Nitrate, Exercise and Vascular Function in Midlife Women

Wider research context: Advancing age is a major risk factor for cardiovascular diseases (CVD). In women, the decline in the sex hormone oestrogen with menopause contributes to impaired vascular function and an increased CVD risk, in part via a reduced bioavailability of the endothelium-derived signaling molecule nitric oxide (NO), chronic low-grade inflammation and increased oxidative stress. Aerobic (or endurance) exercise training is a key lifestyle strategy to prevent CVD. However, data indicate that exercise is less effective for improving cardiovascular health in postmenopausal women as compared with men of similar age. Oestrogen treatment may restore vascular training adaptations but is associated with health risks. The main objective of this research is to examine whether dietary nitrate as a nutritional 'adjuvant' to regular exercise could be an innovative lifestyle intervention to favorably modulate vascular training adaptations and health in midlife women. This research expands upon findings by the investigators and others showing that inorganic nitrate from vegetables exerts benefits on physical function and cardiovascular health by increasing NO availability through the nitrate-nitrite-NO pathway and by attenuating inflammation and oxidative stress. Objectives and hypotheses: The investigators propose a clinical study to examine whether the daily consumption of nitrate-rich beetroot juice concomitant with aerobic exercise training improves vascular function, blood pressure, and cardiovascular fitness in postmenopausal women more effectively as compared with nitrate-depleted beetroot juice consumption (as placebo). The hypothesis is that the increased nitrate intake favorably modulates the systemic inflammatory and oxidative stress status and promotes cardiovascular health-related training outcomes. Methods: This study will involve a prospective, randomized, placebo-controlled parallel-group design. 54 untrained postmenopausal women (45-65 years) will be recruited and randomized into two groups. Both groups will undergo 12 weeks of endurance-based exercise training. The training will consist of a supervised training program that meets contemporary guidelines on aerobic physical activity. One group will receive nitrate-rich beetroot juice (containing \~400 mg nitrate, based on available evidence on the physiological and ergogenic benefits of nitrate), and the other nitrate-depleted beetroot juice (placebo), on the background of a low-nitrate diet and an otherwise unaltered lifestyle. 42 participants (21 per group) will be required to complete the study, based on power/sample size calculations with the forearm blood flow response to acetylcholine as primary endpoint. Secondary endpoints and additional measures will include 24 h-ambulatory blood pressure, maximal oxygen uptake, and blood inflammation and oxidative stress biomarkers. Originality and innovation: It is anticipated that this work will provide important new evidence on the efficacy of dietary nitrate to improve the training responsiveness, vascular function, and cardiovascular health in women after menopause. The objective of such a combined nutritional-training approach is to promote, preserve or restore physiological function and delay or possibly prevent the transition to functional limitations and CVD. Research funding and cooperation arrangements: This clinical research is funded by the Austrian Science Fund (FWF) (grant DOI 10.55776/KLP1075624). It is based on close collaborations between the University of Vienna and the Medical University of Vienna (both Austria), with the Department of Clinical Pharmacology at the Medical University of Vienna as the clinical trial center and Prof. M.D. Michael Wolzt as the coordinating physician of the trial center. The sponsor is the University of Vienna, as represented by the Principal Investigator Dr. Oliver Neubauer, Priv.-Doz. (Department of Nutritional Sciences, University of Vienna). Further national collaborations involve the groups of Prof. M.D. Daniel König, Prof. Karl-Heinz Wagner (both University of Vienna), and Prof. Viktoria Weber (University for Continuing Education Krems, Austria). International collaborations include Dr. Catherine P. Bondonno, Prof. Jonathan M. Hodgson (both Edith Cowan University), Prof. Richard J. Woodman (Flinders University) (all Australia), Prof. Karsten Krüger (Justus Liebig University of Giessen, Germany), and Prof. Jason D. Allen (University of Virginia, USA).