BioMediTech Institute and Faculty of Biomedical Sciences and Engineering, Tampere University of Technology, Tampere, Finland.
Department of Computer Science, University of Oxford, Oxford, United Kingdom.
Heart Rhythm. 2017 Nov;14(11):1704-1712. doi: 10.1016/j.hrthm.2017.07.026. Epub 2017 Jul 27.
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are in vitro models with the clear advantages of their human origin and suitability for human disease investigations. However, limitations include their incomplete characterization and variability reported in different cell lines and laboratories.
The purpose of this study was to investigate in silico ionic mechanisms potentially explaining the phenotypic variability of hiPSC-CMs in long QT syndrome type 3 (LQT3) and their response to antiarrhythmic drugs.
Populations of in silico hiPSC-CM models were constructed and calibrated for control (n = 1,463 models) and LQT3 caused by I channelopathy (n = 1,401 models), using experimental recordings for late sodium current (I) and action potentials (APs). Antiarrhythmic drug therapy was evaluated by simulating mexiletine and ranolazine multichannel effects.
As in experiments, LQT3 hiPSC-CMs yield prolonged action potential duration at 90% repolarization (APD) (+34.3% than controls) and large electrophysiological variability. LQT3 hiPSC-CMs with symptomatic APs showed overexpression of I, I, and I, underexpression of I, and increased sensitivity to both drugs compared to asymptomatic LQT3 models. Simulations showed that both mexiletine and ranolazine corrected APD prolongation in the LQT3 population but also highlighted differences in drug response. Mexiletine stops spontaneous APs in more LQT3 hiPSC-CMs models than ranolazine (784/1,401 vs 53/1,401) due to its stronger action on I.
In silico simulations demonstrate our ability to recapitulate variability in LQT3 and control hiPSC-CM phenotypes, and the ability of mexiletine and ranolazine to reduce APD prolongation, in agreement with experiments. The in silico models also identify potential ionic mechanisms of phenotypic variability in LQT3 hiPSC-CMs, explaining APD prolongation in symptomatic vs asymptomatic LQT3 hiPSC-CMs.
人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）是体外模型，具有其人类起源和适合人类疾病研究的明显优势。然而，其局限性包括其不完全特征化以及在不同细胞系和实验室中报道的可变性。
本研究旨在探讨潜在的离子机制，这些机制可能解释了长 QT 综合征 3 型（LQT3）中 hiPSC-CMs 的表型变异性及其对抗心律失常药物的反应。
使用实验记录的晚期钠电流（I）和动作电位（APs），构建并校准用于对照（n = 1463 个模型）和由 I 通道病引起的 LQT3（n = 1401 个模型）的虚拟 hiPSC-CM 模型种群。通过模拟美西律和雷诺嗪多通道效应来评估抗心律失常药物治疗。
与实验结果一样，LQT3 hiPSC-CMs 的动作电位复极 90%时程（APD）延长（比对照长 34.3%）和电生理变异性大。与无症状 LQT3 模型相比，具有症状性 APs 的 LQT3 hiPSC-CMs 表现出 I、I 和 I 的过度表达、I 的表达不足，以及对两种药物的敏感性增加。模拟表明，美西律和雷诺嗪均能纠正 LQT3 人群的 APD 延长，但也突出了药物反应的差异。由于其对 I 的更强作用，美西律比雷诺嗪在更多的 LQT3 hiPSC-CMs 模型中停止自发性 APs（784/1401 比 53/1401）。
体内模拟证明了我们能够重现 LQT3 和对照 hiPSC-CM 表型的变异性，以及美西律和雷诺嗪降低 APD 延长的能力，这与实验结果一致。体内模型还确定了 LQT3 hiPSC-CMs 表型变异性的潜在离子机制，解释了症状性与无症状性 LQT3 hiPSC-CMs 中的 APD 延长。
