble fiber only) group for 12 weeks. Pre- and post-intervention blood was collected by venipuncture, and endothelial function was assessed with the Endo-PAT 2000 via the reactive hyperemia index (RHI). Enzyme-linked immunosorbent assays were used to assess homocysteine, high-density lipoprotein (HDL), low-density lipoprotein (LDL)/very low-density lipoprotein (VLDL), glucose, and insulin. A multilevel linear regression model with random effects and an unstructured covariance matrix was employed to analyze treatment effect over the 12-week study with the Kenward and Rogers degrees of freedom method. RESULTS: Compared with placebo, the 12-week curcumin intervention reduced homocysteine levels (-26.7 v. +17.6, P = 0.038, group by time interaction) and increased HDL levels (+15.2 v. -17.4, P = 0.047, group by time interaction). The changes from baseline to 12 weeks in low-density lipoprotein (LDL)/very low-density lipoprotein (VLDL), glucose, and insulin were not significantly different between groups (P > 0.05). There was also no significant difference between groups on the change in RHI from baseline to 12 weeks (-0.06 v. -1.18, P = 0.667). CONCLUSION: Enhanced bioavailable curcumin may be an effective strategy to improve homocysteine and HDL levels in young apparently-healthy obese men that, in turn, may reduce future CVD risk.