PDF(Pubmed)
Abstract：
In Brugada syndrome (BrS), phase 2 re-excitation/re-entry (P2R) induced by the transient outward potassium current (Ito) is a proposed arrhythmia mechanism; yet, the most common genetic defects are loss-of-function sodium channel mutations.
The authors used computer simulations to investigate how sodium channel dysfunction affects P2R-mediated arrhythmogenesis in the presence and absence of Ito.
Computer simulations were carried out in 1-dimensional cables and 2-dimensional tissue using guinea pig and human ventricular action potential models.
In the presence of Ito sufficient to generate robust P2R, reducing sodium current (INa) peak amplitude alone only slightly potentiated P2R. When INa inactivation kinetics were also altered to simulate reported effects of BrS mutations and sodium channel blockers, however, P2R occurred even in the absence of Ito. These effects could be potentiated by delaying L-type calcium channel activation or increasing ATP-sensitive potassium current, consistent with experimental and clinical findings. INa-mediated P2R also accounted for sex-related, day and night-related, and fever-related differences in arrhythmia risk in BrS patients.
Altered INa kinetics synergize powerfully with reduced INa amplitude to promote P2R-induced arrhythmias in BrS in the absence of Ito, establishing a robust mechanistic link between altered INa kinetics and the P2R-mediated arrhythmia mechanism.
The authors used computer simulations to investigate how sodium channel dysfunction affects P2R-mediated arrhythmogenesis in the presence and absence of Ito.
Computer simulations were carried out in 1-dimensional cables and 2-dimensional tissue using guinea pig and human ventricular action potential models.
In the presence of Ito sufficient to generate robust P2R, reducing sodium current (INa) peak amplitude alone only slightly potentiated P2R. When INa inactivation kinetics were also altered to simulate reported effects of BrS mutations and sodium channel blockers, however, P2R occurred even in the absence of Ito. These effects could be potentiated by delaying L-type calcium channel activation or increasing ATP-sensitive potassium current, consistent with experimental and clinical findings. INa-mediated P2R also accounted for sex-related, day and night-related, and fever-related differences in arrhythmia risk in BrS patients.
Altered INa kinetics synergize powerfully with reduced INa amplitude to promote P2R-induced arrhythmias in BrS in the absence of Ito, establishing a robust mechanistic link between altered INa kinetics and the P2R-mediated arrhythmia mechanism.
摘要：
背景：在Brugada综合征（BrS）中，由瞬态外向钾电流（Ito）引起的第2阶段重新激发/重新进入（P2R）是一种拟议的心律失常机制；然而，最常见的遗传缺陷是功能缺失的钠通道突变.
目的：我们使用计算机模拟来研究在存在和不存在Ito的情况下钠通道功能障碍如何影响P2R介导的心律失常发生。
方法：使用豚鼠和人类心室动作电位模型在一维电缆和二维组织中进行计算机模拟。
结果：在存在足以产生稳健P2R的Ito的情况下，仅降低钠电流（INa）峰值幅度仅略微增强P2R。当INa失活动力学也被改变以模拟BrS突变和钠通道阻滞剂的报道效果时，然而,P2R甚至在没有Ito的情况下也发生。这些作用可以通过延迟L型钙通道激活或增加ATP敏感性钾电流来增强。与实验和临床结果一致。INa介导的P2R也占性别相关，白天和黑夜有关，BrS患者心律失常风险与发热相关的差异。
结论：在没有Ito的情况下，改变的INa动力学与降低的INa振幅有效协同作用，以促进P2R引起的BrS心律失常，在改变的INa动力学和P2R介导的心律失常机制之间建立可靠的机械联系。
目的：我们使用计算机模拟来研究在存在和不存在Ito的情况下钠通道功能障碍如何影响P2R介导的心律失常发生。
方法：使用豚鼠和人类心室动作电位模型在一维电缆和二维组织中进行计算机模拟。
结果：在存在足以产生稳健P2R的Ito的情况下，仅降低钠电流（INa）峰值幅度仅略微增强P2R。当INa失活动力学也被改变以模拟BrS突变和钠通道阻滞剂的报道效果时，然而,P2R甚至在没有Ito的情况下也发生。这些作用可以通过延迟L型钙通道激活或增加ATP敏感性钾电流来增强。与实验和临床结果一致。INa介导的P2R也占性别相关，白天和黑夜有关，BrS患者心律失常风险与发热相关的差异。
结论：在没有Ito的情况下，改变的INa动力学与降低的INa振幅有效协同作用，以促进P2R引起的BrS心律失常，在改变的INa动力学和P2R介导的心律失常机制之间建立可靠的机械联系。
