Effects of short-term dietary nitrate supplementation on exercise and coronary blood flow responses in patients with peripheral artery disease.

Background: Peripheral arterial disease (PAD) is a prevalent vascular disorder characterized by atherosclerotic occlusion of peripheral arteries, resulting in reduced blood flow to the lower extremities and poor walking ability. Older patients with PAD are also at a markedly increased risk of cardiovascular events, including myocardial infarction. Recent evidence indicates that inorganic nitrate supplementation, which is abundant in certain vegetables, augments nitric oxide (NO) bioavailability and may have beneficial effects on walking, blood pressure, and vascular function in patients with PAD. Objective: We sought to determine if short-term nitrate supplementation (via beetroot juice) improves peak treadmill time and coronary hyperemic responses to plantar flexion exercise relative to placebo (nitrate-depleted juice) in older patients with PAD. The primary endpoints were peak treadmill time and the peak coronary hyperemic response to plantar flexion exercise. Methods: Eleven PAD patients (52-80 yr.; 9 men/2 women; Fontaine stage II) were randomized (double-blind) to either nitrate-rich (Beet-IT, 0.3 g inorganic nitrate twice/day; BRnitrate) or nitrate-depleted (Beet-IT, 0.04 g inorganic nitrate twice/day, BRplacebo) beetroot juice for 4 to 6 days, followed by a washout of 7 to 14 days before crossing over to the other treatment. Patients completed graded plantar flexion exercise with their most symptomatic leg to fatigue, followed by isometric handgrip until volitional fatigue at 40% of maximum on day 4 of supplementation, and a treadmill test to peak exertion 1-2 days later while continuing supplementation. Hemodynamics and exercise tolerance, and coronary blood flow velocity (CBV) responses were measured. Results: Although peak walking time and claudication onset time during treadmill exercise did not differ significantly between BRplacebo and BRnitrate, the diastolic blood pressure response at the peak treadmill walking stage was significantly lower in the BRnitrate condition. Increases in CBV from baseline to peak plantar flexion exercise after BRplacebo and BRnitrate showed a trend for a greater increase in CBV at the peak workload of plantar flexion with BRnitrate (p = 0.06; Cohen's d = 0.56). Conclusion: Overall, these preliminary findings suggest that inorganic nitrate supplementation in PAD patients is safe, well-tolerated, and may improve the coronary hyperemic and blood pressure responses when their calf muscles are most predisposed to ischemia.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT02553733.

The acute effects of dietary nitrate supplementation on postmenopausal endothelial resistance to ischemia reperfusion injury: A randomized, placebo-controlled, double blind, crossover clinical trial.

Postmenopausal cardiovascular health is a critical determinant of longevity. Consumption of beetroot juice (BR) and other nitrate rich foods is a safe, effective non-pharmacological intervention strategy to increase systemic bioavailability of the vasoprotective molecule, nitric oxide (NO), through the exogenous nitrate (NO3-)-nitrite (NO2-)-NO pathway. We hypothesized that a single dose of nitrate-rich beetroot juice (BRnitrate 600 mg NO3- / 140 mL, BRplacebo ~ 0 mg/ 140 mL) would improve resting endothelial function and resistance to ischemia-reperfusion (IR) injury to a greater extent in early- (1-6 years following their final menstrual period (FMP), n=12) compared to late- (6+ years after FMP, n=12) postmenopausal women. Analyses with general linear models revealed a significant (p<0.05) time*treatment interaction effect for brachial artery adjusted FMD. Pairwise comparisons revealed adjusted FMD was significantly lower following IR-injury in comparison to all other time points with BRplacebo (Early FMD 2.51 ± 1.18%, Late FMD 1.30 ± 1.10, p<0.001) and was lower than post-IR with BRnitrate (Early FMD 3.84 ± 1.21%, Late FMD 3.21 ± 1.13 %, p=0.014). Considering the postmenopausal stage-dependent variations in endothelial responsiveness to dietary nitrate at rest and post-IR, we predict differing mechanisms underpin macrovascular protection against IR injury. NCT03644472.

Seven-day dietary nitrate supplementation clinically significantly improves basal macrovascular function in postmenopausal women: a randomized, placebo-controlled, double-blind, crossover clinical trial.

