title: Impaired Right Ventricular-Pulmonary Arterial Coupling and Effect of Sildenafil in Heart Failure With Preserved Ejection Fraction: An Ancillary Analysis From the Phosphodiesterase-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) Trial.
abstract: BACKGROUND
  Right ventricular (RV) dysfunction (RVD) is a poor prognostic factor in heart failure with preserved ejection fraction (HFpEF). The physiological perturbations associated with RVD or RV function indexed to load (RV-pulmonary arterial [PA] coupling) in HFpEF have not been defined. HFpEF patients with marked impairment in RV-PA coupling may be uniquely sensitive to sildenafil.
  
  
  RESULTS
  In a subset of HFpEF patients enrolled in the Phosphodiesteas-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial, physiological variables and therapeutic effect of sildenafil were examined relative to the severity of RVD (tricuspid annular plane systolic excursion [TAPSE]) and according to impairment in RV-PA coupling (TAPSE/pulmonary artery systolic pressure) ratio. The prevalence of atrial fibrillation and diuretic use, n-terminal probrain natriuretic peptide levels, renal dysfunction, neurohumoral activation, myocardial necrosis and fibrosis biomarkers, and the severity of diastolic dysfunction all increased with severity of RVD. Peak oxygen consumption decreased and ventilatory inefficiency (VE/VCO2 slope) increased with increasing severity of RVD. Many but not all physiological derangements were more closely associated with the TAPSE/pulmonary artery systolic pressure ratio. Compared with placebo, at 24 weeks, TAPSE decreased, and peak oxygen consumption and VE/CO2 slope were unchanged with sildenafil. There was no interaction between RV-PA coupling and treatment effect, and sildenafil did not improve TAPSE, peak oxygen consumption, or VE/VCO2 in patients with pulmonary hypertension and RVD.
  
  
  CONCLUSIONS
  HFpEF patients with RVD and impaired RV-PA coupling have more advanced heart failure. In RELAX patients with RVD and impaired RV-PA coupling, sildenafil did not improve RV function, exercise capacity, or ventilatory efficiency.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.
authors.affiliation: From the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (I.H., S.F.M., B.A.B., M.M.R.); Temple University, Philadelphia, PA (P.R.F.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L.); Duke Clinical Research Institute, Durham, NC (D.S.G.).
authors.forename: Imad
authors.initials: I
authors.lastname: Hussain
authors.affiliation: From the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (I.H., S.F.M., B.A.B., M.M.R.); Temple University, Philadelphia, PA (P.R.F.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L.); Duke Clinical Research Institute, Durham, NC (D.S.G.).
authors.forename: Selma F
authors.initials: SF
authors.lastname: Mohammed
authors.affiliation: From the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (I.H., S.F.M., B.A.B., M.M.R.); Temple University, Philadelphia, PA (P.R.F.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L.); Duke Clinical Research Institute, Durham, NC (D.S.G.).
authors.forename: Paul R
authors.initials: PR
authors.lastname: Forfia
authors.affiliation: From the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (I.H., S.F.M., B.A.B., M.M.R.); Temple University, Philadelphia, PA (P.R.F.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L.); Duke Clinical Research Institute, Durham, NC (D.S.G.).
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Lewis
authors.affiliation: From the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (I.H., S.F.M., B.A.B., M.M.R.); Temple University, Philadelphia, PA (P.R.F.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L.); Duke Clinical Research Institute, Durham, NC (D.S.G.).
authors.forename: Barry A
authors.initials: BA
authors.lastname: Borlaug
authors.affiliation: From the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (I.H., S.F.M., B.A.B., M.M.R.); Temple University, Philadelphia, PA (P.R.F.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L.); Duke Clinical Research Institute, Durham, NC (D.S.G.).
authors.forename: Dianne S
authors.initials: DS
authors.lastname: Gallup
authors.affiliation: From the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (I.H., S.F.M., B.A.B., M.M.R.); Temple University, Philadelphia, PA (P.R.F.); Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston (G.D.L.); Duke Clinical Research Institute, Durham, NC (D.S.G.). redfield.margaret@mayo.edu.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Redfield
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003971:Diastole / Q000187:drug effects*; D017079:Exercise Tolerance / Q000187:drug effects*; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010101:Oxygen Consumption / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects*; D012123:Pulmonary Ventilation / Q000187:drug effects; D020127:Recovery of Function; D012720:Severity of Illness Index; D000068677:Sildenafil Citrate / Q000009:adverse effects / Q000627:therapeutic use*; D013318:Stroke Volume / Q000187:drug effects*; D013997:Time Factors; D016896:Treatment Outcome; D014463:Ultrasonography; D018497:Ventricular Dysfunction, Right / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate
keywords: diastole; exercise; heart failure; hypertension; pulmonary hypertension