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

BackgroundWave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown.Methods and ResultsWe randomized 44 patients with heart failure with preserved ejection fraction in a double‐blinded fashion to isosorbide dinitrate (ISDN; n=13), ISDN+hydralazine (ISDN+hydral; n=15), or placebo (n=16) for 6 months. The primary end point was the change in reflection magnitude (RM; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6‐minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI, 0.14–0.17], 3 months=0.11 [95% CI, 0.10–0.13], 6 months=0.10 [95% CI, 0.08–0.12] mm Hg/mL per second; P=0.003) and forward wave amplitude (Pf, mean baseline=54.8 [95% CI, 47.6–62.0], 3 months=42.2 [95% CI, 33.2–51.3]; 6 months=37.0 [95% CI, 27.2–46.8] mm Hg, P=0.04), but had no effect on RM (P=0.64), left ventricular mass (P=0.33), or fibrosis (P=0.63). ISDN+hydral increased RM (mean baseline=0.39 [95% CI, 0.35–0.43]; 3 months=0.31 [95% CI, 0.25–0.36]; 6 months=0.44 [95% CI, 0.37–0.51], P=0.03), reduced 6‐minute walk distance (mean baseline=343.3 [95% CI, 319.2–367.4]; 6 months=277.0 [95% CI, 242.7–311.4] meters, P=0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI, 1002.7–1029.7]; 6 months=1054.5 [95% CI, 1036.5–1072.3], P=0.021). A high proportion of patients experienced adverse events with active therapy (ISDN=61.5%, ISDN+hydral=60.0%; placebo=12.5%; P=0.007).Conclusions ISDN, with or without hydralazine, does not exert beneficial effects on RM, left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN+hydral appears to have deleterious effects on RM, myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction.Clinical Trial Registration URL: www.clinicaltrials.gov. Unique identifier: NCT01516346.

Aims To assess the hemodynamic effects of organic vs. inorganic nitrate administration among patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We assessed carotid and aortic pressure-flow relations non-invasively before and after the administration of 0.4 mg of sublingual-nitroglycerin (NTG; n=26), and in a separate sub-study, in response to 12.9 mmol of inorganic nitrate (n=16). NTG did not consistently reduce wave reflections arriving at the proximal aorta (change in real part of reflection coefficient, 1st harmonic:-0.09; P=0.01; 2nd harmonic:-0.045, P=0.16; 3rd harmonic:+0.087; P=0.05), but produced profound vasodilation in the carotid territory, with a significant reduction in systolic blood pressure (133.6 vs 120.5 mmHg; P=0.011) and a marked reduction in carotid bed vascular resistance (19580 vs. 13078 dynes·s/cm5; P=0.001) and carotid characteristic impedance (3440 vs. 1923 dynes·s/cm5; P=0.002). Inorganic nitrate, in contrast, consistently reduced wave reflections across the first 3 harmonics (change in real part of reflection coefficient, 1st harmonic: -0.12; P=0.03; 2nd harmonic:-0.11, P=0.01; 3rd harmonic:-0.087; P=0.09) and did not reduce blood pressure, carotid bed vascular resistance or carotid characteristic impedance (P=NS). Conclusions NTG produces marked vasodilation in the carotid circulation, with a pronounced reduction in blood pressure and inconsistent effects on central wave reflections. Inorganic nitrate, in contrast, produces consistent reductions in wave reflections, and unlike NTG, it does so without significant hypotension or cerebrovascular dilatation. These hemodynamic differences may underlie the different effects on exercise capacity and side effect profile of inorganic vs. organic nitrate in HFpEF.