Introduction: Cardiovascular disease (CVD) is the leading cause of death in women, with increased risk following menopause. Dietary intake of beetroot juice and other plant-based nitrate-rich foods is a promising non-pharmacological strategy for increasing systemic nitric oxide and improving endothelial function in elderly populations. The purpose of this randomized, placebo-controlled, double-blind, crossover clinical trial was to determine the effects of short-term dietary nitrate (NO3 -) supplementation, in the form of beetroot juice, on resting macrovascular endothelial function and endothelial resistance to whole-arm ischemia-reperfusion (IR) injury in postmenopausal women at two distinct stages of menopause. Methods: Early-postmenopausal [1-6 years following their final menstrual period (FMP), n = 12] and late-postmenopausal (6+ years FMP, n = 12) women consumed nitrate-rich (400 mg NO3 -/70 mL) and nitrate-depleted beetroot juice (approximately 40 mg NO3 -/70 mL, placebo) daily for 7 days. Brachial artery flow-mediated dilation (FMD) was measured pre-supplementation (Day 0), and approximately 24 h after the last beetroot juice (BR) dose (Day 8, post-7-day BR). Consequently, FMD was measured immediately post-IR injury and 15 min later (recovery). Results: Results of the linear mixed-effects model revealed a significantly greater increase in resting FMD with 7 days of BRnitrate compared to BRplacebo (mean difference of 2.21, 95% CI [0.082, 4.34], p = 0.042); however, neither treatment blunted the decline in post-IR injury FMD in either postmenopausal group. Our results suggest that 7-day BRnitrate-mediated endothelial protection is lost within the 24-h period following the final dose of BRnitrate. Conclusion: Our findings demonstrate that nitrate-mediated postmenopausal endothelial protection is dependent on the timing of supplementation in relation to IR injury and chronobiological variations in dietary nitrate metabolism. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT03644472.

Single and 7-day handgrip and squat exercise prevents endothelial ischemia-reperfusion injury in individuals with cardiovascular disease risk factors.

Whole body exercise provides protection against endothelial ischemia-reperfusion (IR) injury. In this crossover study, we examined the effects of 1) single bout of local exercise (handgrip, squats) on endothelial responses to IR, and 2) if 7 days of daily local exercise bolsters these effects in individuals with cardiovascular disease (CVD) risk factors. Fifteen participants (9 women, 58 ± 5 yr, ≥2 CVD risk factors) attended the laboratory for six visits. Subsequent to familiarization (visit 1), during visit 2 (control) brachial artery flow-mediated dilation (FMD) was measured before and after IR (15-min upper-arm ischemia, 15-min reperfusion). One week later, participants were randomized to 4 × 5-min unilateral handgrip (50% maximal voluntary contraction, 25 rpm) or squat exercises (15 rpm), followed by IR plus FMD measurements. Subsequently, home-based exercise was performed (6 days), followed by another visit to the laboratory for the IR protocol plus FMD measurements (18-24 h after the last exercise bout). After a 2-wk washout period, procedures were repeated with the alternative exercise mode. For a single exercise bout, we found a significant IR injury × exercise mode interaction (P < 0.01) but no main effect of injury (P = 0.08) or condition (P = 0.61). A lower post-IR FMD was evident after control (pre-IR: 4.3 ± 2.1% to post-IR: 2.9 ± 1.9%, P < 0.01) but not after handgrip (pre-IR: 3.8 ± 1.6% to post-IR: 3.4 ± 1.5%, P = 0.31) or squats (pre-IR: 3.9 ± 1.8% to post-IR: 4.0 ± 1.9%, P = 0.74). After 7 days of daily exercise, we found no change in FMD post-IR following handgrip (pre-IR: 4.3 ± 1.9% to post-IR: 4.7 ± 3.2%) or squats (pre-IR: 3.7 ± 2.1% to post-IR: 4.7 ± 3.0%, P > 0.05). Single bouts of dynamic, local exercise (handgrip, squats) provide remote protection against endothelial IR-induced injury in individuals with CVD risk factors, with 1-wk daily, home-based exercise preserving these effects for up to 24 h following the last exercise bout.NEW & NOTEWORTHY We show that single bouts of dynamic handgrip and squat exercise provide remote protection against endothelial ischemia-reperfusion (IR)-induced injury in individuals with cardiovascular disease (CVD) risk factors, with 1-wk daily, home-based exercise preserving these effects for up to 24 h following the last exercise bout.

Menopausal stage differences in endothelial resistance to ischemia-reperfusion injury.

BACKGROUND: In postmenopausal women, reduced ovarian function precedes endothelial dysfunction and attenuated endothelial resistance to ischemia-reperfusion (IR) injury. We hypothesized that IR injury would lower endothelial function, with premenopausal women demonstrating the greatest protection from injury, followed by early, then late postmenopausal women. METHODS: Flow-mediated dilation (FMD) was assessed at baseline and following IR injury in premenopausal (n = 11), early (n = 11; 4 ± 1.6 years since menopause), and late (n = 11; 15 ± 5.5 years since menopause) postmenopausal women. RESULTS: There were significant group differences in baseline FMD (p = 0.007); post hoc analysis revealed a similar resting FMD between premenopausal (7.8% ± 2.1%) and early postmenopausal (7.1% ± 2.7%), but significantly lower FMD in late postmenopausal women (4.5% ± 2.3%). Results showed an overall decline in FMD after IR injury (p < 0.001), and a significant condition*time interaction (p = 0.048), with early postmenopausal women demonstrating the most significant decline in FMD following IR. CONCLUSION: Our findings indicate that endothelial resistance to IR injury is attenuated in healthy early postmenopausal women.

