Potassium Channel Blockade Enhances Atrial Fibrillation-Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade
Potassium Channel Blockade Enhances Atrial Fibrillation-Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade
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DOI：
10.1161/circulationaha.115.018016
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发表时间：
2015-12-08
期刊：
影响因子：
37.8
通讯作者：
Nattel, Stanley
中科院分区：
文献类型：
--
作者：
Aguilar, Martin;Xiong, Feng;Nattel, Stanley
研究背景：开发安全有效的抗心律失常药物来控制心房颤动（AF）的节律是一个尚未满足的临床需求。多通道阻滞剂被认为比单通道阻滞剂对AF有优势，但迄今为止，它们的开发完全是经验性的。我们测试了这一假设，即增加K+通道阻滞剂可以改善心房选择性电生理特征和优化的Na+通道阻滞剂的抗AF作用。方法和结果-真实的心肌细胞，组织和状态依赖性Na+通道阻滞数学模型，光学映射，采用动作电位记录技术研究Na ~+电流（INa）阻断伴或不伴快速或超速延迟整流钾电流抑制（分别为IKr和IKur）。在数学模型中，最大的AF选择性获得了一个失活状态的Na+通道阻滞剂。与优化的Na+通道阻滞剂单独使用相比，优化的Na+通道阻滞剂与IKr阻滞剂联合使用增加了频率依赖性和心房选择性的峰值I Na降低，增加了AF选择性，并更有效地终止AF。优化的Na+通道阻滞剂与IKr阻滞联合使用具有相似的效果，但没有IKr阻滞诱导的心室动作电位延长。与数学模型一致，在冠状动脉灌注的犬心脏中，多非利特（选择性I Kr阻滞剂）与匹西卡尼（选择性I Na阻滞剂）的添加对最大0相上冲程和传导速度产生增强的心房选择性作用。此外，吡西卡尼联合多非利特终止AF的疗效高于吡西卡尼单药。单独使用Pilsicainide对AF inductiveness没有统计学显著影响，而Pilsicainide加dofetilide使AF noninducible. Conclusions-K+通道阻滞增强了AF选择性抗AF效果，可与优化的Na+通道阻滞。结合优化的钠通道阻滞与心房钾电流阻滞是一种潜在的有价值的AF选择性抗心律失常药物策略。
Background-The development of effective and safe antiarrhythmic drugs for atrial fibrillation (AF) rhythm control is an unmet clinical need. Multichannel blockers are believed to have advantages over single-channel blockers for AF, but their development has been completely empirical to date. We tested the hypothesis that adding K+-channel blockade improves the atrium-selective electrophysiological profile and anti-AF effects of optimized Na+-channel blockers.Methods and Results-Realistic cardiomyocyte-, tissue-, and state-dependent Na+-channel block mathematical models, optical mapping, and action potential recording were used to study the effect of Na+-current (I Na) blockade with or without concomitant inhibition of the rapid or ultrarapid delayed-rectifier K+ currents (I Kr and I Kur, respectively). In the mathematical model, maximal AF selectivity was obtained with an inactivated-state Na+-channel blocker. Combining optimized Na+-channel blocker with I Kr block increased rate-dependent and atrium-selective peak I Na reduction, increased AF selectivity, and more effectively terminated AF compared with optimized Na+-channel blocker alone. Combining optimized Na+-channel blocker with I Kur block had similar effects but without I Kr block-induced ventricular action potential prolongation. Consistent with the mathematical model, in coronary-perfused canine hearts, the addition of dofetilide (selective I Kr blocker) to pilsicainide (selective I Na blocker) produced enhanced atrium-selective effects on maximal phase 0 upstroke and conduction velocity. Furthermore, pilsicainide plus dofetilide had higher AF termination efficacy than pilsicainide alone. Pilsicainide alone had no statistically significant effect on AF inducibility, whereas pilsicainide plus dofetilide rendered AF noninducible.Conclusions-K+-channel block potentiates the AF-selective anti-AF effects obtainable with optimized Na+-channel blockade. Combining optimized Na+-channel block with blockade of atrial K+ currents is a potentially valuable AF-selective antiarrhythmic drug strategy.