Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure

Background: Congestive heart failure (CHF) is a common cause of atrial fibrillation (AF). Oxidative stress and inflammation (profibrotic) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha, antifibrotic) factors may be involved in CHF-related remodeling. We evaluated the effects of simvastatin (antioxidant, anti-inflammatory) and fenofibrate (PPAR-alpha activator) on CHF-related atrial remodeling. Methods and results: Dogs were subjected to 2-week ventricular tachypacing (VTP) in the absence and presence of simvastatin (20 or 80 mg/day) or fenofibrate. Induced AF duration (DAF) was increased by VTP from 36 +/- 14 (non-paced controls) to 1005 +/- 257 s (p<0.01). Simvastatin prevented VTP-induced DAF increases (147 +/- 37 and 84 +/- 37 s at 20 and 90 mg/day, respectively), but fenofibrate did not (1018 +/- 352 s). Simvastatin also attenuated CHF-induced conduction abnormalities (heterogeneity-index reduced from 1.5 +/- 0.1 to 1.1 +/- 0.1 and 1.0 +/- 0.1 at 20 and 80 mg/day, p<0.01) and atrial fibrosis (from 19.4 +/- 1.3% to 10.8 +/- 0.8% and 9.9 +/- 0.8% at 20 and 80 mg/day, p<0.01), while fenofibrate did not. Simvastatin (but not fenofibrate) also attenuated VTP-induced left-ventricular nitric-oxide synthase and nitrotyrosine increases, along with hemodynamic dysfunction. Atrial fibroblast proliferation increased with 24-h fetal bovine serum (FBS) stimulation from 654 +/- 153 to 7264 +/- 1636 DPM (p<0.001). Simvastatin, but not fenofibrate, suppressed fibroblast proliferation (664 +/- 192 DPM, p<0.001). Simvastatin also significantly attenuated transforming growth factor-beta 1-stimulated alpha-smooth muscle actin (alpha-SMA) expression (indicating myofibroblast differentiation) from 1.3 +/- 0.1 to 1.0 +/- 0.1 times baseline (p<0.05). Conclusions: CHF-induced atrial structural remodeling and AF promotion are attenuated by simvastatin, but not fenofibrate. Statin-induced inhibition of profibrotic atrial fibroblast responses and attenuation of left-ventricular dysfunction may contribute to preventing the CHF-induced fibrotic AF substrate. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.