Maximal calf conductance is associated with 6-minute walk distance in participants with and without peripheral artery disease.

INTRODUCTION: The aims were (a) to compare the maximal calf conductance and 6-minute walk distance of participants with and without peripheral artery disease (PAD) and claudication, (b) to determine whether maximal calf conductance was more strongly associated with 6-minute walk distance in participants with PAD than in the controls, and (c) to determine whether this association was significant in participants with PAD after adjusting for ABI, as well as for demographic, anthropometric, and comorbid variables. METHODS: Participants with PAD (n = 633) and without PAD (n = 327) were assessed on maximal calf conductance using venous occlusion plethysmography, and on 6-minute walk distance. Participants were further characterized on ABI, and on demographic, anthropometric, and comorbid variables. RESULTS: The PAD group had lower maximal calf conductance than the control group (0.136 ± 0.071 vs 0.201 ± 0.113 mL/100 mL/min/mmHg, p < 0.001). Additionally, the PAD group had a lower 6-minute walk distance (375 ± 98 m vs 480 ± 107 m, p < 0.001). Maximal calf conductance was positively associated with 6-minute walk distance in both groups (p < 0.001) and was more strongly associated in the PAD group (p < 0.001). In adjusted analyses, maximal calf conductance remained positively associated with 6-minute walk distance in the PAD group (p < 0.001) and in the control group (p < 0.001). CONCLUSIONS: Participants with PAD and claudication had impaired maximal calf conductance and a lower 6-minute walk distance than those without PAD, and maximal calf conductance was positively and independently associated with 6-minute walk distance within each group before and after adjusting for ABI, and for demographic, anthropometric, and comorbid variables.

Increased pulse wave velocity is related to impaired working memory and executive function in older adults with metabolic syndrome.

Age-related vascular alterations promote the pathogenesis of vascular cognitive impairment (VCI). Cardiovascular risk factors that accelerate vascular aging exacerbate VCI. Metabolic syndrome (MetS) constitutes a cluster of critical cardiovascular risk factors (abdominal obesity, hypertension, elevated triglycerides, elevated fasting glucose, reduced HDL cholesterol), which affects nearly 37% of the adult US population. The present study was designed to test the hypotheses that MetS exacerbates cognitive impairment and that arterial stiffening moderates the association between cognitive dysfunction and MetS in older adults. MetS was defined by the NCEP ATP III guidelines. Cognitive function (digit span and trail-making tests) and brachial-ankle pulse wave velocity (baPWV; a non-invasive clinical measurement of arterial stiffness) were assessed in older adults with MetS and age- and sex-matched controls. Multiple linear regression models were applied to test for the main effects of MetS, baPWV, and their interaction on cognitive performance. Fifty-three participants with MetS (age: 68 ± 8 years) and 39 age-matched individuals without MetS (age: 66 ± 9 years) were enrolled into the study. In adjusted multivariable regression analyses of the digit span backward length score, both MetS (ß = 1.97, p = 0.048) and MetS by baPWV interaction (ß = - 0.001, p = 0.026) were significant predictors. In participants with MetS, higher baPWV was associated with poorer performance on digit span backward length score, a test of working memory (R = - 0.44, p = 0.0012), but there was no association in those without MetS (R = 0.035, p = 0.83). MetS was negatively associated with performance on the digit span backward length score, baPWV was negatively associated with multiple neuropsychological outcomes, and baPWV moderated the association between digit span backward length score and MetS, as individuals with both MetS and higher baPWV had the most impaired cognitive function. Our findings add to the growing body of evidence that individuals with MetS and higher baPWV may be prone to VCI.

Inorganic nitrate supplementation and blood flow restricted exercise tolerance in post-menopausal women.

Exercise tolerance appears to benefit most from dietary nitrate (NO3-) supplementation when muscle oxygen (O2) availability is low. Using a double-blind, randomized cross-over design, we tested the hypothesis that acute NO3- supplementation would improve blood flow restricted exercise duration in post-menopausal women, a population with reduced endogenous nitric oxide bioavailability. Thirteen women (57-76 yr) performed rhythmic isometric handgrip contractions (10% MVC, 30 per min) during progressive forearm blood flow restriction (upper arm cuff gradually inflated 20 mmHg each min) on three study visits, with 7-10 days between visits. Approximately one week following the first (familiarization) visit, participants consumed 140 ml of NO3- concentrated (9.7 mmol, 0.6 gm NO3-) or NO3-depleted beetroot juice (placebo) on separate days (≥7 days apart), with handgrip exercise beginning 100 min post-consumption. Handgrip force recordings were analyzed to determine if NO3- supplementation enhanced force development as blood flow restriction progressed. Nitrate supplementation increased plasma NO3- (16.2-fold) and NO2- (4.2-fold) and time to volitional fatigue (61.8 ± 56.5 s longer duration vs. placebo visit; p = 0.03). Nitrate supplementation increased the rate of force development as forearm muscle ischemia progressed (p = 0.023 between 50 and 75% of time to fatigue) with non-significant effects thereafter (p = 0.052). No effects of nitrate supplementation were observed for mean duration of contraction or relaxation rates (all p > 0.150). These results suggest that acute NO3- supplementation prolongs time-to-fatigue and speeds grip force development during progressive forearm muscle ischemia in postmenopausal women.

