Luo Cunjin, Wang Kuanquan, Zhang Henggui
School of Computer Science and Technology, Harbin Institute of Technology (HIT), Harbin, 150001, China.
School of Physics and Astronomy, The University of Manchester, Manchester, M13 9PL, UK.
Biomed Eng Online. 2017 Jun 7;16(1):69. doi: 10.1186/s12938-017-0369-0.
Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (I ), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS. Therefore, in this study, we used computational modeling to assess the effects of amiodarone, class III anti-arrhythmic agent, on human ventricular electrophysiology in SQT3.
The ten Tusscher et al. model for the human ventricular action potentials (APs) was modified to incorporate I formulations based on experimental data of Kir2.1 channels (including WT, WT-D172N and D172N conditions). The modified cell model was then implemented to construct one-dimensional (1D) and 2D tissue models. The blocking effects of amiodarone on ionic currents were modeled using IC and Hill coefficient values from literatures. Effects of amiodarone on APD, ERP and pseudo-ECG traces were computed. Effects of the drug on the temporal and spatial vulnerability of ventricular tissue to genesis and maintenance of re-entry were measured, as well as on the dynamic behavior of re-entry.
Amiodarone prolonged the ventricular cell APD and decreased the maximal voltage heterogeneity (δV) among three difference cells types across transmural ventricular wall, leading to a decreased transmural heterogeneity of APD along a 1D model of ventricular transmural strand. Amiodarone increased cellular ERP, prolonged QT interval and decreased the T-wave amplitude. It reduced tissue's temporal susceptibility to the initiation of re-entry and increased the minimum substrate size necessary to sustain re-entry in the 2D tissue.
At the therapeutic-relevant concentration of amiodarone, the APD and ERP at the single cell level were increased significantly. The QT interval in pseudo-ECG was prolonged and the re-entry in tissue was prevented. This study provides further evidence that amiodarone may be a potential pharmacological agent for preventing arrhythmogenesis for SQT3 patients.
短QT综合征（SQTS）是一种新发现的临床疾病，与心房和/或心室心律失常以及心脏性猝死（SCD）风险增加相关。SQTS 3型与KCNJ2基因的D172N突变有关，该突变导致内向整流钾通道电流（I ）功能增强，从而缩短心室动作电位时程（APD）和有效不应期（ERP）。SQTS的促心律失常作用已得到表征，但关于SQTS可能的药物治疗知之甚少。因此，在本研究中，我们使用计算建模来评估III类抗心律失常药物胺碘酮对SQT3患者人心室电生理的影响。
对ten Tusscher等人的人心室动作电位（AP）模型进行修改，以纳入基于Kir2.1通道实验数据（包括野生型、野生型-D172N和D172N条件）的I 公式。然后将修改后的细胞模型用于构建一维（1D）和二维（2D）组织模型。使用文献中的IC和希尔系数值对胺碘酮对离子电流的阻断作用进行建模。计算胺碘酮对APD、ERP和伪心电图轨迹的影响。测量药物对心室组织发生和维持折返的时间和空间易损性的影响，以及对折返动态行为的影响。
胺碘酮延长了心室细胞APD，并降低了跨室壁三种不同细胞类型之间的最大电压异质性（δV），导致沿心室跨壁束一维模型的APD跨壁异质性降低。胺碘酮增加了细胞ERP，延长了QT间期并降低了T波振幅。它降低了组织对折返起始的时间易感性，并增加了在二维组织中维持折返所需的最小底物大小。
在胺碘酮的治疗相关浓度下，单细胞水平的APD和ERP显著增加。伪心电图中的QT间期延长，组织中的折返被阻止。本研究提供了进一步的证据，表明胺碘酮可能是预防SQT3患者心律失常发生的潜在药物。
