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.

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.