The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure

• Published in: Journal of the American College of Cardiology Vol. 44; no. 12; pp. 2339 - 2348
• Main Authors: Guazzi, Marco, Tumminello, Gabriele, Di Marco, Fabio, Fiorentini, Cesare, Guazzi, Maurizio D.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 21.12.2004; Elsevier Science; Elsevier Limited
• Subjects: 3',5'-Cyclic-GMP Phosphodiesterases; Biological and medical sciences; Carbon dioxide; Carbon monoxide; Cardiac Output, Low - drug therapy; Cardiac Output, Low - physiopathology; Cardiology; Cardiology. Vascular system; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Diffusion; Drug therapy; Efficiency; Exercise; Exercise Tolerance - drug effects; Female; Flow velocity; Heart; Heart failure; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Hemodynamics - drug effects; Humans; Kinetics; Male; Medical sciences; Middle Aged; Oxygen; Oxygen Consumption - drug effects; Permeability; Phosphodiesterase Inhibitors - therapeutic use; Phosphoric Diester Hydrolases - drug effects; Piperazines - therapeutic use; Pulmonary arteries; Pulmonary Circulation - drug effects; Pulmonary Diffusing Capacity - drug effects; Pulmonary hypertension; Purines; Respiration - drug effects; Sildenafil Citrate; Sulfones; Veins & arteries; Ventilation; United States > US; California; CHF; PDE5; CPET; VE/VCO2slope; DM; tau; VA; Vc; AT; DLco; VCO2; VO2; ΔVO2/ΔWR; Physical exercise; Human; Heart failure; Oxygen; Enzyme; 3',5'-Cyclic-GMP phosphodiesterase; Lung; Cardiovascular disease; Esterases; Phosphoric diester hydrolases; Uptake; Chronic; Capacity; Efficiency; Heart disease; Hydrolases; Exercise tolerance test; Kinetics; Hemodynamics; Inhibition; Sildenafil; Diffusion
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2004.09.041

We sought to investigate the effects of sildenafil, a phosphodiesterase-5 (PDE5) inhibitor, on lung function and exercise performance in chronic heart failure (CHF). In CHF, nitric oxide-mediated regulation of lung vascular tone and alveolar-capillary membrane conductance is impaired and contributes to exercise intolerance. The potential for benefits due to increased nitric-oxide availability is unexplored. In 16 patients with CHF and 8 normal subjects, we measured—before and 60 min after sildenafil (50 mg) or placebo—ejection fraction, pulmonary hemodynamics, carbon monoxide diffusion capacity (DLco), with its membrane (DM) and capillary blood volume (Vc) subcomponents, endothelial function (brachial reactive hyperemia) at rest, peak oxygen uptake (VO2), increments in VO2versus work rate (ΔVO2/ΔWR), changes in ventilation versus CO2production (VE/VCO2) slope, and recovery VO2time constant (tau) on exertion. In CHF, sildenafil did not affect cardiac index, wedge pulmonary pressure, or ejection fraction; it significantly (p < 0.01) decreased pulmonary mean artery pressure (−20.4%) and arteriolar resistance (−45.1%), VE/VCO2slope (−9.0%) and recovery tau (−25.8%), and increased (p < 0.01) DLco (+11.1%), DM(+9.9%) peak VO2(+19.7%), ΔVO2/ΔWR (+11.0%), and brachial reactive hyperemia (+33.3%). No variations occurred in normal subjects and after placebo. Changes in DLco were related to those in VE/VCO2slope (r = −0.71; p = 0.002), and changes in brachial hyperemia correlated with those in ΔVO2/ΔWR (r = 0.80; p = 0.0002). This study shows that in CHF PDE5inhibition modulates pulmonary pressure and vascular tone, and improves DLco, exercise peak VO2, aerobic (ΔVO2/ΔWR) and ventilatory (VE/VCO2slope) efficiencies, and oxygen debt (recovery tau). Endothelial mechanisms may underlie these effects.