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

Jocelyn M Delgado Spicuzza; Jigar Gosalia; Liezhou Zhong; Catherine Bondonno; Kristina S Petersen; Mary Jane De Souza; Elmira Alipour; Daniel B Kim-Shapiro; Yasina B Somani; David N Proctor

doi:10.3389/fnut.2024.1359671

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

Front Nutr. 2024 Jun 10:11:1359671. doi: 10.3389/fnut.2024.1359671. eCollection 2024.

Authors

Affiliations

¹ Integrative Vascular Physiology Lab, Integrative and Biomedical Physiology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA, United States.
² Integrative Vascular Physiology Lab, Department of Kinesiology, College of Health and Human Development, The Pennsylvania State University, University Park, PA, United States.
³ Nutrition and Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
⁴ Medical School, The University of Western Australia, Perth, WA, Australia.
⁵ Cardiometabolic Nutrition Research Lab, Department of Nutritional Sciences, College of Health and Human Development, The Pennsylvania State University, University Park, PA, United States.
⁶ Women's Health and Exercise Lab, Department of Kinesiology, College of Health and Human Development, The Pennsylvania State University, University Park, PA, United States.
⁷ Department of Physics, Wake Forest University, Winston-Salem, NC, United States.
⁸ Faculty of Biological Sciences, Department of Biological Sciences, University of Leeds, Leeds, United Kingdom.

Abstract

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 BR_nitrate compared to BR_placebo (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 BR_nitrate-mediated endothelial protection is lost within the 24-h period following the final dose of BR_nitrate.

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.

Keywords: aging; dietary nitrate supplementation; endothelium; menopause; nitric oxide.

Associated data

ClinicalTrials.gov/NCT03644472

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH) through grant UL1 TR002014. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The project described was also supported by the NIH T32GM108563, T32DK120509, and the Huck Endowment for Nutritional Research in Family and Community Medicine at Penn State College of Medicine and University Park.