Abstract

BACKGROUND: -Pulmonary hypertension as frequent complication of left heart disease (PH-LHD) is characterized by lung endothelial dysfunction and vascular remodeling. While PH-LHD contributes to morbidity and mortality in heart failure, established therapies for PH-LHD are yet lacking. Here, we tested the effect of chronic sildenafil treatment in an experimental model of PH-LHD.

METHODS AND RESULTS: -In Sprague-Dawley rats, PH-LHD was induced by supracoronary aortic banding. Oral sildenafil treatment (60 mg/kg daily) was initiated after 7 days, and lung endothelial function (n=5), vascular remodeling, and right ventricular function (n=11 each) were analyzed 9 weeks post banding. As compared to sham-operated controls, aortic banding induced pulmonary hypertension and lung endothelial dysfunction evident as lack of endothelial NO production and endothelium-dependent vasodilation. These changes were associated with an increased pulmonary vascular resistance, medial thickening, and biventricular cardiac hypertrophy. Sildenafil treatment largely attenuated these pathologic changes, and was not associated with detectable adverse effects pertinent to lung vascular barrier function, edema formation, or systemic hemodynamics.

CONCLUSIONS: -Our data identify sildenafil as a promising therapy for PH-LHD. In light of its documented protective effects at the myocardial level in heart failure, sildenafil presents a particularly attractive strategy in that it simultaneously targets cardiac remodeling and secondary PH-LHD.