Copyright © 2007, European Society of Cardiology
Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure
aDepartment of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Canada
bDepartment of Pathology, Montreal Heart Institute and Université de Montréal, Canada
cDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
dDepartment of Radiation, Stress Cell Biology, University of Groningen, The Netherlands
eCardiology Department, Saiseikai Central Hospital, Tokyo, Japan
fCardiology Division, Keio University School of Medicine, Tokyo, Japan
* Corresponding author. 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8. Tel.: +1 514 376 3330; fax: +1 514 376 1355. Email address: stanley.nattel{at}icm-mhi.org
Background: Congestive heart failure (CHF) is a common cause of atrial fibrillation (AF). Oxidative stress and inflammation (profibrotic) and peroxisome proliferator-activated receptor-
(PPAR-, antifibrotic) factors may be involved in CHF-related remodeling. We evaluated the effects of simvastatin (antioxidant, anti-inflammatory) and fenofibrate (PPAR- 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 80 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-β1-stimulated -smooth muscle actin (-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.
KEYWORDS Antiarrhythmic agents; Arrhythmia (mechanisms); Remodeling; Statins; Heart failure
Supported by Canadian Institutes of Health Research (CIHR), Quebec Heart and Stroke Foundation, Dutch Organization for Scientific Research (NWO program grant 916.46.043), and Interuniversity Cardiology Institute of The Netherlands.
Time for primary review 26 days
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