Dietary Nitrate, Vascular Function and Inflammation
Condition: Hypertension; Inflammation
MeSH terms: Inflammation
Study type: Interventional

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.
    

Detailed description: 
      This clinical research is funded by the Austrian Science Fund (FWF, project number: KLI 858).
      It is based on close collaborations between the University of Vienna and the Medical
      University of Vienna, 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 trial center's
      coordinating physician. The sponsor is the University of Vienna, as represented by the
      Principal Investigator Dr. Oliver Neubauer (Research Platform Active Ageing). International
      collaborations include Dr. Catherine Bondonno, Prof. Hodgson (both Edith Cowan University)
      Dr. Jonathan Peake (Queensland University of Technology), and Prof. Richard Woodman (Flinders
      University) (all Australia).

      Wider research context / theoretical framework:

      Aging is a major risk factor for cardiovascular disease (CVD). Developing effective
      strategies to improve cardiovascular health with ageing is a high priority. Emerging data
      indicate that inorganic dietary nitrate, found in green leafy vegetables and beetroot juice
      (BRJ), is important for cardiovascular health (Blekkenhorst et al. 2018). These data suggest
      that small increases in nitrate intake among those with elevated risk for CVD would have a
      substantial impact, by improving the bioavailability of nitric oxide (NO) through the
      enterosalivary nitrate- nitrite-NO pathway (involving the oral microbiome). Results from the
      study group's research suggest beneficial short-term effects of nitrate-rich BRJ on blood
      pressure and vascular inflammation markers in healthy older adults (Raubenheimer et al.
      2017).

      Hypotheses / research questions / objectives:

      The proposed clinical study is aimed to examine whether the daily consumption of 2×70 mL BRJ
      over 4 weeks translates into improved clinical outcomes in older adults with treated grade 1
      hypertension. The primary hypothesis is that the increased dietary nitrate intake lowers
      blood pressure and improves vascular function. The secondary hypotheses are that the
      increased dietary nitrate intake results in changes in the oral microbiome, favorably
      modulates the systemic inflammatory status, and that these changes correlate with
      cardiovascular-related outcomes.

      Approach / methods:

      This randomized, placebo-controlled crossover study will involve two 4-week treatment
      periods, consisting of interventions with nitrate-rich BRJ and nitrate-depleted BRJ,
      separated by a 4-week washout period. Thirty-five men and women, between the ages of 55 and
      70 years, who have been diagnosed with grade 1 hypertension will be recruited. Twenty-nine
      participants will be required to complete the study, based on power/sample size calculations
      with the forearm blood flow (FBF) response to acetylcholine and 24 h-ambulatory systolic
      blood pressure as the primary endpoints. Principal secondary endpoints are the number of
      CD11b-expressing blood granulocytes and the FBF response to glyceryltrinitrate. Among various
      additional secondary and exploratory endpoints, plasma nitrate and nitrite and a broad range
      of inflammation biomarkers will be measured. Furthermore, the oral microbiome will be
      analyzed.

      Level of originality / innovation:

      Beneficial effects of nitrate have predominantly been observed in healthy populations, but
      evidence of cardiovascular benefits and anti-inflammatory effects in clinical populations is
      limited (Raubenheimer et al. 2019). This study addresses the need to determine the efficacy
      of dietary nitrate to improve cardiovascular health and counteract chronic low-grade
      inflammation in humans at risk of CVD.
    

Intervention name(s): High-nitrate intervention; Low-nitrate intervention
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): The 2×70 mL of nitrate-rich (i.e., 'high nitrate') beetroot juice contains 12.9 mmol nitrate (NO3-).; The 2×70 mL of nitrate-depleted (i.e., 'low nitrate') beetroot juice contains 0.04 mmol (or less) nitrate.
Other intervention name(s): HI-NI; LO-NI
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: 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.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: dietary nitrate; inorganic nitrate-nitrite-nitric oxide pathway; oral microbiome; chronic low-grade inflammation; vascular integrity; high blood pressure; cardiovascular health