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.

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.

Citation

Damy, T., Hobkirk, J., Walters, M., Ciobanu, A., Rigby, A. S., Kallvikbacka-Bennett, A., Guellich, A., Dubois-Rande, J.-L., Hittinger, L., Clark, A. L., & 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. https://doi.org/10.1097/fjc.0000000000000262

• 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
• Publisher: Lippincott, Williams & Wilkins
• Peer Reviewed: Peer Reviewed
• Volume: 66
• Issue: 3
• Pages: 229-238
• DOI: https://doi.org/10.1097/fjc.0000000000000262
• Keywords: Chronic heart failure, Pulmonary hypertension, Sildenafil, Noninvasive hemodynamics, Echocardiography
• Public URL: https://hull-repository.worktribe.com/output/436673
• Publisher URL: http://journals.lww.com/cardiovascularpharm/pages/articleviewer.aspx?year=2015&issue=09000&article=00001&type=abstract
• Additional Information: Copy of article first published in Journal of cardiovascular pharmacology, 2015, v.66 issue 3.
• Contract Date: Apr 21, 2016