CSAHi study: Detection of drug-induced ion channel/receptor responses, QT prolongation, and arrhythmia using multi-electrode arrays in combination with human induced pluripotent stem cell-derived cardiomyocytes.
BACKGROUND
The use of multi-electrode arrays (MEA) in combination with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provides a promising method to predict comprehensive cardiotoxicity, including drug-induced QT prolongation and arrhythmia. We previously demonstrated that MEA in combination with hiPSC-CMs could provide a generalizable platform by using 7 reference drugs at 10 testing facilities. Using this approach, we evaluated responses to reference drugs that modulate a range of cardiac ion currents and have a range of arrhythmogenic effects.


METHODS
We used the MEA system (MED64) and commercially available hiPSC-CMs (iCell cardiomyocytes) to evaluate drug effects on the beat rate, field potential duration (FPD), FPD corrected by Fridericia's formula (FPDc), and the incidence of arrhythmia-like waveforms.


RESULTS
This assay detected the repolarization effects of Bay K8644, mibefradil, NS1643, levcromakalim, and ouabain; and the chronotropic effects of isoproterenol, ZD7288, and BaCl2. Chronotropy was also affected by K+and Ca2+current modulation. This system detected repolarization delays and the arrhythmogenic effects of quinidine, cisapride, thioridazine, astemizole, bepridil, and pimozide more sensitively than the established guinea pig papillary muscle action potential assay. It also predicted clinical QT prolongation by drugs with multiple ion channel effects (fluoxetine, amiodarone, tolterodine, vanoxerine, alfuzosin, and ranolazine).


CONCLUSIONS
MEA in combination with hiPSC-CMs may provide a powerful method to detect various cardiac electrophysiological effects, QT prolongation, and arrhythmia during drug discovery. However, the data require careful interpretation to predict chronotropic effects and arrhythmogenic effects of candidate drugs with multiple ion channel effects.
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), 2-3-11 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Discovery Research, Mochida Pharmaceutical Co., Ltd., 722, Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan. Electronic address: takashi.kitaguchi@mochida.co.jp.
Takashi
T
Kitaguchi
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Discovery Research, Mochida Pharmaceutical Co., Ltd., 722, Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan.
Yuta
Y
Moriyama
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Biopharmaceutical Assessment Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Tomohiko
T
Taniguchi
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Biopharmaceutical Assessment Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Sanae
S
Maeda
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Safety Research Laboratories, Ono Pharmaceutical Co., Ltd., 50-10, Yamagishi, Mikuni-cho, Sakai-shi, Fukui 913-8538, Japan.
Hiroyuki
H
Ando
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Safety Research Laboratories, Ono Pharmaceutical Co., Ltd., 50-10, Yamagishi, Mikuni-cho, Sakai-shi, Fukui 913-8538, Japan.
Takaaki
T
Uda
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Research Administration Department, Ina Research Inc., 2148-188, Nishiminowa, Ina-shi, Nagano 399-4501, Japan.
Koji
K
Otabe
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Research Administration Department, Ina Research Inc., 2148-188, Nishiminowa, Ina-shi, Nagano 399-4501, Japan.
Masao
M
Oguchi
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Bioresearch Center, CMIC Pharma Science Co., Ltd., 10221, Kobuchisawa-cho, Hokuto-shi, Yamanashi 408-0044, Japan.
Shigekazu
S
Shimizu
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Bioresearch Center, CMIC Pharma Science Co., Ltd., 10221, Kobuchisawa-cho, Hokuto-shi, Yamanashi 408-0044, Japan.
Hiroyuki
H
Saito
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda, Saitama 335-8505, Japan.
Atsushi
A
Toratani
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda, Saitama 335-8505, Japan.
Mahoko
M
Asayama
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Pharmaceutical Development Research Laboratories, Toxicology Research Department, Teijin Pharma Ltd., 4-3-2, Asahigaoka, Hino-shi, Tokyo 191-8512, Japan.
Wataru
W
Yamamoto
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Pharmaceutical Development Research Laboratories, Toxicology Research Department, Teijin Pharma Ltd., 4-3-2, Asahigaoka, Hino-shi, Tokyo 191-8512, Japan.
Emi
E
Matsumoto
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Shiga Laboratory, Nisseibilis Co., Ltd., 555, Ukawa, Minakuchi-cho, Koka, Shiga 528-0052, Japan.
Daisuke
D
Saji
Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Shiga Laboratory, Nisseibilis Co., Ltd., 555, Ukawa, Minakuchi-cho, Koka, Shiga 528-0052, Japan.
Hiroki
H
Ohnaka
Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA), 2-3-11 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi), Japan(1); Biopharmaceutical Assessment Core Function Unit, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Norimasa
N
Miyamoto
D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D054715:Cardiotoxins / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000502:physiology; D007473:Ion Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology
D002316:Cardiotonic Agents; D054715:Cardiotoxins; D007473:Ion Channels
(±)-Bay K8644 (PubChem CID: 2303); BaCl(2) dihydrate (PubChem CID: 5284346); CSAHi; Field potential; Human induced pluripotent stem cell-derived cardiomyocytes; Isoproterenol hydrochloride (PubChem CID: 5807); Levcromakalim (PubChem CID: 93504); Methods; Mibefradil dihydrochloride (PubChem CID: 60662); Multi-electrode array; NS1643 (PubChem CID: 10177784); Ouabain octahydrate (PubChem CID: 122130920); Proarrhythmia; QT prolongation; Torsade de pointes; ZD7288 (PubChem CID: 123983)