Sildenafil improves exercise peak oxygen consumption and ventilation efficiency by a synergistic effect on endothelial function and alveolar gas diffusion in heart failure patients

Background: Reduction in oxygen consumption at peak exercise (peak VO2) and impairment in ventilatory efficiency (i.e. elevated VE/VCO2 slope) are hallmarks of heart failure (HF) syndrome. Sildenafil increases NO availability, which is critically involved in the regulation of both endothelial function and pulmonary capillary tone and permeability. Objectives: To investigate whether these NO-mediated effects may be associated with and possibly provide a background for an improvement of peak VO2 and VE/VCO2 slope in patients with stable HF, when they are given sildenafil. Methods: 15 stable HF patients (NYHA class II to III) treated with ACE-inhibitors and beta-blockers were randomly assigned to receive placebo or sildenafil (25 and 50 mg) according to a double-blind, crossover design. Diffusing lung capacity for carbon monoxide (DLco) at rest and its normalization for alveolar volume (DLco/VA), as well as brachial artery flow-mediated hyperemic response were investigated before and after (1 hour) drug administration. Peak VO2 and VE/VCO2 slope (cycle ergometry ramp protocol) were assessed in the baseline and after drug randomization. Results: Placebo Sildenafil (25 mg) Sildenafil (50 mg) DLco (ml/min/kg) 21±3 22±4 23±3 DLco/VA 4.2±0.8 4.4±0.7 4.9±0.8 Brachial hyperemic flow (ml/min) 420±100 470±100 530±90 peak VO2 16±4 17±3 19±4 VE/VCO2 slope 33±4 31±4 28±4 Changes in VE/VCO2 slope after 50 mg sildenafil were inversely related with those in DLco and DLco/VA (r = −0.76, p<0.05; r  = −0.59, p<0.05). ∗p<0.01 Conclusions: In HF, sildenafil induces a dose-related synergistic effect on endothelial function and alveolar-capillary gas diffusion capacity associated with a significant amelioration in peak VO2 and exercise VE/VCO2 slope. Long-term use of sildenafil as an adjunctive therapy in stable HF patients seems worthy of trial.