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Modeling Short QT Syndrome Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
背景
短QT综合征（SQTS）是一种与特征性心电图QT段缩短相关的病症，易使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，但由于缺乏合适的人类细胞模型的紊乱，对人类细胞表型的理解和发现最佳疗法已经滞后。这项研究的目的是使用人类诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）建立SQTS细胞模型。
方 法
本研究招募了1例携带KCNH2中的突变(N588K)基因的短型QT综合征1型的病人，在KCNH2以及2个健康对照受试者。我们从他们的皮肤成纤维细胞诱导产生hiPSC，并将hiPSC分化成心肌细胞（hiPSC-CM）进行生理学和药理学研究。
结 果
与健康对照hiPSC-CM相比，来自患者的hiPSC-CM显示出增大的快速激活延迟整流钾通道电流（IKr）密度和缩短的动作电位持续时间。此外，他们表现出钙瞬变和节律活动异常。卡巴胆碱可增加SQTS的心律失常事件，但不能增加对照组细胞的心律失常事件。基因和蛋白质表达谱显示SQTS细胞中KCNH2表达增加。奎尼丁但不是索他洛尔或美托洛尔延长动作电位持续时间并消除由卡巴胆碱诱导的心律失常活性。
结 论
患者特异性hiPSC-CM能够重述SQTS的单细胞表型特征并提供新的机会来进一步阐明细胞疾病机制和测试药物的影响。
原始文献摘要
BACKGROUND: 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).
METHODS AND RESULTS: 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 (IKr) 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.
CONCLUSIONS: 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..
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