Nitrate, Exercise and Vascular Function in Midlife Women

NCT06527248 | Not Yet Recruiting

• 1 other identifier: UVienna_Women's-Beet
• Study Type: interventional
• Target: 54
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this clinical study in women after menopause is to investigate whether the daily intake of nitrate from beetroot juice over 12 weeks enhances the positive effect of exercise training on vascular function, blood pressure and physical performance. The risk of cardiovascular diseases (CVD) increases with advancing age and women are particularly affected. In women, the decline in the sex hormone oestrogen in the blood circulation with menopause contributes to impaired vascular function and an increased CVD risk; in part through increased inflammatory processes, oxidative stress, and a reduced body's own production of nitric oxide (NO). NO is a signaling molecule that is important for vascular function. Endurance-based exercise training is a key lifestyle strategy to prevent CVD. However, studies indicate that exercise is less effective in terms of its health-promoting adaptations in women after menopause as compared with men of similar age. This study investigates the effect of exercise training in combination with the intake of nitrate-rich beetroot juice on functions of the cardiovascular system. Nitrate is a nitrogen compound that is found naturally in plant foods (e.g. beetroot juice) and is converted to NO in the human body. Results of previous studies indicate vasodilatory, blood pressure-lowering and performance-enhancing effects as well as positive influences on inflammatory processes and oxidative stress following nitrate intake. The hypothesis is that nitrate intake concomitant to training promotes training adaptations and further improves vascular function, blood pressure and physical performance compared to training without nitrate intake. For the study, 54 untrained postmenopausal women (with the ages between 45 and 65 years) will be recruited and randomly allocated into two groups. Both groups will undergo 12 weeks of endurance-based exercise training. One group will receive nitrate-rich beetroot juice, and the other nitrate-depleted beetroot juice (as placebo). Vascular function, blood pressure, maximum oxygen uptake, and blood biomarkers for nitrate metabolism, inflammation status and oxidative stress will be examined. The anticipated study results will provide new insights into whether nitrate as a 'training adjunct' improves health-promoting training adaptations in women after menopause. The overall aim is to improve the cardiovascular health and performance of middle-aged women and reduce their increased CVD risk.

Conditions

Healthy; Menopause; Hypertension; Inflammation

Keywords

Women after menopause; Vascular function; Exercise training responsiveness; Cardiovascular health; Dietary nitrate-nitrite-nitric oxide-pathway; Beetroot juice

Outcome Measures

Primary Outcomes (1)

• Forearm blood flow (FBF) response to acetylcholine (FBFACh)

  Endothelial-dependent microvascular function

  Change from baseline FBFACh to after the 12-week intervention period

Secondary Outcomes (2)

• 24-hour ambulatory systolic blood pressure

  Change from baseline 24 hour-ambulatory systolic blood pressure to after the 12-week intervention period

• Maximal oxygen uptake (V̇O2 max)

  Change from baseline V̇O2 max to after the 12-week intervention period

Other Outcomes (4)

• FBF response to glyceryltrinitrate (FBFGTN)

  Change from baseline FBFGTN to after the 12-week intervention period

• Clinic blood pressure

  Change from baseline clinic blood pressure to after the 12-week intervention period

• Plasma and saliva nitrate and nitrite

  Change from baseline plasma and saliva nitrate and nitrite to after the 12-week intervention period

Study Arms (2)

Nitrate group

ACTIVE COMPARATOR

Daily consumption of 70 mL nitrate-rich beetroot juice concomitant with 12 weeks of exercise training

Dietary Supplement: Nitrate group

Placebo group

PLACEBO COMPARATOR

Daily consumption of 70 mL nitrate-depleted beetroot juice (placebo) concomitant with 12 weeks of exercise training

Dietary Supplement: Placebo group

Interventions

Nitrate group DIETARY_SUPPLEMENT

Daily consumption of 70 mL beetroot juice containing \~400 mg nitrate over an intervention period of 12 weeks concomitant to exercise training, either 3 hours pre-exercise on training days or with breakfast on non-training days.

