School of Computer Science and Technology, Harbin Institute of Technology (HIT), Harbin 150001, People's Republic of China.
Physiol Meas. 2017 Sep 21;38(10):1859-1873. doi: 10.1088/1361-6579/aa8695.
Short QT syndrome (SQTS) is an inherited cardiac channelopathy, but at present little information is available on its pharmacological treatment. SQT3 variant (linked to the inward rectifier potassium current I ) of SQTS, results from a gain-of-function mutation (Kir2.1 D172N) in the KCNJ2-encoded channels, which is associated with ventricular fibrillation (VF). Using biophysically-detailed human ventricular computer models, this study investigated the potential effects of quinidine, disopyramide, and E-4031 on SQT3.
The ten Tusscher et al model of human ventricular myocyte action potential (AP) was modified to recapitulate the changes in I due to heterozygous and homozygous forms of the D172N mutation. Wild-type (WT) and mutant WT-D172N and D172N formulations were incorporated into one-dimensional (1D) and 2D tissue models with transmural heterogeneities. Effects of drugs on channel-blocking activity were modelled using half-maximal inhibitory concentration (IC) and Hill coefficient (nH) values. Effects of drugs on AP duration (APD), effective refractory period (ERP) and QT interval of pseudo-ECGs were quantified, and both temporal and spatial vulnerability to re-entry was measured. Re-entry was simulated in the 2D ventricular tissue.
At the single cell level, the drugs quinidine, disopyramide, and E-4031 prolonged APD at 90% repolarization (APD), and decreased maximal transmural voltage heterogeneity (δV); this caused the decreased transmural dispersion of APD. Quinidine prolonged the QT interval and decreased the T-wave amplitude. Furthermore, quinidine increased ERP and reduced temporal vulnerability and increased spatial vulnerability, resulting in a reduced susceptibility to arrhythmogenesis in SQT3. In the 2D tissue, quinidine was effective in terminating and preventing re-entry associated with the heterozygous D172N condition. Quinidine exhibited significantly better therapeutic effects on SQT3 than disopyramide and E-4031.
This study substantiates a causal link between quinidine and QT interval prolongation in SQT3 Kir2.1 mutations and highlights possible pharmacological agent quinidine for treating SQT3 patients.
短 QT 综合征（SQTS）是一种遗传性心脏通道病，但目前关于其药物治疗的信息很少。SQTS 的 SQT3 变体（与内向整流钾电流 I 相关）是由 KCNJ2 编码的通道中的功能获得性突变（Kir2.1 D172N）引起的，与心室颤动（VF）有关。本研究使用具有生物物理细节的人类心室计算机模型，研究了奎尼丁、双异丙吡胺和 E-4031 对 SQT3 的潜在影响。
采用 ten Tusscher 等人心室肌动作电位（AP）模型，对杂合和纯合形式的 D172N 突变导致的 I 变化进行模拟。野生型（WT）和突变型 WT-D172N 和 D172N 制剂被整合到具有跨壁异质性的一维（1D）和二维（2D）组织模型中。使用半最大抑制浓度（IC）和 Hill 系数（nH）值对药物的通道阻断活性进行建模。量化了药物对 AP 持续时间（APD）、有效不应期（ERP）和假性 ECGs 的 QT 间期的影响，并测量了时空易感性。在 2D 心室组织中模拟折返。
在单细胞水平上，药物奎尼丁、双异丙吡胺和 E-4031 延长了 90%复极时的 APD（APD），并降低了最大跨壁电压异质性（δV）；这导致 APD 的跨壁离散度降低。奎尼丁延长 QT 间期并降低 T 波振幅。此外，奎尼丁增加了 ERP，降低了时间易感性，并增加了空间易感性，从而降低了 SQT3 心律失常发生的易感性。在 2D 组织中，奎尼丁有效终止和预防与杂合 D172N 条件相关的折返。奎尼丁对 SQT3 的治疗效果明显优于双异丙吡胺和 E-4031。
本研究证实了奎尼丁与 SQT3 Kir2.1 突变中 QT 间期延长之间的因果关系，并强调了奎尼丁作为治疗 SQT3 患者的潜在药物治疗剂。
