title: Development of a Human Model for the Study of Effects of Hypoxia, Exercise, and Sildenafil on Cardiac and Vascular Function in Chronic Heart Failure.
abstract: BACKGROUND
  Pulmonary hypertension is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a noninvasive model for studying pulmonary vasoreactivity in CHF and characterize sildenafil's acute cardiovascular effects.
  
  
  RESULTS
  In a crossover study, 18 patients with CHF participated 4 times [sildenafil (2 × 20 mg)/or placebo (double-blind) while breathing air or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance were recorded. Left and right ventricular (RV) function and transtricuspid systolic pressure gradient (RVTG) were measured echocardiographically. At rest, hypoxia caused SaO2 (P = 0.001) to fall and RVTG to rise (5 ± 4 mm Hg; P = 0.001). Sildenafil reduced SaO2 (-1 ± 2%; P = 0.043), systemic vascular resistance (-87 ± 156 dyn·s·cm; P = 0.034), and RVTG (-2 ± 5 mm Hg; P = 0.05). Exercise caused cardiac output (2.1 ± 1.8 L/min; P < 0.001) and RVTG (19 ± 11 mm Hg; P < 0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil.
  
  
  CONCLUSIONS
  Sildenafil reduces SaO2 at rest while breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation-perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in pulmonary hypertension.
authors: *Department of Cardiology, University of Hull, Castle Hill Hospital, Kingston upon Hull, United Kingdom; †Department of Cardiology, AP-HP Groupe, Henri-Mondor Albert-Chenevier, Créteil, France; ‡INSERM, Unité U955, Créteil, France; §Université Paris Est, Faculté de Médecine and DHU ATVB and INSERM Clinical Investigation Center 006, Créteil, France; and ¶National Heart & Lung Institute, Imperial College, London, United Kingdom.
authors: Thibaud
authors: T
authors: Damy
authors: James
authors: J
authors: Hobkirk
authors: Mandy
authors: M
authors: Walters
authors: Andrea
authors: A
authors: Ciobanu
authors: Alan S
authors: AS
authors: Rigby
authors: Anna
authors: A
authors: Kallvikbacka-Bennett
authors: Aziz
authors: A
authors: Guellich
authors: Jean-Luc
authors: JL
authors: Dubois-Randé
authors: Luc
authors: L
authors: Hittinger
authors: Andrew L
authors: AL
authors: Clark
authors: John G F
authors: JG
authors: Cleland
mesh_terms: D002908:Chronic Disease; D018592:Cross-Over Studies; D004311:Double-Blind Method; D015150:Echocardiography, Doppler; D015444:Exercise; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D000068677:Sildenafil Citrate / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D016278:Ventricular Function, Right / Q000187:drug effects / Q000502:physiology
chemical_list: D014665:Vasodilator Agents; D000068677:Sildenafil Citrate