Randomised, double-blind, placebo-controlled study investigating the effects of inorganic nitrate on vascular function, platelet reactivity and restenosis in stable angina: protocol of the NITRATE-OCT study.

INTRODUCTION: The mainstay treatment for reducing the symptoms of angina and long-term risk of heart attacks in patients with heart disease is stent implantation in the diseased coronary artery. While this procedure has revolutionised treatment, the incidence of secondary events remains a concern. These repeat events are thought to be due, in part, to continued enhanced platelet reactivity, endothelial dysfunction and ultimately restenosis of the stented artery. In this study, we will investigate whether a once a day inorganic nitrate administration might favourably modulate platelet reactivity and endothelial function leading to a decrease in restenosis. METHODS AND DESIGN: NITRATE-OCT is a double-blind, randomised, single-centre, placebo-controlled phase II trial that will enrol 246 patients with stable angina due to have elective percutaneous coronary intervention procedure with stent implantation. Patients will be randomised to receive 6 months of a once a day dose of either nitrate-rich beetroot juice or nitrate-deplete beetroot juice (placebo) starting up to 1 week before their procedure. The primary outcome is reduction of in-stent late loss assessed by quantitative coronary angiography and optical coherence tomography at 6 months. The study is powered to detect a 0.22±0.55 mm reduction in late loss in the treatment group compared with the placebo group. Secondary end points include change from baseline assessment of endothelial function measured using flow-mediated dilation at 6 months, target vessel revascularisation (TVR), restenosis rate (diameter>50%) and in-segment late loss at 6 months, markers of inflammation and platelet reactivity and major adverse cardiac events (ie, myocardial infarction, death, cerebrovascular accident, TVR) at 12 and 24 months. ETHICS AND DISSEMINATION: The study was approved by the Local Ethics Committee (15/LO/0555). Trial results will be published according to the CONSORT statement and will be presented at conferences and reported in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT02529189 and ISRCTN17373946, Pre-results.

Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study.

BACKGROUND: The beneficial cardiovascular effects of vegetables may be underpinned by their high inorganic nitrate content. OBJECTIVE: We sought to examine the effects of a 6-wk once-daily intake of dietary nitrate (nitrate-rich beetroot juice) compared with placebo intake (nitrate-depleted beetroot juice) on vascular and platelet function in untreated hypercholesterolemics. DESIGN: A total of 69 subjects were recruited in this randomized, double-blind, placebo-controlled parallel study. The primary endpoint was the change in vascular function determined with the use of ultrasound flow-mediated dilatation (FMD). RESULTS: Baseline characteristics were similar between the groups, with primary outcome data available for 67 patients. Dietary nitrate resulted in an absolute increase in the FMD response of 1.1% (an ∼24% improvement from baseline) with a worsening of 0.3% in the placebo group (P < 0.001). A small improvement in the aortic pulse wave velocity (i.e., a decrease of 0.22 m/s; 95% CI: -0.4, -0.3 m/s) was evident in the nitrate group, showing a trend (P = 0.06) to improvement in comparison with the placebo group. Dietary nitrate also caused a small but significant reduction (7.6%) in platelet-monocyte aggregates compared with an increase of 10.1% in the placebo group (P = 0.004), with statistically significant reductions in stimulated (ex vivo) P-selectin expression compared with the placebo group (P < 0.05) but no significant changes in unstimulated expression. No adverse effects of dietary nitrate were detected. The composition of the salivary microbiome was altered after the nitrate treatment but not after the placebo treatment (P < 0.01). The proportions of 78 bacterial taxa were different after the nitrate treatment; of those taxa present, 2 taxa were responsible for >1% of this change, with the proportions of Rothia mucilaginosa trending to increase and Neisseria flavescens (P < 0.01) increased after nitrate treatment relative to after placebo treatment. CONCLUSIONS: Sustained dietary nitrate ingestion improves vascular function in hypercholesterolemic patients. These changes are associated with alterations in the oral microbiome and, in particular, nitrate-reducing genera. Our findings provide additional support for the assessment of the potential of dietary nitrate as a preventative strategy against atherogenesis in larger cohorts. This trial was registered at clinicaltrials.gov as NCT01493752.