Rationale Nitrate-rich beetroot juice has been shown to improve exercise capacity in Heart Failure with Preserved Ejection Fraction (HFpEF), but studies using pharmacologic preparations of inorganic nitrate are lacking. Objectives To determine: (1) the dose-response effect of potassium nitrate (KNO3) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO3 in HFpEF. Methods and Results We randomized 12 subjects with HFpEF to oral KNO3 (n=9) or potassium chloride (KCl, n=3). Subjects received 6mmol twice-daily during Week-1, followed by 6mmol thrice-daily during Week-2. Supine cycle ergometry was performed at baseline (Visit 1) and after each week (Visits 2&3). Quality of life (QOL) was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ). The primary efficacy outcome, peak O2-uptake, did not significantly improve (P=0.13). Exploratory outcomes included exercise duration and quality of life. Exercise duration increased significantly with KNO3 (Visit 1: 9.87 [95%CI=9.31–10.43]; Visit 2: 10.73 [95%CI=10.13–11.33]; Visit 3: 11.61 [95%CI=11.05–12.17] minutes, P=0.002). Improvements in the KCCQ total symptom (Visit 1: 58.0 [95%CI=52.5–63.5], Visit 2: 66.8 [95%CI=61.3–72.3]; Visit 3: 70.8 [95%CI=65.3–76.3], P=0.016) and functional status scores (Visit 1: 62.2 [95%CI=58.5–66.0], Visit 2: 68.6 [95%CI=64.9–72.3], Visit 3: 71.1 [95%CI=67.3–74.8]; P=0.01) were seen after KNO3. Pronounced elevations in trough levels of nitric oxide metabolites (NOm) occurred with KNO3 (Visit 2: 199.5 [95%CI=98.7–300.2]; Visit 3: 471.8 [95%CI=377.8–565.8]) versus baseline (Visit 1: 38.0 [95%CI=0.00–132.0] μM; P<0.001). KNO3 did not lead to clinically-significant hypotension or methemoglobinemia. Following 6 mmol of KNO3, systolic blood pressure was reduced by a maximum of 17.9 (95%CI −28.3-[−7.6]) mmHg 3.75 hours later. Peak NOm concentrations were 259.3 (95%CI 176.2–342.4) μM 3.5 hours after ingestion, and the median half-life was 73.0 (IQR 33.4–232.0) minutes. Conclusions KNO3 is potentially well-tolerated and improves exercise duration and QOL in HFpEF. This study reinforces the efficacy of KNO3 and suggests that larger randomized trials are warranted. ClinicalTrials.gov NCT02256345; https://www.clinicaltrials.gov/ct2/show/NCT02256345

BackgroundStable plasma nitric oxide (NO) metabolites (NOM), composed predominantly of nitrate and nitrite, are attractive biomarkers of NO bioavailability. NOM levels integrate the influence of NO‐synthase‐derived NO production/metabolism, dietary intake of inorganic nitrate/nitrite, and clearance of NOM. Furthermore, nitrate and nitrite, the most abundant NOM, can be reduced to NO via the nitrate‐nitrite‐NO pathway.Methods and ResultsWe compared serum NOM among subjects without heart failure (n=126), subjects with heart failure and preserved ejection fraction (HFpEF; n=43), and subjects with heart failure and reduced ejection fraction (HFrEF; n=32). LV mass and extracellular volume fraction were measured with cardiac MRI. Plasma NOM levels were measured after reduction to NO via reaction with vanadium (III)/hydrochloric acid. Subjects with HFpEF demonstrated significantly lower unadjusted levels of NOM (8.0 μmol/L; 95% CI 6.2–10.4 μmol/L; ANOVA P=0.013) than subjects without HF (12.0 μmol/L; 95% CI 10.4–13.9 μmol/L) or those with HFrEF (13.5 μmol/L; 95% CI 9.7–18.9 μmol/L). There were no significant differences in NOM between subjects with HFrEF and subjects without HF. In a multivariable model that adjusted for age, sex, race, diabetes mellitus, body mass index, current smoking, systolic blood pressure, and glomerular filtration rate, HFpEF remained a predictor of lower NOM (β=−0.43; P=0.013). NOM did not correlate with LV mass, or LV diffuse fibrosis.Conclusions HFpEF, but not HFrEF, is associated with reduced plasma NOM, suggesting greater endothelial dysfunction, enhanced clearance, or deficient dietary ingestion of inorganic nitrate. Our findings may underlie the salutary effects of inorganic nitrate supplementation demonstrated in recent clinical trials in HFpEF.

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