Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac disease characterized by arrhythmias under adrenergic stress. Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for CPVT. We characterized electrophysiological properties of CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying different mutations in RYR2 and evaluated effects of carvedilol and flecainide on action potential (AP) and contractile properties of hiPSC-CMs. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion (E3D) and L4115F mutation in RYR2. APs and contractile movement were recorded simultaneously from the same hiPSC-CMs. Differences in AP properties of ventricular like CMs were seen in CPVT and control CMs: APD90 of both E3D (n = 20) and L4115F (n = 25) CPVT CMs was shorter than in control CMs (n = 15). E3D-CPVT CMs had shortest AP duration, lowest AP amplitude, upstroke velocity and more depolarized diastolic potential than controls. Adrenaline had positive and carvedilol and flecainide negative chronotropic effect in all hiPSC CMs. CPVT CMs had increased amount of delayed after depolarizations (DADs) and early after depolarizations (EADs) after adrenaline exposure. E3D CPVT CMs had the most DADs, EADs, and tachyarrhythmia. Discordant negatively coupled alternans was seen in L4115F CPVT CMs. Carvedilol cured almost all arrhythmias in L4115F CPVT CMs. Both drugs decreased contraction amplitude in all hiPSC CMs. E3D CPVT CMs have electrophysiological properties, which render them more prone to arrhythmias. iPSC-CMs provide a unique platform for disease modeling and drug screening for CPVT. Combining electrophysiological measurements, we can gain deeper insight into mechanisms of arrhythmias.

中文翻译：

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CPVT患者心律失常和药物反应的突变特异性差异：iPSC衍生心肌细胞的同时膜片钳和视频成像。

儿茶酚胺能性多形性室性心动过速（CPVT）是一种遗传性心脏病，其特征是在肾上腺素能应激下心律不齐。心脏ryanodine受体（RYR2）的突变是CPVT的主要原因。我们表征了CPVT患者特异性诱导的多能干细胞衍生的心肌细胞（hiPSC-CMs）在RYR2中携带不同突变的电生理特性，并评估了卡维地洛和氟卡尼对hiPSC-CMs的动作电位（AP）和收缩特性的影响。iPSC-CMs是由CPVT患者的皮肤活检产生的，这些患者在RYR2中携带外显子3缺失（E3D）和L4115F突变。从同一hiPSC-CM同时记录AP和收缩运动。在CPVT和对照CM中观察到心室样CM AP特性的差异：E3D（n = 20）和L4115F（n = 25）CPVT CM的APD90均比对照CM（n = 15）短。与对照组相比，E3D-CPVT CM具有最短的AP持续时间，最低的AP振幅，上冲速度和更大的去极化舒张电位。在所有hiPSC CM中，肾上腺素具有正，卡维地洛和氟卡尼的负变时性作用。CPVT CM的去极化后（DAD）和肾上腺素暴露后的去极化后（EAD）早期延迟量增加。E3D CPVT CM的DAD，EAD和心律失常最多。在L4115F CPVT CM中发现不一致的负耦合交替素。卡维地洛可治愈L4115F CPVT CM中的几乎所有心律不齐。两种药物均降低了所有hiPSC CM的收缩幅度。E3D CPVT CM具有电生理特性，这使其更易于出现心律不齐。iPSC-CM为CPVT的疾病建模和药物筛选提供了一个独特的平台。结合电生理测量，我们可以更深入地了解心律不齐的机制。