Electrical dysfunctions in human-induced pluripotent stemcell-derived cardiomyocytes from a patient with an arrhythmogenic right ventricular cardiomyopathy
Electrical dysfunctions in human-induced pluripotent stemcell-derived cardiomyocytes from a patient with an arrhythmogenic right ventricular cardiomyopathy
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DOI：
10.1093/europace/euy042
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发表时间：
2018-06-01
期刊：
影响因子：
6.1
通讯作者：
Akin, Ibrahim
中科院分区：
文献类型：
--
作者：
El-Battrawy, Ibrahim;Zhao, Zhihan;Akin, Ibrahim
目的我们的目的是研究促发性右心室心肌病（ARVC）患者的促发机制，通过使用人诱导的多能干细胞衍生的心肌细胞（hiPSC-CMs）。方法和结果人诱导的多能干细胞衍生的心肌细胞从两个健康供体的人皮肤成纤维细胞和一个ARVC患者与桥粒芯蛋白-2（DSG 2）突变。采用膜片钳、定量聚合酶链反应和钙离子成像技术进行研究。ARVC细胞动作电位（AP）的幅度和最大上升速度（Vmax）均小于健康供体细胞，而静息电位和AP时程（APD）无明显变化。降低的V-max由降低的峰值钠电流引起。APD未检测到变化的原因可能是减少的瞬时外向、小电导Ca 2+激活的、三磷酸腺苷敏感的Na/Ca交换器（I-NCX）电流和增强的快速延迟整流电流的反作用。异丙肾上腺素（Iso）减少了供体和ARVC-hiPSC-CM中的I-NCX并缩短了APD。然而，Iso在ARVC细胞中的作用明显大于供体细胞。结论携带DSG 2基因突变的ARVC患者心肌细胞存在多种离子通道功能障碍和细胞电生理异常，对肾上腺素能刺激的敏感性增强。这些可能是ARVC患者的血管生成的基础。
Aims Our aim is to investigate the arrhythmogenic mechanism in arrhythmogenic right ventricular cardiomyopathy (ARVC)-patients by using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).Methods and results Human-induced pluripotent stem cell-derived cardiomyocytes were generated from human skin fibroblasts of two healthy donors and an ARVC-patient with a desmoglein-2 (DSG2) mutation. Patch clamp, quantitative polymerase chain reaction, and calcium imaging techniques were employed for the study. The amplitude and maximal upstroke velocity (V-max) of action potential (AP) in ARVC-cells were smaller than that in healthy donor cells, whereas the resting potential and AP duration (APD) was not changed. The reduced V-max resulted from decreased peak sodium current. The reason for undetected changes in APD may be the counter-action of reduced transient outward, small conductance Ca2+-activated, adenosine triphosphate-sensitive, Na/Ca exchanger (I-NCX) currents, and enhanced rapidly delayed rectifier currents. Isoprenaline (Iso) reduced I-NCX and shortened APD in both donor and ARVC-hiPSC-CMs. However, the effects of Iso in ARVC-cells are significantly larger than that in donor cells. In addition, ARVC-hiPSC-CMs showed more frequently than donor cells arrhythmogenic events induced by adrenergic stimulation.Conclusion Cardiomyocytes derived from the ARVC patient with a DSG2 mutation displayed multiple ion channel dysfunctions and abnormal cellular electrophysiology as well as enhanced sensitivity to adrenergic stimulation. These may underlie the arrhythmogenesis in ARVC patients.