Herbs and spices at a relatively high culinary dosage improves 24-hour ambulatory blood pressure in adults at risk of cardiometabolic diseases: a randomized, crossover, controlled-feeding study.

BACKGROUND: Intake of a single meal containing herbs and spices attenuates postprandial lipemia, hyperglycemia, and oxidative stress, and improves endothelial function. There has been limited investigation of the effect of longer-term intake of mixed herbs and spices on risk factors for cardiometabolic diseases. OBJECTIVES: The objective was to assess the effect of an average American diet containing herbs and spices at 0.5 (low-spice diet; LSD), 3.3 (moderate-spice diet; MSD), and 6.6 (high-spice diet; HSD) g · d-1 · 2100 kcal-1 on lipids and lipoproteins as well as other risk factors for cardiometabolic diseases in at-risk adults. METHODS: A 3-period, randomized, crossover, controlled-feeding study with 71 participants was conducted at the Pennsylvania State University. Each diet was consumed for 4 wk with a minimum 2-wk washout period. Outcomes were assessed at baseline and the end of each diet period. RESULTS: No between-diet effects were observed for LDL cholesterol, the primary outcome. Between-diet differences were observed for mean 24-h systolic (P = 0.02) and diastolic (P = 0.005) ambulatory blood pressure. The HSD lowered mean 24-h systolic blood pressure compared with the MSD (-1.9 mm Hg; 95% CI: -3.6, -0.2 mm Hg; P = 0.02); the difference between the HSD and LSD was not statistically significant (-1.6 mm Hg; 95% CI: -3.3, 0.04 mm Hg; P = 0.058). The HSD lowered mean 24-h diastolic blood pressure compared with the LSD (-1.5 mm Hg; 95% CI: -2.5, -0.4 mm Hg; P = 0.003). No differences were detected between the LSD and MSD. No between-diet effects were observed for clinic-measured blood pressure, markers of glycemia, or vascular function. CONCLUSIONS: In the context of a suboptimal US-style diet, addition of a relatively high culinary dosage of mixed herbs and spices (6.6 g · d-1 · 2100 kcal-1) tended to improve 24-h blood pressure after 4 wk, compared with lower dosages (0.5 and 3.3 g · d-1 · 2100 kcal-1), in adults at elevated risk of cardiometabolic diseases.This trial was registered at clinicaltrials.gov as NCT03064932.

Bilateral NIRS measurements of muscle mitochondrial capacity: Feasibility and repeatability.

BACKGROUND: Non-invasive determination of mitochondrial capacity via near infrared spectroscopy (NIRS) typically involves voluntary exercise of a single muscle group followed by as many as 26 brief ischemic cuff occlusions to determine a single recovery rate constant (k). PURPOSE: To determine the within- and between-visit repeatability of a shortened bilateral NIRS protocol, and to establish the feasibility of hamstring k measurements. METHODS: Sixteen young (eight women, eight men; 22 ± 3 years) active adults underwent a bilateral electrical stimulation protocol in which multiple (n = 4) measurements of k for the vastus lateralis (VL) and medial hamstring (MH) muscles were determined on two visits. Repeatability (CV% and intraclass correlations, ICC) and equivalency across visits were assessed for both muscles. RESULTS: Mean k values in the VL were consistent with published values and within-visit ICCs were moderately high for both muscles in both sexes. In men, average k values on visit 2 were within 1% (VL muscle) and 5% (MH muscle) of the values on visit 1 (all p > 0.78). In women, average k values were 10%-15% lower on visit 2 (p = 0.01 and p = 0.15 for MH and VL) with the largest between-visit differences in a subset of participants with the most days between visits. CONCLUSIONS: This bilateral NIRS protocol is time efficient and provides valid estimates of k in both sexes and muscle groups with acceptable within-visit repeatability. Lower than expected between-visit repeatability in some participants reinforces the need for further investigation of this newly developed protocol to identify and control for experimental and behavioral sources of variation.

Consumption of Dried Fruits Is Associated with Greater Intakes of Underconsumed Nutrients, Higher Total Energy Intakes, and Better Diet Quality in US Adults: A Cross-Sectional Analysis of the National Health and Nutrition Examination Survey, 2007-2016.

