title: Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To determine (1) the dose-response effect of potassium nitrate (KNO3) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO3in heart failure with preserved ejection fraction.
  
  
  RESULTS
  We randomized 12 subjects with heart failure with preserved ejection fraction to oral KNO3(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 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% 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;P=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;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 occurred with KNO3(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;P<0.001). KNO3did not lead to clinically significant hypotension or methemoglobinemia. After 6 mmol of KNO3, 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
  KNO3is potentially well tolerated and improves exercise duration and quality of life in heart failure with preserved ejection fraction. This study reinforces the efficacy of KNO3and suggests that larger randomized trials are warranted.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT02256345.
authors.affiliation: 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.). pzamani@upenn.edu.
authors.forename: Payman
authors.initials: P
authors.lastname: Zamani
authors.affiliation: 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.).
authors.forename: Victor
authors.initials: V
authors.lastname: Tan
authors.affiliation: 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.).
authors.forename: Haideliza
authors.initials: H
authors.lastname: Soto-Calderon
authors.affiliation: 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.).
authors.forename: Melissa
authors.initials: M
authors.lastname: Beraun
authors.affiliation: 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.).
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Brandimarto
authors.affiliation: 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.).
authors.forename: Lien
authors.initials: L
authors.lastname: Trieu
authors.affiliation: 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.).
authors.forename: Swapna
authors.initials: S
authors.lastname: Varakantam
authors.affiliation: 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.).
authors.forename: Paschalis-Thomas
authors.initials: PT
authors.lastname: Doulias
authors.affiliation: 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.).
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Townsend
authors.affiliation: 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.).
authors.forename: Jesse
authors.initials: J
authors.lastname: Chittams
authors.affiliation: 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.).
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.affiliation: 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.).
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.affiliation: 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.).
authors.forename: David C
authors.initials: DC
authors.lastname: Poole
authors.affiliation: 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.).
authors.forename: Harry
authors.initials: H
authors.lastname: Ischiropoulos
authors.affiliation: 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.).
authors.forename: Julio A
authors.initials: JA
authors.lastname: Chirinos
mesh_terms: D000368:Aged; D015444:Exercise; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000534:rehabilitation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000009:adverse effects / Q000493:pharmacokinetics*; D017680:Potassium Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*; D011788:Quality of Life; D013318:Stroke Volume
chemical_list: D009566:Nitrates; D017680:Potassium Compounds; C023844:potassium nitrate
keywords: exercise capacity; heart failure; nitric oxide