Department of Physics, School of Physical Science and Technology, Ningbo University, Ningbo, Zhejiang, China; Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
Heart Rhythm Management Centre, Postgraduate Program in Cardiac Electrophysiology and Pacing, Universitair Ziekenhuis Brussel-Vrije Universiteit Brussel, European Reference Networks Guard-Heart, Brussels, Belgium.
JACC Clin Electrophysiol. 2023 Dec;9(12):2459-2474. doi: 10.1016/j.jacep.2023.08.027. Epub 2023 Oct 11.
In Brugada syndrome (BrS), phase 2 re-excitation/re-entry (P2R) induced by the transient outward potassium current (I) 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 I.
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 I sufficient to generate robust P2R, reducing sodium current (I) peak amplitude alone only slightly potentiated P2R. When I inactivation kinetics were also altered to simulate reported effects of BrS mutations and sodium channel blockers, however, P2R occurred even in the absence of I. These effects could be potentiated by delaying L-type calcium channel activation or increasing ATP-sensitive potassium current, consistent with experimental and clinical findings. I-mediated P2R also accounted for sex-related, day and night-related, and fever-related differences in arrhythmia risk in BrS patients.
Altered I kinetics synergize powerfully with reduced I amplitude to promote P2R-induced arrhythmias in BrS in the absence of I, establishing a robust mechanistic link between altered I kinetics and the P2R-mediated arrhythmia mechanism.
在 Brugada 综合征（BrS）中，由瞬时外向钾电流（I）引起的 2 相折返/折返（P2R）是一种拟议的心律失常机制；然而，最常见的遗传缺陷是钠通道功能丧失突变。
作者使用计算机模拟来研究钠通道功能障碍如何影响存在和不存在 I 时 P2R 介导的心律失常发生。
使用豚鼠和人心室动作电位模型在 1 维电缆和 2 维组织中进行计算机模拟。
在足以产生强烈 P2R 的 I 存在下，仅降低钠电流（I）峰值幅度仅略微增强 P2R。然而，当改变 I 失活动力学以模拟 BrS 突变和钠通道阻滞剂的报道影响时，即使没有 I，P2R 也会发生。这些影响可以通过延迟 L 型钙通道激活或增加 ATP 敏感性钾电流来增强，这与实验和临床发现一致。I 介导的 P2R 还解释了 BrS 患者心律失常风险的性别相关、昼夜相关和发热相关差异。
改变的 I 动力学与降低的 I 幅度协同作用，在没有 I 的情况下促进 BrS 中的 P2R 诱导性心律失常，在改变的 I 动力学和 P2R 介导的心律失常机制之间建立了一个强大的机制联系。
