The Impact of Inorganic Nitrate on Endothelial Function: A Systematic Review of Randomized Controlled Trials and Meta-analysis

Context: Inorganic nitrate is an exogenous source of nitric oxide, an established regulator of vascular homeostasis via the nitrate-nitrite-nitric oxide pathway. Here, we evaluate the impact of inorganic nitrate on endothelial function, a risk factor for cardiovascular disease. Objective: A systematic review of the existing literature and meta-analysis was performed. Trials testing inorganic nitrate compared with a control were selected and the change in forearm endothelial function (as assessed by flow-mediated dilatation [FMD]) were included. Data Sources: The following databases were searched: Medline, Web of Science, and Scopus. Data Extraction: and Analysis Standardized mean differences in %FMD were pooled using a random-effects model and 13 studies were included in the analysis. Quality assessment was performed using the Cochrane risk-of-bias score. Results: Inorganic nitrate was associated with improved Δ%FMD compared with the control; the standardized mean difference was 1.48% (95% CI: 0.70%–2.27%; P<0.01); high heterogeneity (I ² = 98.2%) was observed. The significant effect observed remained irrespective of dose (±600mg nitrate), duration (acute or chronic consumption), health status (± health conditions), and type of nitrate (dietary or nondietary). Notably, acute studies had a greater FMD response than chronic studies (1.93% [95% CI: 0.71%–3.15%] vs 0.90% [95% CI: 0.48%–1.31%]). More than half of the studies reviewed showed low risk of bias; the rest of the studies were classified as “some concern” due to lack of information about randomization process and lack of prespecified analysis plans. Conclusion: Our results show that, from a modest number of included trials, inorganic nitrate consumption improves FMD response by more than 1%, a clinically relevant magnitude for the prevention of cardiovascular disease.