Effects of phosphodiesterase type 5 inhibition on systemic and pulmonary hemodynamics and ventricular function in patients with severe symptomatic aortic stenosis

Abstract

Background: Pressure overload resulting from aortic stenosis causes maladaptive ventricular and vascular remodeling that can lead to pulmonary hypertension, heart failure symptoms, and adverse outcomes. Retarding or reversing this maladaptive remodeling and its unfavorable hemodynamic consequences has the potential to improve morbidity and mortality. Preclinical models of pressure overload have shown that phosphodiesterase type 5 inhibition is beneficial; however, the use of phosphodiesterase type 5 inhibitors in patients with aortic stenosis is controversial because of concerns about vasodilation and hypotension.

Methods and results: We evaluated the safety and hemodynamic response of 20 subjects with severe symptomatic aortic stenosis (mean aortic valve area, 0.7 ± 0.2 cm(2); ejection fraction, 60 ± 14%) who received a single oral dose of sildenafil (40 or 80 mg). Compared with baseline, after 60 minutes, sildenafil reduced systemic (-12%; P<0.001) and pulmonary (-29%; P=0.002) vascular resistance, mean pulmonary artery (-25%; P<0.001) and wedge (-17%; P<0.001) pressures, and increased systemic (13%; P<0.001) and pulmonary (45%; P<0.001) vascular compliance and stroke volume index (8%; P=0.01). These changes were not dose dependent. Sildenafil caused a modest decrease in mean systemic arterial pressure (-11%; P<0.001) but was well tolerated with no episodes of symptomatic hypotension.

Conclusions: This study shows for the first time that a single dose of a phosphodiesterase type 5 inhibitor is safe and well tolerated in patients with severe aortic stenosis and is associated with improvements in pulmonary and systemic hemodynamics resulting in biventricular unloading. These findings support the need for longer-term studies to evaluate the role of phosphodiesterase type 5 inhibition as adjunctive medical therapy in patients with aortic stenosis.

Trial registration: ClinicalTrials.gov NCT01060020.

Figures

Figure 1. Unloading of the left ventricle after sildenafil

A decrease in pulmonary capillary wedge pressure (PCWP) was associated with an increase in stroke volume index (mean±SEM) (a). The increase in stroke volume (SV) after sildenafil correlated with a decrease in systemic and pulmonary vascular afterload (b–e), but not with an increase in systolic myocardial function (f). Abbreviations same as Table 2; scMWS, stress-corrected midwall shortening.

Figure 2. Change in mean pulmonary artery pressure after sildenafil

The change in mPAP from baseline to 60 minutes is shown for each patient by dose; error bars (SD) (a). The change from baseline to 60 minutes in the category of severity of pulmonary hypertension (PH) is shown for each subject; no PH (mPAP

Figure 3

Effect of sildenafil on passive (mPAP ≥25 and PVR