BACKGROUND: Dried fruits are shelf-stable alternatives to fresh fruit that avert common barriers to consuming fruit. Consumption of dried fruits may facilitate greater fruit consumption and contribute to better diet quality and nutrient intakes. OBJECTIVE: Our aims were to assess differences in diet quality and cardiometabolic health between dried fruit consumers and nonconsumers, and evaluate differences in nutrient intakes on days when dried fruits were consumed vs not consumed. DESIGN: This is a cross-sectional analysis of data from the National Health and Nutrition Examination Survey 2007-2016. PARTICIPANTS/SETTING: Mean dried fruit intakes were estimated in adults 20 years and older (n = 25,590) who completed a dietary recall. Dried fruit consumers (one-quarter cup-equivalent/day or more) were defined in respondents with 2 complete dietary recalls (n = 22,311). Within-person differences in nutrient intakes were assessed in respondents who consumed dried fruit on 1 of 2 dietary recalls (n = 1,233). MAIN OUTCOME MEASURES: Cardiometabolic risk factors, diet quality scored using the Healthy Eating Index 2015, and nutrient intakes were assessed. STATISTICAL ANALYSES: Diet quality and cardiometabolic health were compared in consumers vs nonconsumers using multivariate linear regression, adjusted for demographic and lifestyle factors. Within-person differences in nutrient intakes on days when dried fruits were consumed vs not were assessed using multivariate linear regression. RESULTS: Mean ± standard error dried fruit intake was 0.04 ± 0.001 cup-equivalents and represented 3.7% of total fruit consumed. Consumers (7.2% of adults) had higher quality diets than nonconsumers (mean ± standard error Healthy Eating Index 2015 score = 60.6 ± 0.5 vs 52.6 ± 0.3; P < 0.001) and lower mean body mass index, waist circumference, and systolic blood pressure (P < 0.01). Total carbohydrate, dietary fiber, potassium, and polyunsaturated fat intakes were greater on days when dried fruits were consumed vs not consumed (P < 0.001). Total calorie intakes were also greater (208-215 kcal; P ≤ 0.002) when dried fruits were consumed. CONCLUSIONS: Dried fruit consumption is associated with higher diet quality and greater intakes of underconsumed nutrients. However, dried fruits do not appear to displace other calorie sources on days when consumed.

Peripheral vasodilation is reduced during exercise in perimenopausal women with elevated cardiovascular risk.

OBJECTIVE: The menopausal transition has a negative effect on peripheral dilation in response to various stimuli including shear stress and exercise. Whether the presence of elevated traditional cardiovascular disease (CVD) risk factors in women going through menopause exacerbates the adverse effect on peripheral vasodilation is unclear. METHODS: Forty-four perimenopausal women with relatively low CVD risk were divided into tertiles based on atherosclerotic CVD (ASCVD) 10-year risk scores (lowest: 0.1%-0.5%, middle: 0.6%-0.9%, higher: >1%). Comparisons were made across tertile groups for the femoral artery vascular conductance (FVC) response to single-leg knee extension exercise (0, 5, 10, 15 W) as measured using Doppler ultrasound. RESULTS: At higher exercise intensities, FVC was lower in women in the tertile group with the highest ASCVD 10-year risk scores (10 W: 6 ±â€Š2 mL/min/mm Hg, 15 W: 8 ±â€Š3 mL/min/mm Hg) compared to women in the lowest tertile group (10 W: 9 ±â€Š3 mL/min/mm Hg, P = 0.01; 15 W: 12 ±â€Š3 mL/min/mm Hg, P < 0.01) and middle tertile group (10 W: 10 ±â€Š4 mL/min/mm Hg, P < 0.01; 15 W: 12 ±â€Š5 mL/min/mm Hg, P < 0.01). The overall increase in FVC during exercise from 0 to 15 W remained lower (P ≤ 0.01) in women with the highest ASCVD risk scores compared to the other two tertile groups even after adjustment for chronological age, arterial stiffness, and fat-free mass adjusted aerobic fitness level. CONCLUSION: Our results show that the presence of mild differences in ASCVD risk scores may be associated with a blunted active limb blood flow during leg exercise in mid-life women transitioning through menopause.

A prospective community engagement initiative to improve clinical research participation in patients with peripheral artery disease.