Also known as: Nitrate-rich beetroot juice

Nitrate group

Placebo group DIETARY_SUPPLEMENT

Daily consumption of 70 mL nitrate-depleted beetroot juice (placebo) over an intervention period of 12 weeks concomitant to exercise training, either 3 hours pre-exercise on training days or with breakfast on non-training days.

Also known as: Nitrate-depleted beetroot juice

Placebo group

Eligibility Criteria

• Age: 45 Years - 65 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Postmenopausal women (amenorrhoeic ≥1 year), between the ages of 45 and 65 years, inclusive, who are either normotensive or are medically treated for stage 1 hypertension
• Written informed consent

You may not qualify if:

• Current or recent (within previous 3 months) engagement in exercise training (i.e., planned, structured, and regular exercise) with an average net exercise time of \>2 hours per week
• Above-average cardiorespiratory fitness levels (i.e., a V̇O2 max max above the 75th percentile of age- and sex-specific normative data: ≥43 mL/kg/min for women aged 45-49 years, ≥38 mL/kg/min for women aged 50-59 years, ≥35 mL/kg/min for women aged 60-65 years)
• Any evidence of acute or chronic diseases such as symptomatic cardiovascular or peripheral vascular disease, moderate or severe chronic kidney disease (estimated glomerular filtration rate (GFR) \<50 mL/min), pulmonary, neural, or musculoskeletal disease, osteoporotic fractures, cancer, or type 1 or 2 diabetes mellitus
• Fasting glucose \>7.0 mmol/L or HbA1c \> 6.5 rel. %
• BMI \<18.5 kg/m2 or \>30kg/m2
• A mean 24-hour ambulatory systolic/diastolic blood pressure of ≥130/80 mm Hg
• Irregular resting electrocardiography (ECG)
• Inability to perform physical exercise
• Abnormal cardiovascular responses during the baseline V ̇O2 max test, including symptoms, ECG abnormalities, arrhythmias, or exaggerated blood pressure responses
• Current or recent (\<12 months) oestrogen-based hormone-replacement therapy
• Chronic use of nitric oxide (NO) donors, organic nitrites/nitrates, Ticagrelor, sodium-glucose cotransporter 2 (SGLT2) inhibitors, high-dose statins (i.e., Simvastatin \>40mg/day, Atorvastatin \>20mg/day, Rosuvastatin \>10mg/day), acetylsalicylic acid \>100mg/day, non-steroidal anti-inflammatory drugs (NSAID)
• A change in drug therapy likely to influence major outcomes within the previous 2 months, or likelihood that drug therapy would change during the study
• Use of antibiotics (within previous 2 months)
• Use of antibacterial mouthwash (volunteers willing to cease using antibacterial mouthwash for a period of 4 weeks before randomization will be included)
• Being vegan or vegetarian or consumption of \>5 serves of vegetables per day

Sponsors & Collaborators

• University of Vienna: lead
• Medical University of Vienna: collaborator
• Danube University Krems: collaborator
• University of Giessen: collaborator
• Edith Cowan University: collaborator
• Flinders University: collaborator

Related Publications (7)

• Raubenheimer K, Bondonno C, Blekkenhorst L, Wagner KH, Peake JM, Neubauer O. Effects of dietary nitrate on inflammation and immune function, and implications for cardiovascular health. Nutr Rev. 2019 Aug 1;77(8):584-599. doi: 10.1093/nutrit/nuz025.

  PMID: 31150091 BACKGROUND

• Woessner MN, McIlvenna LC, Ortiz de Zevallos J, Neil CJ, Allen JD. Dietary nitrate supplementation in cardiovascular health: an ergogenic aid or exercise therapeutic? Am J Physiol Heart Circ Physiol. 2018 Feb 1;314(2):H195-H212. doi: 10.1152/ajpheart.00414.2017. Epub 2017 Nov 3.

