Tranilast prevents atrial remodeling and development of atrial fibrillation in a canine model of atrial tachycardia and left ventricular dysfunction.

Abstract

OBJECTIVES:

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: Yosuke Nakatani, Kunihiro Nishida, Masao Sakabe, Naoya Kataoka, Tamotsu Sakamoto, Yoshiaki Yamaguchi, Jotaro Iwamoto, Koichi Mizumaki, Akira Fujiki, Hiroshi Inoue
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 61 Issue 5 Pg. 582-8 (Feb 05 2013) ISSN: 1558-3597 [Electronic] United States
• PMID: 23273396 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cardiotonic Agents
• ortho-Aminobenzoates
• tranilast

Topics

• Animals
• Atrial Fibrillation (etiology, physiopathology, prevention & control)
• Cardiac Pacing, Artificial (adverse effects)
• Cardiotonic Agents (pharmacology, therapeutic use)
• Disease Models, Animal
• Dogs
• Heart Atria (drug effects, physiopathology)
• Tachycardia (drug therapy, physiopathology)
• Ventricular Dysfunction, Left (drug therapy, physiopathology)
• ortho-Aminobenzoates (pharmacology, therapeutic use)