title: Tranilast prevents atrial remodeling and development of atrial fibrillation in a canine model of atrial tachycardia and left ventricular dysfunction.
abstract: OBJECTIVE
  This study sought to assess the effects of tranilast on atrial remodeling in a canine atrial fibrillation (AF) model.
  
  
  BACKGROUND
  Tranilast inhibits transforming growth factor (TGF)-β1 and prevents fibrosis in many pathophysiological settings. However, the effects of tranilast on atrial remodeling remain unclear.
  
  
  METHODS
  Beagles were subjected to atrial tachypacing (400 beats/min) for 4 weeks while treated with placebo (control dogs, n = 8) or tranilast (tranilast dogs, n = 10). Sham dogs (n = 6) did not receive atrial tachypacing. Atrioventricular conduction was preserved. Ventricular dysfunction developed in the control and tranilast dogs due to rapid ventricular responses.
  
  
  RESULTS
  Atrial fibrillation duration (211 ± 57 s) increased, and AF cycle length and atrial effective refractory period shortened in controls, but these changes were suppressed in tranilast dogs (AF duration, 18 ± 10 s, p < 0.01 vs. control). The L-type calcium channel α1c (Cav1.2) micro ribonucleic acid expression decreased in control dogs (sham 1.38 ± 0.24 vs. control 0.65 ± 0.12, p < 0.01), but not in tranilast dogs (0.97 ± 0.14, p = not significant vs. sham). Prominent atrial fibrosis (fibrous tissue area, sham 0.8 ± 0.1 vs. control 9.3 ± 1.3%, p < 0.01) and increased expression of tissue inhibitor of metalloproteinase protein 1 were observed in control dogs but not in tranilast dogs (fibrous tissue area, 1.4 ± 0.2%, p < 0.01 vs. control). The TGF-β1 (sham 1.00 ± 0.07 vs. control 3.06 ± 0.87, p < 0.05) and Rac1 proteins were overexpressed in control dogs, but their overexpression was inhibited in tranilast dogs (TGF-β1, 1.28 ± 0.20, p < 0.05 vs. control).
  
  
  CONCLUSIONS
  Tranilast prevented atrial remodeling and suppressed AF development in a canine model. Its inhibition of TGF-β1 and Rac1 overexpression may contribute to its antiremodeling effects.
authors.affiliation: Second Department of Internal Medicine, University of Toyama, Toyama, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nakatani
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Nishida
authors.forename: Masao
authors.initials: M
authors.lastname: Sakabe
authors.forename: Naoya
authors.initials: N
authors.lastname: Kataoka
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Jotaro
authors.initials: J
authors.lastname: Iwamoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Mizumaki
authors.forename: Akira
authors.initials: A
authors.lastname: Fujiki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D013610:Tachycardia / Q000188:drug therapy* / Q000503:physiopathology; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000503:physiopathology; D062367:ortho-Aminobenzoates / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002316:Cardiotonic Agents; D062367:ortho-Aminobenzoates; C012293:tranilast