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Development of a human model for the study of effects of hypoxia, exercise, and sildenafil on cardiac and vascular function in chronic heart failure

Damy, Thibaud; Hobkirk, James; Walters, Mandy; Ciobanu, Andrea; Rigby, Alan S.; Kallvikbacka-Bennett, Anna; Guellich, Aziz; Dubois-Rande, Jean-Luc; Hittinger, Luc; Clark, Andrew L.; Cleland, John G. F.


Thibaud Damy

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Dr James Hobkirk
Lecturer in Physiology & Pathophysiology & Honorary Medical Scientist

Mandy Walters

Andrea Ciobanu

Anna Kallvikbacka-Bennett

Aziz Guellich

Jean-Luc Dubois-Rande

Luc Hittinger

Andrew L. Clark

John G. F. Cleland


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.


Damy, T., Hobkirk, J., Walters, M., Ciobanu, A., Rigby, A. S., Kallvikbacka-Bennett, A., …Cleland, J. G. F. (2015). Development of a human model for the study of effects of hypoxia, exercise, and sildenafil on cardiac and vascular function in chronic heart failure. Journal of Cardiovascular Pharmacology, 66(3), 229-238.

Journal Article Type Article
Acceptance Date Mar 25, 2015
Publication Date Sep 21, 2015
Deposit Date Apr 21, 2016
Publicly Available Date Apr 21, 2016
Journal Journal of cardiovascular pharmacology
Print ISSN 0160-2446
Electronic ISSN 1533-4023
Publisher Lippincott, Williams & Wilkins
Peer Reviewed Peer Reviewed
Volume 66
Issue 3
Pages 229-238
Keywords Chronic heart failure, Pulmonary hypertension, Sildenafil, Noninvasive hemodynamics, Echocardiography
Public URL
Publisher URL
Additional Information Copy of article first published in Journal of cardiovascular pharmacology, 2015, v.66 issue 3.
Contract Date Apr 21, 2016


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