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

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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. © 2013 American College of Cardiology Foundation.

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Nakatani, Y., Nishida, K., Sakabe, M., Kataoka, N., Sakamoto, T., Yamaguchi, Y., … Inoue, H. (2013). Tranilast prevents atrial remodeling and development of atrial fibrillation in a canine model of atrial tachycardia and left ventricular dysfunction. Journal of the American College of Cardiology, 61(5), 582–588. https://doi.org/10.1016/j.jacc.2012.11.014

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