Early repolarization syndrome (ERS) is defined as occurring in patients with early repolarization pattern who have survived idiopathic ventricular fibrillation with clinical evaluation unrevealing for other explanations. The pathophysiologic basis of the ERS is currently uncertain. The objective of the present study was to examine the electrophysiological mechanism of ERS utilizing induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 genome editing. Whole genome sequencing was used to identify the DPP6 (c.2561T > C/p.L854P) variant in four families with sudden cardiac arrest induced by ERS. Cardiomyocytes were generated from iPSCs from a 14-year-old boy in the four families with ERS and an unrelated healthy control subject. Patch clamp recordings revealed more significant prolongation of the action potential duration (APD) and increased transient outward potassium current (I_to) (103.97 ± 18.73 pA/pF vs 44.36 ± 16.54 pA/pF at +70 mV, P < 0.05) in ERS cardiomyocytes compared with control cardiomyocytes. Of note, the selective correction of the causal variant in iPSC-derived cardiomyocytes using CRISPR/Cas9 gene editing normalized the I_to, whereas prolongation of the APD remained unchanged. ERS cardiomyocytes carrying DPP6 mutation increased I_to and lengthen APD, which maybe lay the electrophysiological foundation of ERS.

早期复极综合征（ERS）被定义为发生在特发性心室颤动中幸存下来的具有早期复极模式的患者，但临床评估无法揭示其他解释。 ERS 的病理生理学基础目前尚不确定。本研究的目的是利用诱导多能干细胞 (iPSC) 和 CRISPR/Cas9 基因组编辑来检查 ERS ​​的电生理机制。全基因组测序用于鉴定 4 个由 ERS ​​引起的心脏骤停家系的 DPP6 (c.2561T > C/p.L854P) 变异。心肌细胞是从四个患有 ERS ​​的家庭中的一名 14 岁男孩和一名无关的健康对照受试者的 iPSC 中产生的。膜片钳记录显示 ERS ​​中动作电位持续时间 (APD) 更显着延长，瞬态外向钾电流 (I _to ) 增加（+70 mV 时为 103.97 ± 18.73 pA/pF vs 44.36 ± 16.54 pA/pF，P < 0.05）心肌细胞与对照心肌细胞相比。值得注意的是，使用 CRISPR/Cas9 基因编辑对 iPSC 衍生心肌细胞中的因果变异进行选择性校正，使 I 正常化_为，而 APD 的延长保持不变。携带DPP6突变的ERS心肌细胞It_增加，APD延长，这可能奠定了ERS的电生理学基础。