Borgdorff Marinus A, Bartelds Beatrijs, Dickinson Michael G, van Wiechen Maarten P H, Steendijk Paul, de Vroomen Maartje, Berger Rolf M F
Center for Congenital Heart Diseases, Division of Pediatric Cardiology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and
Center for Congenital Heart Diseases, Division of Pediatric Cardiology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and.
Am J Physiol Heart Circ Physiol. 2014 Aug 1;307(3):H361-9. doi: 10.1152/ajpheart.00843.2013. Epub 2014 May 30.
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.
右心室（RV）功能是先天性心脏病、肺动脉高压和心力衰竭预后的重要决定因素。在固定右心室压力负荷模型中，预防性使用西地那非治疗已显示可增强右心室收缩功能并提高运动能力。然而，当在已确立的右心室功能障碍（这在临床上更具相关性）开始治疗时，西地那非是否具有有益作用尚不清楚。我们的目的是评估西地那非治疗对因固定后负荷导致的已确立右心室功能障碍模型中右心室功能和纤维化的影响。对大鼠进行肺动脉环扎（PAB），4周后诱导出右心室功能障碍，其特征为运动能力下降、三尖瓣环平面收缩期位移减少和右心室扩张。从第4周起，50%的大鼠接受西地那非治疗（100 mg·kg⁻¹·天⁻¹，n = 9；PAB-SIL组）或溶剂对照（n = 9；PAB-VEH组）。在第8周时，使用笼轮评估运动能力，并在麻醉下通过有创右心室压力-容积测量评估右心室功能。与溶剂对照相比，西地那非治疗改善了右心室射血分数（44±2%对34±2%，P<0.05，PAB-SIL组对PAB-VEH组），降低了右心室舒张末期压力（2.3±0.5对5.1±0.9 mmHg，P<0.05）和右心室扩张（收缩末期容积：468±45对643±71 μl，P = 0.05）。西地那非治疗还减轻了右心室纤维化（30±6对17±3‰，P<0.05），但不影响收缩末期弹性、运动能力或PKG或PKA活性。总之，西地那非可改善已确立右心室功能障碍大鼠的右心室舒张功能并减轻间质纤维化，与后负荷无关。这些结果表明西地那非治疗对已确立的右心室功能障碍具有治疗潜力。