OBJECTIVE: Patients diagnosed with peripheral artery disease are difficult to recruit into clinical trials. However, there is currently no high-quality, patient-centered information explaining why peripheral artery disease patients choose to participate or not participate in clinical research studies. METHODS: The current study was a prospective community engagement initiative that specifically asked patients with and without peripheral artery disease: (1) what motivates them to participate in clinical research studies, (2) their willingness to participate in different research procedures, (3) the barriers to participation, (4) preferences about study design, and (5) demographic and disease-related factors influencing participation. Data were gathered through focus groups (n = 19, participants aged 55-79 years) and mailed questionnaires (n = 438, respondents aged 18-85 years). RESULTS: More than half of the respondents stated that they would be willing to participate in a study during evening or weekend time slots. Peripheral artery disease patients (n = 45) were more willing than those without peripheral artery disease (n = 360) to participate in drug infusion studies (48% versus 18%, p < 0.001) and trials of investigational drugs (44% versus 21%, p < 0.001). Motivating factors and barriers to participation were largely consistent with previous studies. CONCLUSION: Adults in our geographic region are interested in participating in clinical research studies related to their health; they would like their doctor to tell them what studies they qualify for and they prefer to receive a one-page advertisement that has color pictures of the research procedures. Peripheral artery disease patients are more willing than those without peripheral artery disease to participate in drug infusion studies, trials of investigational drugs, microneurography, and spinal/epidural infusions.

The effect of culinary doses of spices in a high-saturated fat, high-carbohydrate meal on postprandial lipemia and endothelial function: a randomized, controlled, crossover pilot trial.

Previously it has been shown that incorporation of >11 g of spices into a mixed meal blunts postprandial lipemia, which may reduce acute endothelial impairment. The effect of lower doses of spices remains unclear. The aim was to examine the postprandial effect of a meal high in saturated fat and carbohydrate inclusive of spices (2 g or 6 g) or exclusive of spices (0 g) on flow mediated dilation (FMD), lipids and lipoproteins, glucose, and insulin in men at-risk for cardiovascular disease. A 3-period randomized, controlled, crossover, pilot study was conducted. In random order, subjects consumed a high-saturated fat, high-carbohydrate meal (1076 kcal, 39 g saturated fat, 98 g carbohydrate) with 0 g, 2 g and 6 g of mixed spices. After meal consumption, blood was drawn hourly for 4 hours and FMD was measured at 2 and 4 hours. Serum lipids and lipoproteins, and insulin were measured in the fasting state and at each post-meal time point; plasma glucose was also assessed at each time point. Subjects were 13 men aged 52 ± 9 years that were overweight or obese (29.9 ± 3.1 kg m-2), and had an enlarged waist circumference (102.2 ± 8.9 cm). Time (p < 0.05) and treatment (p < 0.05) effects existed for FMD and triglycerides; no time by treatment interactions were detected. Post hoc testing showed that the meal with 6 g of spices lessened the postprandial reduction in FMD compared to the meal with no spices (-0.87 ± 0.32%; p = 0.031); no other pairwise differences were observed. Triglyceride levels were lower following the meal with 2 g of spices vs. the no spice meal (-18 ± 6 mg dL-1; p = 0.015); no difference was observed between the meal with 6 g of spice and the no spice meal (-13 ± 6 mg dL-1; p = 0.12). Glucose and insulin were unaffected by the presence of spices in the meal. In conclusion, this study provides preliminary evidence suggesting that lower doses of spices (2 and 6 g) than previously tested may attenuate postprandial lipemia and impairments in endothelial function caused by a high-saturated fat, high-carbohydrate meal.

Acute application of a transdermal nitroglycerin patch protects against prolonged forearm ischemia-induced microvascular dysfunction.

INTRODUCTION: Prolonged limb blood flow occlusion (ie, tourniquet application during limb surgery) causes transient microvascular dysfunction. We examined the ability of a local nitric oxide donor (transdermal nitroglycerin) administered during prolonged cuff forearm occlusion to protect against microvascular dysfunction and to alter brachial artery dilation. METHODS: Ten healthy men (28 ± 8 years) participated in the study. During the control visit, they completed three vascular occlusion tests in the right arm termed, PRE (5-min occlusion), POSTimmediate (20-min occlusion), and POST30min (5-min occlusion). During the nitroglycerin visit, subjects completed the same vascular occlusion tests, but with a nitroglycerin patch placed over the contralateral forearm during the 20-min occlusion test. Micro- and macrovascular function were assessed using the near-infrared spectroscopy-derived reperfusion upslope (reperfusion slope, %.s-1 ) and flow-mediated dilation (%FMD), respectively. RESULTS: The reperfusion slope (1.44 ± 0.72%.s-1 ) and the %FMD (15.0 ± 2.8%) of the POSTimmediate test of the nitroglycerin condition were significantly (P < .05) higher than the reperfusion slope (1.01 ± 0.37%.s-1 ) and %FMD (6.77 ± 1.8%) during the POSTimmediate test of the control visit. CONCLUSION: Transdermal nitroglycerin protects against ischemia-induced microvascular dysfunction and causes marked dilation of the brachial artery %FMD.

Aging women and their endothelium: probing the relative role of estrogen on vasodilator function.

