title: Effects of sildenafil on ventricular and vascular function in heart failure with preserved ejection fraction.
abstract: BACKGROUND
  Early studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction.
  
  
  RESULTS
  A subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28 mm Hg/mL versus +0.02±0.29, P=0.008) and tended to improve reactive hyperemia index (+0.30±0.45 versus -0.17±0.30, P=0.054). In contrast, left ventricular contractility was reduced by 11% to 16% with sildenafil compared with placebo (ΔPWR/EDV -52±70 versus +0±40 mm Hg/s, P=0.006; ΔSW/EDV +0.3±5.8 versus -6.0±5.1 mm Hg, P=0.04). Sildenafil had no effect on pulmonary artery systolic pressure.
  
  
  CONCLUSIONS
  In subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.
authors.affiliation: From the Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., H.C., G.L., M.M.R.); Department of Medicine, Massachusetts General Hospital, Boston (G.D.L., M.J.S.); Department of Medicine, Duke Clinical Research Institute, Durham, NC (S.E.M.); Department of Medicine, Cardiology Unit, University of Vermont College of Medicine, Burlington (M.L.W.); Department of Medicine, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); and Department of Medicine, University of Pennsylvania, Translational Research Center, Philadelphia (K.B.M.). borlaug.barry@mayo.edu.
authors.forename: Barry A
authors.initials: BA
authors.lastname: Borlaug
authors.affiliation: From the Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., H.C., G.L., M.M.R.); Department of Medicine, Massachusetts General Hospital, Boston (G.D.L., M.J.S.); Department of Medicine, Duke Clinical Research Institute, Durham, NC (S.E.M.); Department of Medicine, Cardiology Unit, University of Vermont College of Medicine, Burlington (M.L.W.); Department of Medicine, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); and Department of Medicine, University of Pennsylvania, Translational Research Center, Philadelphia (K.B.M.).
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Lewis
authors.affiliation: From the Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., H.C., G.L., M.M.R.); Department of Medicine, Massachusetts General Hospital, Boston (G.D.L., M.J.S.); Department of Medicine, Duke Clinical Research Institute, Durham, NC (S.E.M.); Department of Medicine, Cardiology Unit, University of Vermont College of Medicine, Burlington (M.L.W.); Department of Medicine, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); and Department of Medicine, University of Pennsylvania, Translational Research Center, Philadelphia (K.B.M.).
authors.forename: Steven E
authors.initials: SE
authors.lastname: McNulty
authors.affiliation: From the Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., H.C., G.L., M.M.R.); Department of Medicine, Massachusetts General Hospital, Boston (G.D.L., M.J.S.); Department of Medicine, Duke Clinical Research Institute, Durham, NC (S.E.M.); Department of Medicine, Cardiology Unit, University of Vermont College of Medicine, Burlington (M.L.W.); Department of Medicine, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); and Department of Medicine, University of Pennsylvania, Translational Research Center, Philadelphia (K.B.M.).
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Semigran
authors.affiliation: From the Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., H.C., G.L., M.M.R.); Department of Medicine, Massachusetts General Hospital, Boston (G.D.L., M.J.S.); Department of Medicine, Duke Clinical Research Institute, Durham, NC (S.E.M.); Department of Medicine, Cardiology Unit, University of Vermont College of Medicine, Burlington (M.L.W.); Department of Medicine, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); and Department of Medicine, University of Pennsylvania, Translational Research Center, Philadelphia (K.B.M.).
authors.forename: Martin
authors.initials: M
authors.lastname: LeWinter
authors.affiliation: From the Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., H.C., G.L., M.M.R.); Department of Medicine, Massachusetts General Hospital, Boston (G.D.L., M.J.S.); Department of Medicine, Duke Clinical Research Institute, Durham, NC (S.E.M.); Department of Medicine, Cardiology Unit, University of Vermont College of Medicine, Burlington (M.L.W.); Department of Medicine, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); and Department of Medicine, University of Pennsylvania, Translational Research Center, Philadelphia (K.B.M.).
authors.forename: Horng
authors.initials: H
authors.lastname: Chen
authors.affiliation: From the Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., H.C., G.L., M.M.R.); Department of Medicine, Massachusetts General Hospital, Boston (G.D.L., M.J.S.); Department of Medicine, Duke Clinical Research Institute, Durham, NC (S.E.M.); Department of Medicine, Cardiology Unit, University of Vermont College of Medicine, Burlington (M.L.W.); Department of Medicine, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); and Department of Medicine, University of Pennsylvania, Translational Research Center, Philadelphia (K.B.M.).
authors.forename: Grace
authors.initials: G
authors.lastname: Lin
authors.affiliation: From the Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., H.C., G.L., M.M.R.); Department of Medicine, Massachusetts General Hospital, Boston (G.D.L., M.J.S.); Department of Medicine, Duke Clinical Research Institute, Durham, NC (S.E.M.); Department of Medicine, Cardiology Unit, University of Vermont College of Medicine, Burlington (M.L.W.); Department of Medicine, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); and Department of Medicine, University of Pennsylvania, Translational Research Center, Philadelphia (K.B.M.).
authors.forename: Anita
authors.initials: A
authors.lastname: Deswal
authors.affiliation: From the Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., H.C., G.L., M.M.R.); Department of Medicine, Massachusetts General Hospital, Boston (G.D.L., M.J.S.); Department of Medicine, Duke Clinical Research Institute, Durham, NC (S.E.M.); Department of Medicine, Cardiology Unit, University of Vermont College of Medicine, Burlington (M.L.W.); Department of Medicine, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); and Department of Medicine, University of Pennsylvania, Translational Research Center, Philadelphia (K.B.M.).
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.affiliation: From the Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., H.C., G.L., M.M.R.); Department of Medicine, Massachusetts General Hospital, Boston (G.D.L., M.J.S.); Department of Medicine, Duke Clinical Research Institute, Durham, NC (S.E.M.); Department of Medicine, Cardiology Unit, University of Vermont College of Medicine, Burlington (M.L.W.); Department of Medicine, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); and Department of Medicine, University of Pennsylvania, Translational Research Center, Philadelphia (K.B.M.).
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Redfield
mesh_terms: D000368:Aged; D062186:Arterial Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006940:Hyperemia / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D011687:Purines / Q000009:adverse effects / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate
keywords: diastolic heart failure; heart failure; vascular function; ventricular function