title: Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure.
abstract: 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.
  
  
  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-beta1-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.
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Canada.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shiroshita-Takeshita
authors.forename: Bianca J J M
authors.initials: BJ
authors.lastname: Brundel
authors.forename: Brett
authors.initials: B
authors.lastname: Burstein
authors.forename: Tack-Ki
authors.initials: TK
authors.lastname: Leung
authors.forename: Hideo
authors.initials: H
authors.lastname: Mitamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000209:etiology / Q000517:prevention & control*; D015415:Biomarkers / Q000032:analysis; D002304:Cardiac Pacing, Artificial; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004285:Dogs; D011345:Fenofibrate / Q000627:therapeutic use; D005347:Fibroblasts / Q000187:drug effects; D006325:Heart Atria / Q000737:chemistry; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy*; D006352:Heart Ventricles / Q000737:chemistry; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D023421:Models, Animal; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D047493:PPAR alpha / Q000819:agonists; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D019821:Simvastatin / Q000627:therapeutic use*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000199:Actins; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D000960:Hypolipidemic Agents; D047493:PPAR alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D019821:Simvastatin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011345:Fenofibrate