Despite significant decreases in cardiovascular disease (CVD) mortality in the past three decades, it still remains the leading cause of death in women. Following menopause and the accompanying loss of estrogen, women experience a unique, accelerated rise in CVD risk factors. Dysfunction of the endothelium represents an important antecedent to CVD development, with rapid declines in endothelial vasodilator function reportedly taking place across the menopause transition. Importantly, the decline in endothelial function is independent of chronological age and is associated with estrogen deficiency. Estrogen-mediated effects, including increasing nitric oxide bioavailability and attenuating oxidative stress and inflammation, contribute to preserving endothelial health. This review will discuss studies that have probed the role of estrogen on endothelial vasodilator function in women at discrete stages of the menopause transition and the effects of estradiol supplementation in postmenopausal women. Estrogen receptor signaling is also an important aspect of endothelial function in women, and studies suggest that expression is reduced with both acute and prolonged estrogen deficiency. Changes in regulatory mechanisms of estrogen receptor-α expression as well as sensitivity to estrogen may underlie the differential effects of estrogen therapy in early (≤5 yr past final menstrual period) and late postmenopausal women (>5 yr past final menstrual period). Lastly, this review presents potential therapeutic targets that include increasing l-arginine bioavailability and estrogen receptor activation to prevent endothelial dysfunction in postmenopausal women as a strategy for decreasing CVD mortality in this high-risk population.

Near-infrared spectroscopy detects transient decrements and recovery of microvascular responsiveness following prolonged forearm ischemia.

BACKGROUND: Impairments at the microvascular level might lead to more overt cardiovascular complications, therefore, being able to early detect microvascular dysfunction would be beneficial. Thus, the present study investigated whether near-infrared spectroscopy (NIRS) assessment of microvascular responsiveness (reoxygenation slope, %.s-1) would detect the detrimental effects on the forearm microvasculature following a period of arterial occlusion. Similarly, the effects of prolonged forearm ischemia on brachial artery function were also assessed by flow-mediated dilation (%FMD). METHODS: Fourteen individuals were tested before (Pre), immediately after (PostPI), 30 min after (Post30), and 60 min after (Post60) prolonged forearm ischemia. The Pre, Post30, and Post60 interventions consisted of 5 min of blood flow occlusion, whereas the postPI involved a 20-min occlusion period. RESULTS: The reoxygenation slope was reduced at PostPI (1.33 ±â€¯0.72%.s-1 vs. 1.79 ±â€¯0.68%.s-1 Pre; p < 0.05), but not at Post30 (1.93 ±â€¯0.70%.s-1) and Post60 (1.87 ±â€¯0.85%.s-1) (both p > 0.05 vs. Pre). Similarly, the brachial FMD response was reduced at PostPI (7.4 ±â€¯3.9% vs. 10.9 ±â€¯2.9% Pre; p < 0.05), but not at Post30 (11.3 ±â€¯4.1%) or Post60 (11.8 ±â€¯4.3%) (both p > 0.05 vs. Pre). CONCLUSION: These findings show that NIRS-derived reoxygenation slope detects the transient detrimental effects of prolonged ischemia within the forearm microvasculature. Additionally, this study found that the reduction in forearm microvascular responsiveness might have contributed to the decreased brachial artery FMD responsiveness.

Replacing Saturated Fat With Walnuts or Vegetable Oils Improves Central Blood Pressure and Serum Lipids in Adults at Risk for Cardiovascular Disease: A Randomized Controlled-Feeding Trial.

Background Walnuts have beneficial effects on cardiovascular risk factors, but it is unclear whether these effects are attributable to the fatty acid ( FA ) content, including α-linolenic acid ( ALA ), and/or bioactives. Methods and Results A randomized, controlled, 3-period, crossover, feeding trial was conducted in individuals at risk for cardiovascular disease (n=45). Following a 2-week standard Western diet run-in (12% saturated FAs [ SFA ], 7% polyunsaturated FAs, 12% monounsaturated FAs), participants consumed 3 isocaloric weight-maintenance diets for 6 weeks each: a walnut diet ( WD ; 7% SFA , 16% polyunsaturated FAs, 3% ALA , 9% monounsaturated FAs); a walnut FA -matched diet; and an oleic acid-replaced- ALA diet (7% SFA , 14% polyunsaturated FAs, 0.5% ALA , 12% monounsaturated FAs), which substituted the amount of ALA from walnuts in the WD with oleic acid. This design enabled evaluation of the effects of whole walnuts versus constituent components. The primary end point, central systolic blood pressure, was unchanged, and there were no significant changes in arterial stiffness. There was a treatment effect ( P=0.04) for central diastolic blood pressure; there was a greater change following the WD versus the oleic acid-replaced-ALA diet (-1.78±1.0 versus 0.15±0.7 mm Hg, P=0.04). There were no differences between the WD and the walnut fatty acid-matched diet (-0.22±0.8 mm Hg, P=0.20) or the walnut FA-matched and oleic acid-replaced-ALA diets ( P=0.74). The WD significantly lowered brachial and central mean arterial pressure. All diets lowered total cholesterol, LDL (low-density lipoprotein) cholesterol, HDL (high-density lipoprotein) cholesterol, and non- HDL cholesterol. Conclusions Cardiovascular benefits occurred with all moderate-fat, high-unsaturated-fat diets. As part of a low- SFA diet, the greater improvement in central diastolic blood pressure following the WD versus the oleic acid-replaced-ALA diet indicates benefits of walnuts as a whole-food replacement for SFA . Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT02210767.

