Modeling Short QT Syndrome Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
Modeling Short QT Syndrome Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
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DOI：
10.1161/jaha.117.007394
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发表时间：
2018-03-24
影响因子：
5.4
通讯作者：
Akin I
中科院分区：
文献类型：
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作者：
El-Battrawy I;Lan H;Cyganek L;Zhao Z;Li X;Buljubasic F;Lang S;Yücel G;Sattler K;Zimmermann WH;Utikal J;Wieland T;Ravens U;Borggrefe M;Zhou XB;Akin I
短QT综合征（SQTS）是一种与特征性ECG QT段缩短相关的疾病，易使受影响的患者发生心源性猝死。尽管在评估器官水平的病理生理学和疾病的遗传变化方面取得了一些进展，但由于缺乏适当的人类细胞模型，对人类细胞表型的理解和发现最佳治疗方法已经滞后。本研究的目的是使用人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）建立SQTS的细胞模型。本研究招募了1例携带KCNH 2突变（N588 K）的1型短QT综合征患者以及2例健康对照受试者。我们从他们的皮肤成纤维细胞中产生hiPSC，并将hiPSC分化为心肌细胞（hiPSC-CM）用于生理和药理学研究。与健康对照hiPSC-CM相比，患者的hiPSC-CM显示出快速激活延迟整流钾通道电流（IK r）密度增加和动作电位时程缩短。此外，他们表现出异常的钙瞬变和节律性活动。卡巴胆碱增加SQTS细胞的细胞毒事件，但不增加对照细胞的细胞毒事件。基因和蛋白表达谱显示SQTS细胞中KCNH 2表达增加。奎尼丁延长动作电位时程，消除卡巴胆碱引起的兴奋性活动，而索他洛尔或美托洛尔则无此作用。患者特异性hiPSC-CM能够概括SQTS的单细胞表型特征，并为进一步阐明细胞疾病机制和测试药物作用提供新的机会。
Short QT syndrome (SQTS), a disorder associated with characteristic ECG QT‐segment abbreviation, predisposes affected patients to sudden cardiac death. Despite some progress in assessing the organ‐level pathophysiology and genetic changes of the disorder, the understanding of the human cellular phenotype and discovering of an optimal therapy has lagged because of a lack of appropriate human cellular models of the disorder. The objective of this study was to establish a cellular model of SQTS using human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs). This study recruited 1 patient with short QT syndrome type 1 carrying a mutation (N588K) in KCNH2 as well as 2 healthy control subjects. We generated hiPSCs from their skin fibroblasts, and differentiated hiPSCs into cardiomyocytes (hiPSC‐CMs) for physiological and pharmacological studies. The hiPSC‐CMs from the patient showed increased rapidly activating delayed rectifier potassium channel current (IK r) density and shortened action potential duration compared with healthy control hiPSC‐CMs. Furthermore, they demonstrated abnormal calcium transients and rhythmic activities. Carbachol increased the arrhythmic events in SQTS but not in control cells. Gene and protein expression profiling showed increased KCNH2 expression in SQTS cells. Quinidine but not sotalol or metoprolol prolonged the action potential duration and abolished arrhythmic activity induced by carbachol. Patient‐specific hiPSC‐CMs are able to recapitulate single‐cell phenotype features of SQTS and provide novel opportunities to further elucidate the cellular disease mechanism and test drug effects.