Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure
Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure
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DOI：
10.1161/circulationaha.106.624320
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发表时间：
2006-10-17
期刊：
影响因子：
37.8
通讯作者：
Olgin, Jeffrey E.
中科院分区：
文献类型：
--
作者：
Lee, Ken W.;Everett, Thomas H.;Olgin, Jeffrey E.
背景-心房纤维化是心房颤动（AF）的重要基础，特别是在结构性心脏病的情况下。在犬模型中，充血性心力衰竭（CHF）产生显著的心房纤维化和持续性AF的基质。这种心房重构是潜在的治疗靶点。本研究的目的是评估抗纤维化药物吡非尼酮（PFD）对犬CHF model.Methods和Results中致炎性心房重构的影响-我们研究了15只犬，平均分为3组：对照组，CHF犬未接受PFD治疗，CHF犬接受PFD治疗。通过心室快速起搏（220 bpm持续3周）诱导CHF，并在3周起搏期内给予口服PFD。我们进行了电生理学和房颤易损性研究、心房纤维化测量和心房细胞因子表达研究。仅未治疗CHF组的犬发生持续性AF（> 30分钟，5只犬中的4只; P < 0.05）。用PFD治疗CHF犬可减弱致心律失常性左房重构，并显著降低左房传导异质性指数（中位数[25%~ 75%四分位距] 4.96 [3.53 ~ 5.64]对2.52 [2.11 ~ 2.82]，P < 0.01;起搏周期长度300 ms），左心房纤维化（16.0% [13.0%至17.5%]对比8.7% [5.7%至10.6%]，P < 0.01）和AF持续时间（1800 [1020至1800]秒对比6 [5至22]秒，P < 0.01）。免疫印迹研究表明，药物对多种细胞因子的影响，包括减少转化生长因子-β 1 expression.Conclusions -治疗CHF犬PFD的结果显着减少致炎性心房重构和AF的脆弱性。针对纤维化基质本身的药物治疗可能在AF的管理中发挥重要作用。
Background - Atrial fibrosis is an important substrate in atrial fibrillation (AF), particularly in the setting of structural heart disease. In a canine model, congestive heart failure (CHF) produces significant atrial fibrosis and the substrate for sustained AF. This atrial remodeling is a potential therapeutic target. The objective of the present study is to evaluate the effects of the antifibrotic drug pirfenidone (PFD) on arrhythmogenic atrial remodeling in a canine CHF model.Methods and Results - We studied 15 canines, divided equally into 3 groups: control, CHF canines not treated with PFD, and CHF canines treated with PFD. CHF was induced by ventricular tachypacing (220 bpm for 3 weeks), and oral PFD was administered for the 3-week pacing period. We performed electrophysiology and AF vulnerability studies, atrial fibrosis measurements, and atrial cytokine expression studies. Only canines in the untreated CHF group developed sustained AF (> 30 minutes, 4 of 5 canines; P < 0.05). Treatment of CHF canines with PFD resulted in an attenuation of arrhythmogenic left atrial remodeling, with a significant reduction in left atrial conduction heterogeneity index ( median [25% to 75% interquartile range] 4.96 [3.53 to 5.64] versus 2.52 [2.11 to 2.82], P < 0.01; pacing cycle length 300 ms), left atrial fibrosis (16.0% [13.0% to 17.5%] versus 8.7% [5.7% to 10.6%], P < 0.01), and AF duration ( 1800 [1020 to 1800] seconds versus 6 [5 to 22] seconds, P < 0.01). Immunoblotting studies demonstrated the drug's effects on multiple cytokines, including a reduction in transforming growth factor-beta 1 expression.Conclusions - Treatment of CHF canines with PFD results in significantly reduced arrhythmogenic atrial remodeling and AF vulnerability. Pharmacological therapy targeted at the fibrotic substrate itself may play an important role in the management of AF.