Effects of acute dietary nitrate supplementation on aortic blood pressures and pulse wave characteristics in post-menopausal women.

PURPOSE: Consumption of nitrate-rich beetroot juice can lower blood pressure in peripheral as well as central arteries and may exert additional hemodynamic benefits (e.g. reduced aortic wave reflections). The specific influence of nitrate supplementation on arterial pressures and aortic wave properties in postmenopausal women, a group that experiences accelerated increases in these variables with age, is unknown. Accordingly, the primary aim of this study was to determine the effect of consuming nitrate-rich beetroot juice on resting brachial and aortic blood pressures (BP) and pulse wave characteristics in a group of healthy postmenopausal women, in comparison to a true (nitrate-free beetroot juice) placebo. METHODS: Brachial (oscillometric cuff) and radial (SphygmoCor) pressures and derived-aortic waveforms were measured during supine rest in thirteen healthy postmenopausal women (63 ±â€¯1 yr) before and 100 min after consumption of 140 ml of either nitrate-rich (9.7 mmol, 0.6 gm NO3-) or nitrate-depleted beetroot juice on randomized visits approximately 10 days apart (cross-over design). Ten young premenopausal women (22 ±â€¯1 yr) served as a reference (non-supplemented) cohort. RESULTS: Brachial and derived-aortic variables showed the expected age-associated differences in these women (all p < 0.05). In post-menopausal women, nitrate supplementation reduced (p < 0.05 vs. placebo visit) brachial systolic BP (BRnitrate -4.9 ±â€¯2.1 mmHg vs BRplacebo +1.1 ± 1.8 mmHg), brachial mean BP (BRnitrate -4.1 ±â€¯1.7 mmHg vs BRplacebo +0.9 ± 1.3 mmHg), aortic systolic BP (BRnitrate -6.3 ±â€¯2.0 mmHg vs BRplacebo +0.5 ± 1.7 mmHg) and aortic mean BP (BRnitrate -4.1 ±â€¯1.7 mmHg vs BRplacebo +0.9 ± 1.3 mmHg), and increased pulse pressure amplification (BRnitrate +4.6 ± 2.0% vs BRplacebo +0.7 ± 2.5%, p = 0.04), but did not alter aortic pulse wave velocity or any other derived-aortic variables (e.g., augmentation pressure or index). CONCLUSIONS: Dietary nitrate supplementation favorably modifies aortic systolic and mean blood pressure under resting conditions in healthy postmenopausal women. Acute supplementation of nitrate does not, however, appear to restore indices of aortic stiffness in this group. Future work should evaluate chronic, long-term effects of this non-pharmacological supplement.

Retrograde and oscillatory shear increase across the menopause transition.

Declines in endothelial function can take place rapidly across the menopause transition, placing women at heightened risk for atherosclerosis. Disturbed patterns of conduit artery shear, characterized by greater oscillatory and retrograde shear, are associated with endothelial dysfunction but have yet to be described across menopause. Healthy women, who were not on hormone therapy or contraceptives, were classified into early perimenopausal, late perimenopausal, and early postmenopausal stage. Resting antegrade, retrograde, and oscillatory shear were calculated from blood velocity and diameter measured in the brachial and common femoral artery using Doppler ultrasound. Serum was collected for measurements of estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone. After adjusting for age, brachial artery oscillatory shear was significantly higher in early postmenopausal women (n = 15, 0.17 ± 0.08 a.u.) than both early (n = 12, 0.08 ± 0.05 a.u., P < 0.05) and late (n = 8, 0.08 ± 0.04 a.u) perimenopausal women, and retrograde shear was significantly greater in early postmenopausal versus early perimenopausal women (-19.47 ± 12.97 vs. -9.62 ± 6.11 sec-1 , both P < 0.05). Femoral artery oscillatory and retrograde shear were greater, respectively, in early postmenopausal women (n = 15, 0.19 ± 0.08 a.u.; -13.57 ± 5.82 sec-1 ) than early perimenopausal women (n = 14, 0.11 ± 0.08 a.u.; -8.13 ± 4.43 sec-1 , P < 0.05). Further, Pearson correlation analyses revealed significant associations between FSH and both retrograde and oscillatory shear, respectively, in the brachial (r = -0.40, P = 0.03; r = 0.43, P = 0.02) and common femoral artery (r = -0.45, P = 0.01; r = 0.56, P = 0.001). These results suggest menopause, and its associated changes in reproductive hormones, adversely influences conduit arterial shear rate patterns to greater oscillatory and retrograde shear rates.