Electrophysiological Characteristics of Human iPSC-Derived Cardiomyocytes for the Assessment of Drug-Induced Proarrhythmic Potential
Electrophysiological Characteristics of Human iPSC-Derived Cardiomyocytes for the Assessment of Drug-Induced Proarrhythmic Potential
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人 iPSC 来源的心肌细胞的电生理特征用于评估药物诱导的致心律失常电位
作者：
Wataru R. Yamamoto;K. Asakura;Hiroyuki Ando;Tomohiko Taniguchi;Atsuko Ojima;Takaaki Uda;Tomoharu Osada;S. Hayashi;Chieko Kasai;N. Miyamoto;Hiroyuki Tashibu;T. Yoshinaga;D. Yamazaki;A. Sugiyama;Y. Kanda;K. Sawada;Y. Sekino
本研究的目的是(1)确定与QT-RR关系等临床特征相对应的人诱导多能干细胞来源的心肌细胞(HiPSC-CMS)的基本电生理成分；(2)确定QT校正和分析方法的适用性；(3)确定这些体外参数是否以及如何用于尖端扭矩(TDP)等药物不良反应的风险评估。使用在记录溶液中带有和不带有离子通道拮抗剂的多电极阵列(MEA)平台，从商用的HiPSC-CMS获得场电位记录。在对照条件下，MEA测量的间期和场电位时程(FPD)分别在1049到1635毫秒和334到527毫秒之间变化，并提供了与正在进行的基于心血管的弗雷明翰心脏研究中的人类心电分析获得的自然QT-RR曲线图相似的正线性回归系数。与最小化心率对QT间期的影响类似，Fridericia和Bazett的校正减少了心率对HiPSC-CM FPD的影响。在快速延迟整流钾电流的阻断剂E-4031和西沙必利存在下，HiPSC-CMS表现出反向使用依赖性的FPD延长。分类分析通常应用于临床QT研究，适用于HiPSC-CMS，用于评估合并FPD和/或校正FPD的生殖器致病风险。综上所述，这项研究的结果将HiPSC-CM电生理终点与自然心电图终点联系起来，证明了临床分析实践应用于HiPSC-CMS的适当性，并表明HiPSC-CMS是评估候选药物在人类体内引发心律失常潜力的可靠模型。
The aims of this study were to (1) characterize basic electrophysiological elements of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that correspond to clinical properties such as QT-RR relationship, (2) determine the applicability of QT correction and analysis methods, and (3) determine if and how these in-vitro parameters could be used in risk assessment for adverse drug-induced effects such as Torsades de pointes (TdP). Field potential recordings were obtained from commercially available hiPSC-CMs using multi-electrode array (MEA) platform with and without ion channel antagonists in the recording solution. Under control conditions, MEA-measured interspike interval and field potential duration (FPD) ranged widely from 1049 to 1635 ms and from 334 to 527 ms, respectively and provided positive linear regression coefficients similar to native QT-RR plots obtained from human electrocardiogram (ECG) analyses in the ongoing cardiovascular-based Framingham Heart Study. Similar to minimizing the effect of heart rate on the QT interval, Fridericia’s and Bazett’s corrections reduced the influence of beat rate on hiPSC-CM FPD. In the presence of E-4031 and cisapride, inhibitors of the rapid delayed rectifier potassium current, hiPSC-CMs showed reverse use-dependent FPD prolongation. Categorical analysis, which is usually applied to clinical QT studies, was applicable to hiPSC-CMs for evaluating torsadogenic risks with FPD and/or corrected FPD. Together, this results of this study links hiPSC-CM electrophysiological endpoints to native ECG endpoints, demonstrates the appropriateness of clinical analytical practices as applied to hiPSC-CMs, and suggests that hiPSC-CMs are a reliable models for assessing the arrhythmogenic potential of drug candidates in human.