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 SD 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. 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). 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.
Conclusions—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.
- Received September 2, 2011.
- Accepted January 23, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited