Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen-Tawil syndrome-iPS cell-derived cardiomyocytes.
Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen-Tawil syndrome-iPS cell-derived cardiomyocytes.
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DOI：
10.1016/j.bbrep.2017.01.002
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发表时间：
2017-03
影响因子：
2.7
通讯作者：
Fukuda K
中科院分区：
文献类型：
--
作者：
Kuroda Y;Yuasa S;Watanabe Y;Ito S;Egashira T;Seki T;Hattori T;Ohno S;Kodaira M;Suzuki T;Hashimoto H;Okata S;Tanaka A;Aizawa Y;Murata M;Aiba T;Makita N;Furukawa T;Shimizu W;Kodama I;Ogawa S;Kokubun N;Horigome H;Horie M;Kamiya K;Fukuda K
安德森-塔维尔综合征 (ATS) 是一种罕见的遗传性离子通道病。 ATS 的心脏表型以突出的 U 波和室性心律失常为典型。这种疾病的有效治疗方法仍有待建立。我们对三名 ATS 患者的体细胞进行了重新编程，以产生诱导多能干细胞 (iPSC)。使用多电极阵列 (MEA) 记录 iPSC 来源的心肌细胞的细胞外电图，揭示 ATS-iPSC 来源的心肌细胞中强烈的心律失常事件。装载 Ca2+ 指示剂 Fluo-4 的细胞的 Ca2+ 成像使我们能够检查细胞内 Ca2+ 处理特性，我们发现 ATS-iPSC 衍生的心肌细胞中不规则 Ca2+ 释放的发生率明显高于对照 iPSC 衍生的心肌细胞。使用 ATS-iPSC 来源的心肌细胞进行的药物测试进一步表明，抗心律失常药物氟卡尼（而非钠通道阻滞剂匹西卡尼）显着抑制这些不规则的 Ca2+ 释放和心律失常事件，表明氟卡尼在这些心肌细胞中的作用并非通过钠通道阻断。还发现反向模式 Na+/Ca2+ 交换器 (NCX) 抑制剂 KB-R7943 可以抑制不规则的 Ca2+ 释放，离体豚鼠心室肌细胞的全细胞电压钳证实氟卡尼可以直接影响 NCX 电流 (INCX)。 ATS-iPSC 衍生的心肌细胞再现了异常的电生理表型，氟卡尼通过 INCX 的调节抑制心律失常事件。 iPS 细胞由三名 ATS 患者产生。 ATS-iPS 细胞来源的心肌细胞表现出异常的电生理表型。 Flecainide 抑制 ATS-iPS 细胞衍生的心肌细胞中异常的电生理表型。
Andersen-Tawil syndrome (ATS) is a rare inherited channelopathy. The cardiac phenotype in ATS is typified by a prominent U wave and ventricular arrhythmia. An effective treatment for this disease remains to be established. We reprogrammed somatic cells from three ATS patients to generate induced pluripotent stem cells (iPSCs). Multi-electrode arrays (MEAs) were used to record extracellular electrograms of iPSC-derived cardiomyocytes, revealing strong arrhythmic events in the ATS-iPSC-derived cardiomyocytes. Ca2+ imaging of cells loaded with the Ca2+ indicator Fluo-4 enabled us to examine intracellular Ca2+ handling properties, and we found a significantly higher incidence of irregular Ca2+ release in the ATS-iPSC-derived cardiomyocytes than in control-iPSC-derived cardiomyocytes. Drug testing using ATS-iPSC-derived cardiomyocytes further revealed that antiarrhythmic agent, flecainide, but not the sodium channel blocker, pilsicainide, significantly suppressed these irregular Ca2+ release and arrhythmic events, suggesting that flecainide's effect in these cardiac cells was not via sodium channels blocking. A reverse-mode Na+/Ca2+exchanger (NCX) inhibitor, KB-R7943, was also found to suppress the irregular Ca2+ release, and whole-cell voltage clamping of isolated guinea-pig cardiac ventricular myocytes confirmed that flecainide could directly affect the NCX current (INCX). ATS-iPSC-derived cardiomyocytes recapitulate abnormal electrophysiological phenotypes and flecainide suppresses the arrhythmic events through the modulation of INCX. iPS cells are generated from three patients with ATS. ATS-iPS cell-derived cardiomyocytes show abnormal electrophysiological phenotypes. Flecainide suppresses abnormal electrophysiological phenotypes in ATS-iPS cell-derived cardiomyocytes.