Long-Term Effects of Sildenafil in a Rat Model of Chronic Mitral Regurgitation

Abstract

Background: Recent reports have noted the favorable pleiotropic effects of sildenafil in heart failure. We tested the hypothesis that chronic treatment with sildenafil attenuates left ventricular (LV) remodeling and prevents exercise intolerance in chronic mitral regurgitation (MR).

Methods: 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 (SIL) treatment (MR+SIL group, 50mg/kg p.o. bid, N=16) or normal saline only group (MR group, N=16) and continued for 4 months. Sixteen sham rats were compared to MR rats.

Results: Three of 16 rats in MR group died during the study period. No deaths were noted in MR+SIL and sham group. After 4 months, LV size was smaller in MR+SIL compared to MR (LV end-systolic dimension, 4.7±0.3 for sham vs 5.9±0.3 for MR+SIL vs 7.4 ± 0.5 mm for MR p<0.05

LV end-diastolic dimension,8.3±0.4 vs 10.5±0.2 vs 11.7±0.61 mm, p<0.05). LV ejection fraction was greater in MR+SIL than MR. (70.2%±2.2 for sham vs 67.0±4.2 for MR+SIL vs 58.9±2.5 for MR, p=0.01). In pressure-volume analysis, MR+SIL showed greater LV end-systolic pressure-volume relation than MR. Serial treadmill test revealed that exercise capacity was reduced in MR but not in MR+SIL. Transcriptional profiling of cardiac apical tissues revealed that gene sets related with inflammatory response, DNA damage response, cell cycle checkpoint, and cellular signaling pathways were significantly enriched by genes with reciprocal changes. Pathological analysis showed perivascular fibrosis was more prominent in MR than MR+SIL and the percentage of TUNEL-positive cells was two-fold greater in MR compared to MR+SIL. Conclusion: Sildenafil significantly attenuates LV remodeling and prevents exercise intolerance in a rat model of chronic MR. This benefit might be associated with anti-apoptotic, anti-inflammatory effects of sildenafil.