Whittaker Dominic G, Hancox Jules C, Zhang Henggui
Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom.
Biological Physics Group, School of Physics and Astronomy, The University of Manchester, Manchester, United Kingdom.
Front Physiol. 2019 Jan 11;9:1888. doi: 10.3389/fphys.2018.01888. eCollection 2018.
Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the (), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, . In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs-disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant was incorporated into a contemporary human atrial action potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for /hERG and sodium current, , were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined and block based pharmacological strategies in the treatment of SQT1-linked AF.
短QT综合征1型（SQT1）是由于编码携带快速延迟整流钾电流（I Kr）通道α亚基的（hERG）发生功能获得性突变所致。除QT间期缩短和室性心律失常外，SQT1还与心房颤动（AF）风险增加相关，而AF往往是唯一的临床表现。然而，在SQT1背景下，AF的潜在机制及其药物治疗仍未完全明确。在本研究中，采用计算建模来研究SQT1突变导致人心房心律失常发生的机制，以及所选I类药物（双异丙吡胺、奎尼丁和普罗帕酮）的药物治疗效果。将描述野生型（WT）和N588K-hERG突变体I Kr的马尔可夫链公式纳入当代人心房动作电位（AP）模型，该模型被整合到一维（1D）组织束、理想化二维薄片和三维异质性解剖人心房模型中。考虑了双异丙吡胺、奎尼丁和普罗帕酮的多通道药理作用，包括它们对I Kr/hERG和钠电流（I Na）的结合动力学。N588K-hERG突变的杂合子和纯合子形式分别使动作电位时程（APD）缩短了53和86毫秒，这缩短了组织中的有效不应期（ERP）和兴奋波长，增加了三维解剖人心房中环行波的寿命和主导频率（DF）。在本研究测试的浓度下，奎尼丁在SQT1情况下最有效地延长了APD和ERP，其次是双异丙吡胺和普罗帕酮。在二维模拟中，双异丙吡胺和奎尼丁通过增加折返波长促进折返终止，而普罗帕酮诱导使折返电路不稳定的次级波。在三维模拟中，双异丙吡胺和奎尼丁使折返的DF以剂量依赖方式降低，普罗帕酮的降低程度较小。所有抗心律失常药物均促进药物转复，最常按奎尼丁>普罗帕酮 = 双异丙吡胺的顺序终止折返。我们的研究结果为深入了解SQT1相关AF的机制提供了进一步的见解，并为在治疗SQT1相关AF中寻求基于I Kr和I Na阻断的联合药理策略提供了合理依据。
