Sildenafil Improves Exercise Hemodynamics and Oxygen Uptake in Patients With Systolic Heart Failure

Abstract

Background-Heart failure (HF) is frequently associated with dysregulation of nitric oxide-mediated pulmonary vascular tone. Sildenafil, a type 5 phosphodiesterase inhibitor, lowers pulmonary vascular resistance in pulmonary hypertension by augmenting intracellular levels of the nitric oxide second messenger, cyclic GMP. We tested the hypothesis that a single oral dose of sildenafil (50 mg) would improve exercise capacity and exercise hemodynamics in patients with chronic systolic HF through pulmonary vasodilation. Methods and Results-Thirteen patients with New York Heart Association class III HF underwent assessment of right heart hemodynamics, gas exchange, and first-pass radionuclide ventriculography at rest and with cycle ergometry before and 60 minutes after administration of 50 mg of oral sildenafil. Sildenafil reduced resting pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance, and increased resting and exercise cardiac index (PϽ0.05 for all) without altering mean arterial pressure, heart rate, or pulmonary capillary wedge pressure. Sildenafil reduced exercise pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular resistance/ systemic vascular resistance ratio, which indicates a selective pulmonary vasodilator effect with exercise. Peak V O 2 increased (15Ϯ9%) and ventilatory response to CO 2 output (V E/V CO 2 slope) decreased (16Ϯ5%) after sildenafil treatment. Improvements in right heart hemodynamics and exercise capacity were confined to patients with secondary pulmonary hypertension (rest pulmonary arterial pressure Ͼ25 mm Hg). Conclusions-The present study shows that in patients with systolic HF, type 5 phosphodiesterase inhibition with sildenafil improves peak V O 2 , reduces V E/V CO 2 slope, and acts as a selective pulmonary vasodilator during rest and exercise in patients with HF and pulmonary hypertension.

Pulmonary Hypertension in Heart Failure Preserved Ejection Fraction

“…These studies may challenge this scenario based on some At variance with other pulmonary vasodilators, evidence is accumulating that inhibition of phosphodiesterase-5 (PDE5), the isoenzyme that breaks down cGMP to its inactive form, may be an effective and well-tolerated tool for targeting the pulmonary vasculature and unloading the RV in left-sided PH. 53 This is suggested by multiple observations made in patients with left-sided PH of various pathogenesis and severity, with acute [54][55][56][57] and long-term administration [58][59][60][61] of sildenafil. Intriguingly, the benefits of PDE5 inhibitors compared with other classes of pulmonary vasodilators stand on the pulmonary vascular selectivity of PDE5 expression in lung microvessels both in physiological and, even more, pathological conditions, avoiding the untoward systemic hypotensive effect that is typical of other pulmonary vasodilating agents, such as prostanoids and ERAs.…”

Heart Failure with Preserved Ejection Fraction

“…Phosphodieasterase-5 (PDE-5) inhibitors increase cyclic guanosine monophosphate (cGMP) levels by blocking their breakdown. PDE-5 inhibitors reduce ventricular-vascular stiffening, improve endothelial function and reduce pulmonary vascular resistance [160][161][162]. Sildenafil has been recently tested in HFpEF patients in a small randomized controlled trial where it resulted in significant improvement of quality of life, reduction of pulmonary artery pressures, improvement of right ventricular function, reduction of LV mass and improvement of LV diastolic function compared to placebo [163].…”

Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity

“…[9][10][11] The phosphodiesterase-5 (PDE5) inhibitor sildenafil has been shown to improve pulmonary hemodynamics and exercise capacity in adults with group 1 pulmonary hypertension (PH) (defined by right heart catheterization [RHC] as a mean pulmonary artery pressure Ն 25 mmHg, a pulmonary artery occlusion pressure or a left ventricular end diastolic pressure Յ 15 mmHg, and an increased pulmonary vascular resistance) 12 : idiopathic or heritable pulmonary arterial hypertension (PAH), or PAH associated with connective tissue diseases or repaired congenital systemic to pulmonary shunts. 13 Further, sildenafil has been shown to improve exercise capacity in patients with left ventricular systolic dysfunction and pulmonary venous hypertension (defined via cardiac catheterization as a mean pulmonary artery pressure Ն 25 mmHg and a pulmonary artery occlusion pressure or a left ventricular end diastolic pressure Ն 15 mmHg) 14,15 and in healthy volunteers exposed to experimental hypoxia or high altitude, 16,17 suggesting a beneficial role of PDE5 inhibition in patients with group 2 PH (PH with left heart disease) and group 3 PH (PH associated with lung diseases and/or hypoxemia). PDE5 inhibition also prevents and reverses cardiac hypertrophy in mice exposed to chronic left ventricular pressure overload induced by transverse aortic constriction.…”