Original ArticleDevelopment of a Human Model for the Study of Effects of Hypoxia, Exercise, and Sildenafil on Cardiac and Vascular Function in Chronic Heart FailureDamy, Thibaud MD, PhD*,†,‡,§; Hobkirk, James PhD*; Walters, Mandy*; Ciobanu, Andrea MD*; Rigby, Alan S. PhD*; Kallvikbacka-Bennett, Anna*; Guellich, Aziz PhD†,§; Dubois-Randé, Jean-Luc MD, PhD†,‡,§; Hittinger, Luc MD, PhD†,‡,§; Clark, Andrew L. MA, MD, FRCP*; Cleland, John G. F. MD, FACC*,¶Author Information *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. Reprints: Thibaud Damy, MD, PhD, Henri Mondor Teaching Hospital, 51 Avenue Maréchal de Lattre de Tassigny, 94000 Créteil, France (e-mail: email@example.com). T. Damy has received a post-doctoral grant from the Fédération de cardiologie. The remaining authors report no conflicts of interest. Received December 03, 2014 Accepted March 25, 2015 Journal of Cardiovascular Pharmacology: September 2015 - Volume 66 - Issue 3 - p 229-238 doi: 10.1097/FJC.0000000000000262 Buy Metrics 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. Methods and 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−1·cm−2; 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. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.