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From the Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia (P.Z., V.T., H.S.-C., M.B., J.A.B., S.V., K.B.M., T.P.C., J.A.C.); Rowan University School of Osteopathic Medicine, Stratford, NJ (L.T.); Children's Hospital of Philadelphia Research Institute, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); Office of Nursing Research, School of Nursing, University of Pennsylvania, Philadelphia (J.C.); Departments of Kinesiology, Anatomy, and Physiology, Kansas State University, Manhattan (D.C.P.).
Published: March 2017
AI Article Synopsis
Article Abstract
Rationale: Nitrate-rich beetroot juice has been shown to improve exercise capacity in heart failure with preserved ejection fraction, but studies using pharmacological preparations of inorganic nitrate are lacking.
Objectives: To determine (1) the dose-response effect of potassium nitrate (KNO) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO in heart failure with preserved ejection fraction.
Methods And Results: We randomized 12 subjects with heart failure with preserved ejection fraction to oral KNO (n=9) or potassium chloride (n=3). Subjects received 6 mmol twice daily during week 1, followed by 6 mmol thrice daily during week 2. Supine cycle ergometry was performed at baseline (visit 1) and after each week (visits 2 and 3). Quality of life was assessed with the Kansas City Cardiomyopathy Questionnaire. The primary efficacy outcome, peak O-uptake, did not significantly improve (=0.13). Exploratory outcomes included exercise duration and quality of life. Exercise duration increased significantly with KNO (visit 1: 9.87, 95% confidence interval [CI] 9.31-10.43 minutes; visit 2: 10.73, 95% CI 10.13-11.33 minute; visit 3: 11.61, 95% CI 11.05-12.17 minutes; =0.002). Improvements in the Kansas City Cardiomyopathy Questionnaire 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; =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; =0.01) were seen after KNO. Pronounced elevations in trough levels of nitric oxide metabolites occurred with KNO (visit 2: 199.5, 95% CI 98.7-300.2 μmol/L; visit 3: 471.8, 95% CI 377.8-565.8 μmol/L) versus baseline (visit 1: 38.0, 95% CI 0.00-132.0 μmol/L; <0.001). KNO did not lead to clinically significant hypotension or methemoglobinemia. After 6 mmol of KNO, systolic blood pressure was reduced by a maximum of 17.9 (95% CI -28.3 to -7.6) mm Hg 3.75 hours later. Peak nitric oxide metabolites concentrations were 259.3 (95% CI 176.2-342.4) μmol/L 3.5 hours after ingestion, and the median half-life was 73.0 (interquartile range 33.4-232.0) minutes.
Conclusions: KNO is potentially well tolerated and improves exercise duration and quality of life in heart failure with preserved ejection fraction. This study reinforces the efficacy of KNO and suggests that larger randomized trials are warranted.
