Long-Term Effects of Sildenafil in a Rat Model of Chronic Mitral Regurgitation Benefits of Ventricular Remodeling and Exercise Capacity

Background-We tested the hypothesis that chronic treatment with sildenafil attenuates left ventricular (LV) remodeling and prevents exercise intolerance in chronic mitral regurgitation (MR). Methods and Results-MR was created in Sprague-Dawley rats by making a hole on the mitral leaflet. Two weeks after MR creation, MR and LV dilatation were confirmed by echocardiography, and rats were randomly assigned to sildenafil treatment (MR+sildenafil group; 50 mg/kg PO twice a day; n=16) or normal saline only (MR group; n=16) and continued for 4 months. Sixteen sham rats were compared with MR rats. After 4 months, LV size was smaller in the MR+sildenafil compared with the MR group (LV end-systolic dimension, 4.7 +/- 0.3 for sham versus 5.9 +/- 0.3 for MR+sildenafil versus 7.4 +/- 0.5 mm for MR; P<0.05; LV end-diastolic dimension, 8.3 +/- 0.4 versus 10.5 +/- 0.2 versus 11.7 +/- 0.61 mm, respectively; P<0.05). LV ejection fraction was greater in the MR+sildenafil group than in the MR group (70.2 +/- 2.2% for sham versus 67.0 +/- 4.2% for MR +sildenafil versus 58.9 +/- 2.5% for MR; P=0.01). Serial treadmill test revealed that exercise capacity was reduced in the MR but not in the MR +sildenafil group. Transcriptional profiling of cardiac apical tissues revealed that gene sets related to inflammatory response, DNA damage response, cell cycle checkpoint, and cellular signaling pathways were significantly enriched by genes with reciprocal changes. Pathological analysis showed that perivascular fibrosis was more prominent in the MR than in the MR +sildenafil group and that the percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells was 2-fold greater in the MR compared with the MR+sildenafil group. Conclusions-Sildenafil significantly attenuates LV remodeling and prevents exercise intolerance in a rat model of chronic MR. This benefit may be associated with the antiapoptotic, anti-inflammatory effects of sildenafil. (Circulation. 2012; 125:1390-1401.)