Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance
Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance
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DOI：
10.2131/jts.42.183
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发表时间：
2017-04-01
影响因子：
2
通讯作者：
Sugiyama, Atsushi
中科院分区：
文献类型：
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作者：
Izumi-Nakaseko, Hiroko;Nakamura, Yuji;Sugiyama, Atsushi
为了表征人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）片作为检测药物诱导的传导障碍的模型，我们研究了其电生理和电药理学特性，通过使用多电极阵列系统与编程电刺激协议。在药物前控制下，在周期长度为1，000毫秒时，传导速度、有效不应期和场电位持续时间分别为0.14 +/- 0.01 m/秒、453 +/- 10毫秒和361 +/- 9毫秒（n = 18）。将起搏周期长度从1，000 msec缩短至600 msec可降低传导速度和场电位持续时间，但延长有效不应期。丙吡胺、利多卡因和非卡胺降低传导速度，延长有效不应期和场电位时程，而维拉帕米则相反。因此，细胞片层的传导性质可能在很大程度上取决于Na+通道可用性的程度，如在人心室中的情况。重要的是，在Na+通道阻滞剂治疗后，传导延迟和第1（st）峰电位振幅降低之间没有关系。这些发现可能为未来应用这项新技术进行新化学实体的早期安全药理学筛选提供重要指导。
In order to characterize human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets as a model for detecting drug-induced conduction disturbance, we examined their electrophysiological and electropharmacological properties by using the multi-electrode array system with a programmed electrical stimulation protocol. At pre-drug control, the conduction speed, effective refractory period and field potential duration were 0.14 +/- 0.01 m/sec, 453 +/- 10 msec and 361 +/- 9 msec, respectively at a cycle length of 1,000 msec (n = 18). Shortening the pacing cycle length from 1,000 to 600 msec decreased the conduction speed and field potential duration, but prolonged the effective refractory period. Disopyramide, lidocaine and fiecainide decreased the conduction speed but prolonged the effective refractory period and field potential duration, whereas the reverse was true for verapamil. Thus, conduction properties of the cell sheet may largely depend on the extent of Na+ channel availability as is the case in the human ventricle. Importantly, there was no relationship between the conduction delay and 1(st) spike amplitude reduction after the treatment of Na+ channel blockers. These findings may provide crucial guide on future application of this new technology for early phase safety pharmacological screening of new chemical entities.