Nitrate Derived From Beetroot Juice Lowers Blood Pressure in Patients With Arterial Hypertension

Introduction

Beetroot juice (BRJ) is rich in nitrate (NO₃) and has the potential to reduce blood pressure (BP). NO₃ is a precursor for the production of nitric oxide (NO) and increases its concentrations in the bloodstream, optimizing endothelial function (e.g., vasodilation) (1). A recent meta-analysis found that BRJ NO₃ (2–56 days of intervention) reduced typically −3.55 mmHg and −1.32 mmHg for systolic (SBP) and diastolic BP (DBP), respectively, in a mixed sample of individuals with and without arterial hypertension (2). This result is of clinical relevance in the control of arterial hypertension, as a 2-mmHg reduction in BP can reduce mortality from ischemic heart disease by 7 and 10% of mortality from stroke (3). The latest systematic review with only hypertensive patients concluded that there is insufficient evidence to support or refute the use of inorganic NO₃ as a strategy to decrease BP. However, this review included studies intervening with NO₃ salts not from beetroot only and physical exercise programs, lacking an estimate of the effect of the intervention. Therefore, there are significant limitations to the conclusions on the influence of BRJ in hypertensive patients restricted to its findings (4).

Beetroot is rich in bioactive compounds (betalains, flavonoids, and polyphenols), which can influence the endothelial and pressure responses differently from NO₃ salts (5). Although there are a considerable number of clinical studies on BRJ rich in NO₃ and hypertension, it is difficult to indicate the real effects of NO₃ from BRJ on the BP of hypertensive patients because there are still no estimates of the effects of NO₃ derived from BRJ on the BP of patients with hypertension. Based on the information presented above, we raise the following question: is the NO₃ of the BRJ capable of decreasing the BP in hypertensive patients? To clarify this issue, our study aimed to carry out a systematic review with meta-analysis to verify the effects of the NO₃ of the BRJ on the BP of patients with hypertension and to include subanalyses with BP values obtained by clinical measurements and ambulatory 24-h monitoring.

Materials and Methods

Registration

The review was described according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) (6) and is registered in the PROSPERO database (CRD42021269339).

Search Strategy and Study Selection

The searches were accomplished through EMBASE, Cochrane Library, MEDLINE (via PubMed), CINAHL, Web of Science, and LILACS databases with the application of the keywords “Beetroot juice” OR “Nitrates” OR “Red beet” OR “Beta vulgaris” AND “Blood pressure” OR “Hypertension.” The search relied on the Boolean NOT for the descriptor “Exercise.”

All articles identified were exported to the Rayyan QCRI program (Qatar Computing Research Institute, Qatar) to exclude duplicates. The studies were screened in the Rayyan program by reading the title and abstract. The eligibility stage was achieved by reading the articles entirely by two independent reviewers (CJRB and AAP). Another reviewer was invited to give a judgment (VEV) if there was a difference of opinion concerning a study.

The studies were required to originate from peer-reviewed journals published from the interception of the database until July 14, 2021. For inclusion, the articles needed to accomplish all the criteria are described below as follows: single or double-blinded RCTs design; participants older than >18 years old, previously diagnosed with hypertension or higher BP inclusion criteria for baseline SBP > 130 mmHg and DBP > 80 mmHg in accordance to American College of Cardiology (ACC) and American Heart Association (AHA) (7). NO₃ from BRJ should necessarily be consumed in a format that blinded participants and researchers, and control intervention should use BRJ in a NO₃ depleted condition. These studies reported the SBP and DBP values (mmHg) were measured before and after the intervention.

Data Extraction

Information about the author, study design, features of the study participants, intervention, and the results of the respective studies were reported. Missing data were requested by contacting the corresponding study authors. This stage was completed independently by one reviewer (CJRB). When the author's correspondent did not answer, the Web Plot Digitizer® was applied to extract data presented in the graphs. We adopted the criteria of extracting the data postintervention, and the mean and standard deviations (MSD) were logged. Values presented with “standard error” or “confidence intervals” (CI) in the studies were transformed to MSD.

Assessment of the Risk of Bias

The bias analysis was completed at Risk of Bias tools originated in the Cochrane organization (8) via the Review Manager program (RevMan 5.4.1). Risk of bias is a tool founded on the domains (9). The evaluation was split into seven fields: “Random sequence generation,” “Allocation concealment,” “Blinding of participants and personnel,” “Blinding of outcome assessment,” “Incomplete outcome data,” “Selective reporting,” and “Other Bias.” The classification was split into three direct responses: low risk, unclear risk, and high risk. Our deductions were based on the table developed by Carvalho et al. (9), “Reviewer's judgment and criteria for judgment.” Two independent authors achieved the analysis of the risk of bias (CJRB & AAP) and a third (VEV) was consulted if there were any discrepancies in the decisions.

GRADE (Levels of Evidence)

The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) Working Group (GRADE Working Group, 2004) was surveyed to analyze the certainty of the evidence, including the study design of randomized trials (strong evidence). Study quality (detailed study methods and execution) and significant limitations secondarily were considered in the strength of evidence analysis (10). The summary of the findings table was created using GRADEpro GDT version 4® (McMaster University, ON, Canada).

Qualitative Analysis (Systematic Review)

A narrative synthesis was executed to describe detailed data on how each study was completed. The details for each study were introduced in texts and tables. The results of the individual qualitative analysis for each study were made by analyzing the behavior of SBP and DBP (mmHg) pre- and postintervention BRJ rich in NO₃ or without NO₃.

Quantitative Analysis (Meta-Analysis)

In the meta-analysis, we inserted the SBP and DBP clinical values (measured with a sphygmomanometer) and ambulatory 24 h (measuring every 15–30 min during 24-h monitoring). The effects of BRJ interventions on SBP and DBP were assessed on the alteration between the intervention and control groups. The data enforced to construct the meta-analysis was the period postintervention.

Heterogeneity was calculated via the I² statistic, where a number >50% was considered to indicate substantial heterogeneity between the tests (11). For the values of “95% CI” and “Test for overall effect size,” values of p < 0.05 were assumed as significant differences. We enforced a random-effects model, considering that this is a more conservative method which allows that the heterogeneity of the study may fluctuate beyond chance, providing further generalizable results (8). All data was made by the Review Manager Program (RevMan 5.4.1).

Results

A total of 326 studies were identified via searches in the databases. After the removal of duplicates (n = 116), 210 publications were screened for inclusion. Amongst them, 137 records were excluded after reviewing the title/abstract. The remaining 79 papers were selected for full-text reading. Finally, seven studies were included in the qualitative (systematic review) and quantitative (meta-analysis) synthesis. The search process and selection step details are confirmed in the flow diagram of the PRISMA protocol (Figure 1).

References

Original Article: https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2022.823039/full