title: Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction.
abstract: BACKGROUND
  Inorganic nitrate (NO3(-)), abundant in certain vegetables, is converted to nitrite by bacteria in the oral cavity. Nitrite can be converted to nitric oxide in the setting of hypoxia. We tested the hypothesis that NO3(-) supplementation improves exercise capacity in heart failure with preserved ejection fraction via specific adaptations to exercise.
  
  
  RESULTS
  Seventeen subjects participated in this randomized, double-blind, crossover study comparing a single dose of NO3-rich beetroot juice (NO3(-), 12.9 mmol) with an identical nitrate-depleted placebo. Subjects performed supine-cycle maximal-effort cardiopulmonary exercise tests, with measurements of cardiac output and skeletal muscle oxygenation. We also assessed skeletal muscle oxidative function. Study end points included exercise efficiency (total work/total oxygen consumed), peak VO2, total work performed, vasodilatory reserve, forearm mitochondrial oxidative function, and augmentation index (a marker of arterial wave reflections, measured via radial arterial tonometry). Supplementation increased plasma nitric oxide metabolites (median, 326 versus 10 μmol/L; P=0.0003), peak VO2 (12.6±3.7 versus 11.6±3.1 mL O2·min(-1)·kg(-1); P=0.005), and total work performed (55.6±35.3 versus 49.2±28.9 kJ; P=0.04). However, efficiency was unchanged. NO3(-) led to greater reductions in systemic vascular resistance (-42.4±16.6% versus -31.8±20.3%; P=0.03) and increases in cardiac output (121.2±59.9% versus 88.7±53.3%; P=0.006) with exercise. NO3(-) reduced aortic augmentation index (132.2±16.7% versus 141.4±21.9%; P=0.03) and tended to improve mitochondrial oxidative function.
  
  
  CONCLUSIONS
  NO3(-) increased exercise capacity in heart failure with preserved ejection fraction by targeting peripheral abnormalities. Efficiency did not change as a result of parallel increases in total work and VO2. NO3(-) increased exercise vasodilatory and cardiac output reserves. NO3(-) also reduced arterial wave reflections, which are linked to left ventricular diastolic dysfunction and remodeling.
  
  
  BACKGROUND
  www.clinicaltrials.gov. Unique identifier: NCT01919177.
authors.affiliation: From the Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and Departments of Kinesiology, Anatomy, and Physiology, Kansas State University, Manhattan (D.C.P.).
authors.forename: Payman
authors.initials: P
authors.lastname: Zamani
authors.affiliation: From the Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and Departments of Kinesiology, Anatomy, and Physiology, Kansas State University, Manhattan (D.C.P.).
authors.forename: Deepa
authors.initials: D
authors.lastname: Rawat
authors.affiliation: From the Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and Departments of Kinesiology, Anatomy, and Physiology, Kansas State University, Manhattan (D.C.P.).
authors.forename: Prithvi
authors.initials: P
authors.lastname: Shiva-Kumar
authors.affiliation: From the Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and Departments of Kinesiology, Anatomy, and Physiology, Kansas State University, Manhattan (D.C.P.).
authors.forename: Salvatore
authors.initials: S
authors.lastname: Geraci
authors.affiliation: From the Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and Departments of Kinesiology, Anatomy, and Physiology, Kansas State University, Manhattan (D.C.P.).
authors.forename: Rushik
authors.initials: R
authors.lastname: Bhuva
authors.affiliation: From the Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and Departments of Kinesiology, Anatomy, and Physiology, Kansas State University, Manhattan (D.C.P.).
authors.forename: Prasad
authors.initials: P
authors.lastname: Konda
authors.affiliation: From the Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and 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, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and 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, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and 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, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and 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, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and 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, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and 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, Perelman School of Medicine, Philadelphia (P.Z., P.S.-K., P.K., K.B.M., T.P.C., J.A.C.); Division of Cardiology, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA (D.R., P.S.-K., S.G., R.B., J.A.C.); Children's Hospital of Philadelphia Research Institute, Philadelphia, PA (P.-T.D., H.I.); Division of Nephrology/Hypertension. Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.R.T.); and Departments of Kinesiology, Anatomy, and Physiology, Kansas State University, Manhattan (D.C.P.). Julio.Chirinos@uphs.upenn.edu.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Chirinos
mesh_terms: D000368:Aged; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005080:Exercise Test / Q000187:drug effects / Q000379:methods*; D017079:Exercise Tolerance / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000008:administration & dosage*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology*; D016896:Treatment Outcome
chemical_list: D009566:Nitrates
keywords: exercise; heart failure; nitrates; nitric oxide