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\ub13 22\ub14 23\ub13 DLco/VA 4.2\ub10.8 4.4\ub10.7 4.9\ub10.8 Brachial hyperemic flow (ml/min) 420\ub1100 470\ub1100 530\ub190 peak VO2 16\ub14 17\ub13 19\ub14 VE/VCO2 slope 33\ub14 31\ub14 28\ub14 Changes in VE/VCO2 slope after 50 mg sildenafil were inversely related with those in DLco and DLco/VA (r\u2005=\u2005 120.76, p<0.05; r \u2005=\u2005 120.59, p<0.05). 17p