  PMID: 29101174 BACKGROUND

• Shannon OM, Allen JD, Bescos R, Burke L, Clifford T, Easton C, Gonzalez JT, Jones AM, Jonvik KL, Larsen FJ, Peeling P, Piknova B, Siervo M, Vanhatalo A, McGawley K, Porcelli S. Dietary Inorganic Nitrate as an Ergogenic Aid: An Expert Consensus Derived via the Modified Delphi Technique. Sports Med. 2022 Oct;52(10):2537-2558. doi: 10.1007/s40279-022-01701-3. Epub 2022 May 23.

  PMID: 35604567 BACKGROUND

• Moreau KL, Clayton ZS, DuBose LE, Rosenberry R, Seals DR. Effects of regular exercise on vascular function with aging: Does sex matter? Am J Physiol Heart Circ Physiol. 2024 Jan 1;326(1):H123-H137. doi: 10.1152/ajpheart.00392.2023. Epub 2023 Nov 3.

  PMID: 37921669 BACKGROUND

• Baranauskas MN, Freemas JA, Tan R, Carter SJ. Moving beyond inclusion: Methodological considerations for the menstrual cycle and menopause in research evaluating effects of dietary nitrate on vascular function. Nitric Oxide. 2022 Jan 1;118:39-48. doi: 10.1016/j.niox.2021.11.001. Epub 2021 Nov 11.

  PMID: 34774755 BACKGROUND

• Hogwood AC, Ortiz de Zevallos J, Weeldreyer N, Clark JR, Mazzella V, Cain L, Myaing D, Love KM, Weltman A, Allen JD. The acute effects of exercise intensity and inorganic nitrate supplementation on vascular health in females after menopause. J Appl Physiol (1985). 2023 Nov 1;135(5):1070-1081. doi: 10.1152/japplphysiol.00559.2023. Epub 2023 Oct 5.

  PMID: 37795531 BACKGROUND

• Fejes R, Pilat N, Lutnik M, Weisshaar S, Weijler AM, Kruger K, Draxler A, Bragagna L, Peake JM, Woodman RJ, Croft KD, Bondonno CP, Hodgson JM, Wagner KH, Wolzt M, Neubauer O. Effects of increased nitrate intake from beetroot juice on blood markers of oxidative stress and inflammation in older adults with hypertension. Free Radic Biol Med. 2024 Sep;222:519-530. doi: 10.1016/j.freeradbiomed.2024.07.004. Epub 2024 Jul 5.

  PMID: 38972612 BACKGROUND

MeSH Terms

Conditions

Hypertension; Inflammation

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Oliver Neubauer, Dr.Priv.Doz.

  University of Vienna

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Oliver Neubauer, Dr.Priv.Doz.

CONTACT

+4314277; oliver.neubauer@univie.ac.at

Michael Wolzt, Prof.Dr.med.

CONTACT

+43140400; michael.wolzt@meduniwien.ac.at

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: One group will receive nitrate-rich beetroot juice and the other group will receive nitrate-depleted beetroot juice (as placebo) during the training period, on the background of a low-nitrate diet and an otherwise unaltered lifestyle. All products will be obtained from the same supplier (James White Drinks Ltd., UK). The nitrate-depleted beetroot juice is generated for research purposes only. The two juices will be indistinguishable by taste, color, smell and packaging. The investigators involved in the data acquisition and analysis will be blind to the trial allocation until the study has been completed and all analyses have been performed.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr. (PhD) Priv.-Doz.

Model Details: Prospective, mono-center, randomized, double-blind, placebo-controlled, parellel-group study

Study Record Dates

• First Submitted: July 24, 2024
• First Posted: July 30, 2024
• Study Start: January 1, 2025
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027
• Last Updated: August 9, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: The plan is to publish the findings in scientific journals and to present them at scientific meetings and to the public after the study is completed.
• Access Criteria: Supporting the Open Access Policy of the University of Vienna, the PHAIDRA repository enables public access of the research data necessary to reproduce and to verify the results of publications from this research. The Austrian Science Fund (FWF) that funds this clinical research also requires to make peer-reviewed publications based on the results openly accessible on the Internet.