Sildenafil treatment in established right ventricular dysfunction improves diastolic function and attenuates interstitial fibrosis independent from afterload

Abstract

Right ventricular (RV) function is an important determinant of prognosis in congenital heart diseases, pulmonary hypertension, and heart failure. Preventive sildenafil treatment has been shown to enhance systolic RV function and improve exercise capacity in a model of fixed RV pressure load. However, it is unknown whether sildenafil has beneficial effects when treatment is started in established RV dysfunction, which is clinically more relevant. Our aim was to assess the effects of sildenafil treatment on RV function and fibrosis in a model of established RV dysfunction due to fixed afterload. Rats were subjected to pulmonary artery banding (PAB), which induced RV dysfunction after 4 wk, characterized by reduced exercise capacity, decreased tricuspid annular plane systolic excursion, and RV dilatation. From week 4 onward, 50% of rats were treated with sildenafil (100 mg·kg−1·day−1, n = 9; PAB-SIL group) or vehicle ( n = 9; PAB-VEH group). At 8 wk, exercise capacity was assessed using cage wheels, and RV function was assessed using invasive RV pressure-volume measurements under anesthesia. Sildenafil treatment, compared with vehicle, improved RV ejection fraction (44 ± 2% vs. 34 ± 2%, P < 0.05, PAB-SIL vs. PAB-VEH groups), reduced RV end-diastolic pressure (2.3 ± 0.5 vs. 5.1 ± 0.9 mmHg, P < 0.05), and RV dilatation (end-systolic volume: 468 ± 45 vs. 643 ± 71 μl, P = 0.05). Sildenafil treatment also attenuated RV fibrosis (30 ± 6 vs. 17 ± 3‰, P < 0.05) but did not affect end-systolic elastance, exercise capacity, or PKG or PKA activity. In conclusion, sildenafil improves RV diastolic function and attenuates interstitial fibrosis in rats with established RV dysfunction, independent from afterload. These results indicate that sildenafil treatment has therapeutic potential for established RV dysfunction.