title: Electrophysiological Characteristics of Human iPSC-Derived Cardiomyocytes for the Assessment of Drug-Induced Proarrhythmic Potential.
abstract: 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.
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Teijin Pharma Limited, Asahigaoka, Hino-shi, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yamamoto
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Japanese Safety Pharmacology Society (JSPS), Showa-machi, Maebashi, Gunma, Japan.|Nippon Shinyaku Co., Ltd., Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Asakura
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Japanese Safety Pharmacology Society (JSPS), Showa-machi, Maebashi, Gunma, Japan.|Ono Pharmaceutical Co., Ltd., Yamagishi, Mikuni-cho, Sakai-shi, Fukui, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ando
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Eisai Co., Ltd., Tokodai, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Eisai Co., Ltd., Tokodai, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ojima
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Ono Pharmaceutical Co., Ltd., Yamagishi, Mikuni-cho, Sakai-shi, Fukui, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Uda
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Japanese Safety Pharmacology Society (JSPS), Showa-machi, Maebashi, Gunma, Japan.|LSI Medience Corporation, Uchikanda 1-chome, Chiyoda-ku, Tokyo, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Osada
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Japanese Safety Pharmacology Society (JSPS), Showa-machi, Maebashi, Gunma, Japan.|Nippon Shinyaku Co., Ltd., Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Japanese Safety Pharmacology Society (JSPS), Showa-machi, Maebashi, Gunma, Japan.|Astellas Pharma Inc., Miyukigaoka, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Kasai
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Eisai Co., Ltd., Tokodai, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Miyamoto
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Japanese Safety Pharmacology Society (JSPS), Showa-machi, Maebashi, Gunma, Japan.|Ina Research Inc., Nishiminowa, Ina-shi, Nagano, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tashibu
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Japanese Safety Pharmacology Society (JSPS), Showa-machi, Maebashi, Gunma, Japan.|Eisai Co., Ltd., Tokodai, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshinaga
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|National Institute of Health Sciences (NIHS), Kamiyoga, Setagaya-ku, Tokyo, Japan.
authors.forename: Daiju
authors.initials: D
authors.lastname: Yamazaki
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Japanese Safety Pharmacology Society (JSPS), Showa-machi, Maebashi, Gunma, Japan.|Department of Pharmacology, Faculty of Medicine, Toho University, Omori-Nishi, Ota-ku, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|National Institute of Health Sciences (NIHS), Kamiyoga, Setagaya-ku, Tokyo, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Kanda
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Japanese Safety Pharmacology Society (JSPS), Showa-machi, Maebashi, Gunma, Japan.|Eisai Co., Ltd., Tokodai, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sawada
authors.affiliation: Japan iPS Cardiac Safety Assessment (JiCSA), Kamiyoga, Setagaya-ku, Tokyo, Japan.|Japanese Safety Pharmacology Society (JSPS), Showa-machi, Maebashi, Gunma, Japan.|National Institute of Health Sciences (NIHS), Kamiyoga, Setagaya-ku, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekino
mesh_terms: D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D020117:Cisapride / Q000494:pharmacology*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016014:Linear Models; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000166:cytology*; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D002839:Chromans; D010880:Piperidines; D011725:Pyridines; D013449:Sulfonamides; C063968:E 4031; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D020117:Cisapride