Dietary Nitrate, Vascular Function and Inflammation

NCT04584372 | Completed

• 1 other identifier: UVienna_Dietary nitrate
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

The risk for cardiovascular diseases (CVD) increases with advancing age. Developing effective lifestyle-based strategies to promote, preserve or restore cardiovascular health with aging is a high priority. The overall aim of this clinical research is to investigate the innovative concept that an increased intake of dietary nitrate (through beetroot juice) could be a feasible adjuvant therapy to treat elevated blood pressure and improve blood vessel function in older adults. Inorganic dietary nitrate, found in beetroot and green leafy vegetables, is a source of nitric oxide (NO), a signaling molecule that is important for cardiovascular health. NO is also produced in the human body, but the body's production and availability of NO decrease during ageing and CVD. The declined NO availability is associated with impaired blood vessel function, unresolved inflammatory responses, and an increased CVD risk. Dietary nitrate is an additional NO source. Following the intake of nitrate, NO is produced in a pathway that involves commensal bacteria in the mouth. So far, little is known about whether dietary nitrate improves cardiovascular health in older populations with high blood pressure. The aim of this randomized, placebo-controlled crossover study is to investigate whether the daily intake of nitrate-rich beetroot juice over four weeks translates into improved cardiovascular health-related outcomes in older adults with treated mild high blood pressure. Men and women, between the ages of 55 and 70 years, who have been diagnosed with grade 1 high blood pressure and who are taking two or more blood-pressure lowering medications will be recruited. The study will investigate whether the increased dietary nitrate intake further lowers blood pressure and improves blood vessel function. A specific aim is to examine whether the nitrate intake results in favorable changes in the oral bacteria community and the systemic inflammatory status, and whether these changes correlate with cardiovascular-related outcomes. This research will offer information on the value of dietary nitrate to counteract chronic inflammation, the latter of which plays a role in developing or worsening cardiovascular disorders, such as high blood pressure. The expected results of this study will provide important new evidence of whether nitrate-rich beetroot juice could be a key component of therapeutic interventions to improve cardiovascular health in individuals with high blood pressure.

Conditions

Hypertension; Inflammation

Keywords

dietary nitrate; inorganic nitrate-nitrite-nitric oxide pathway; oral microbiome; chronic low-grade inflammation; vascular integrity; high blood pressure; cardiovascular health

Outcome Measures

Primary Outcomes (4)

• Change in forearm blood flow (FBF) response to acetylcholine

  Vascular function

  Change from baseline FBF at 4 weeks of the HI-NI intervention

• Change in forearm blood flow (FBF) response to acetylcholine

  Vascular function

  Change from baseline FBF at 4 weeks of the LO-NI intervention

• Change in 24 hour-ambulatory systolic blood pressure

  Blood pressure

  Change from baseline 24 hour-ambulatory systolic blood pressure at 4 weeks of the HI-NI intervention

• Change in 24 hour-ambulatory systolic blood pressure

  Blood pressure

  Change from baseline 24 hour-ambulatory systolic blood pressure at 4 weeks of the LO-NI intervention

Secondary Outcomes (4)

• Change in granulocyte CD11b expression

  Change from baseline granulocyte CD11b expression at 4 weeks of the HI-NI intervention

• Change in granulocyte CD11b expression

  Change from baseline granulocyte CD11b expression at 4 weeks of the LO-NI intervention

• Change in forearm blood flow (FBF) response to glyceryltrinitrate

  Change from baseline FBF at 4 weeks of the HI-NI intervention

• Change in forearm blood flow (FBF) response to glyceryltrinitrate

  Change from baseline FBF at 4 weeks of the LO-NI intervention

Other Outcomes (8)

• Change in clinical blood pressure

  Change from baseline clinical blood pressure at 4 weeks of the HI-NI intervention

• Change in clinical blood pressure

  Change from baseline clinical blood pressure at 4 weeks of the LO-NI intervention

• Change in plasma nitrate and nitrite

  Change from baseline plasma nitrate and nitrite at 4 weeks of the HI-NI intervention

Study Arms (2)

High-nitrate (HI-NI) intervention

ACTIVE COMPARATOR

The 'active treatment' arm will involve daily consumption of 2×70 mL nitrate-rich (HI-NI) beetroot juice (70 mL with breakfast and 70 mL with dinner) over an intervention period of 4 weeks.

Dietary Supplement: High-nitrate intervention

Low-nitrate (LO-NI) intervention

PLACEBO COMPARATOR

The placebo treatment arm daily consumption of 2×70 mL nitrate-depleted (LO-NI) beetroot juice (70 mL with breakfast and 70 mL with dinner) an intervention period of 4 weeks.

Dietary Supplement: Low-nitrate intervention

Interventions

High-nitrate intervention DIETARY_SUPPLEMENT

The 2×70 mL of nitrate-rich (i.e., 'high nitrate') beetroot juice contains 12.9 mmol nitrate (NO3-).

Also known as: HI-NI

High-nitrate (HI-NI) intervention

Low-nitrate intervention DIETARY_SUPPLEMENT

The 2×70 mL of nitrate-depleted (i.e., 'low nitrate') beetroot juice contains 0.04 mmol (or less) nitrate.

Also known as: LO-NI

Low-nitrate (LO-NI) intervention

Eligibility Criteria

• Age: 55 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ambulant male and females between 55 and 75 years of age, inclusive
• Resting systolic blood pressure between 130 and 170 mmHg, inclusive
• Written informed consent

You may not qualify if:

• Diastolic blood pressure \>110 mmHg
• Type 1 or 2 diabetes mellitus or fasting glucose \>7.0 mmol/L
• Any evidence of acute or chronic disease such as symptomatic cardiovascular or peripheral vascular disease, moderate or severe chronic kidney disease (estimated glomerular filtration rate (GFR) \<50 ml/min)), or cancer which is not in remission
• Consumption of ≥5 serves of vegetables per day
• Consumption of a diet estimated to contain \>200 mg/d of nitrate
• Being vegan or vegetarian
• BMI ≥35 kg/m2 or \<18.5 kg/m2
• Use of nitric oxide donors, organic nitrites/nitrates, sildenafil and related drugs, anti-coagulation, non-steroidal anti-inflammatory or statin-related drugs
• Use of antibacterial mouthwash (volunteers willing to cease using antibacterial mouth wash for a period of 4 weeks before randomisation will be included)
• Use of antibiotics (within previous 2 months)
• A change in drug therapy likely to influence blood pressure or major secondary outcomes within the previous month, or the likelihood that drug therapy would change during the study
• Current or recent (within previous 3 months) engagement in regular structured exercise training (more than 2 hours of moderate to more intense exercise per week)
• Current or recent (within previous 6 months) loss or gain of \>6% of body weight
• Current or recent (\<12 months) regular smoking of \>5 cigarettes/day
• Alcohol intake \>140 g per week for women or \>210 g per week for men and/or binge drinking behaviour

Sponsors & Collaborators

• University of Vienna: lead
• Medical University of Vienna: collaborator
• Queensland University of Technology: collaborator
• Flinders University: collaborator
• Edith Cowan University: collaborator

Study Sites (2)

Medical University of Vienna

Vienna, 1090, Austria

Location

University of Vienna

Vienna, 1090, Austria

Location

Related Publications (5)

• Raubenheimer K, Hickey D, Leveritt M, Fassett R, Ortiz de Zevallos Munoz J, Allen JD, Briskey D, Parker TJ, Kerr G, Peake JM, Pecheniuk NM, Neubauer O. Acute Effects of Nitrate-Rich Beetroot Juice on Blood Pressure, Hemostasis and Vascular Inflammation Markers in Healthy Older Adults: A Randomized, Placebo-Controlled Crossover Study. Nutrients. 2017 Nov 22;9(11):1270. doi: 10.3390/nu9111270.

  PMID: 29165355 BACKGROUND

• 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

• Blekkenhorst LC, Bondonno NP, Liu AH, Ward NC, Prince RL, Lewis JR, Devine A, Croft KD, Hodgson JM, Bondonno CP. Nitrate, the oral microbiome, and cardiovascular health: a systematic literature review of human and animal studies. Am J Clin Nutr. 2018 Apr 1;107(4):504-522. doi: 10.1093/ajcn/nqx046.

  PMID: 29635489 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 DERIVED

• Fejes R, Lutnik M, Weisshaar S, Pilat N, Wagner KH, Stuger HP, Peake JM, Woodman RJ, Croft KD, Bondonno CP, Hodgson JM, Wolzt M, Neubauer O. Increased nitrate intake from beetroot juice over 4 weeks affects nitrate metabolism, but not vascular function or blood pressure in older adults with hypertension. Food Funct. 2024 Apr 22;15(8):4065-4078. doi: 10.1039/d3fo03749e.

  PMID: 38546454 DERIVED

MeSH Terms

Conditions

Hypertension; Inflammation

Condition Hierarchy (Ancestors)

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

Study Officials

• Oliver Neubauer, Dr PhD, PD

  University of Vienna

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The two treatment arm will consist of a 4-week high-nitrate (HI-NI) intervention (using nitrate-rich beetroot juice) and a 4-week low-nitrate (LO-NI) intervention using nitrate-depleted beetroot juice as the placebo. 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: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr PhD, PD

Model Details: Prospective, mono-center, randomized, double-blind, placebo-controlled, crossover study The study will involve a randomized, placebo-controlled crossover design, with two 4-week treatment periods separated by a 4-week washout period. The two treatments will consist of a 4-week high-nitrate (HI-NI) and a 4-week low-nitrate (LO-NI, i.e., placebo) intervention in older adults with treated grade 1 hypertension, on the background of a low-nitrate diet and unaltered lifestyle.

Study Record Dates

• First Submitted: September 29, 2020
• First Posted: October 14, 2020
• Study Start: January 1, 2021
• Primary Completion: March 28, 2023
• Study Completion: March 28, 2023
• Last Updated: May 10, 2023

Record last verified: 2023-05

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.

Locations

AU (2)