title: Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative.
abstract: Recent increasing evidence suggests that the currently-used platforms in vitro IKrand APD, and/or in vivo QT assays are not fully predictive for TdP, and do not address potential arrhythmia (VT and/or VF) induced by diverse mechanisms of action. In addition, other cardiac safety liabilities such as functional dysfunction of excitation-contraction coupling (contractility) and structural damage (morphological damage to cardiomyocytes) are also major causes of drug attrition, but current in vitro assays do not cover all these liabilities. We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi; http://csahi.org/en/), based on the Japan Pharmaceutical Manufacturers Association (JPMA), to verify the application of human iPS/ES cell-derived cardiomyocytes in drug safety evaluation. The main goal of the CSAHi HEART team has been to propose comprehensive screening strategies to predict a diverse range of cardiotoxicities by using recently introduced platforms (multi-electrode array (MEA), patch clamp, cellular impedance, motion field imaging [MFI], and Ca transient systems) while identifying the strengths and weaknesses of each. Our study shows that hiPS-CMs used in these platforms have pharmacological responses more relevant to humans in comparison with existent hERG, APD or Langendorff (MAPD/contraction) assays, and not only MEA but also other methods such as impedance, MFI, and Ca transient systems would offer paradigm changes of platforms for predicting drug-induced QT risk and/or arrhythmia or contractile dysfunctions. Furthermore, we propose a potential multi-parametric platform in which field potential (MEA)-Ca transient-contraction (MFI) could be evaluated simultaneously as an ideal novel platform for predicting a diversity of cardiac toxicities, namely whole effects on the excitation-contraction cascade.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan; Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan. Electronic address: takasuna.kiyoshi.a3@daiichisankyo.co.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takasuna
authors.affiliation: Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Discovery Research Labs., Nippon Shinyaku Co., Ltd., Kyoto, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Asakura
authors.affiliation: Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Safety Research Department, ASKA Pharmaceutical Co., Ltd., Kanagawa, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Araki
authors.affiliation: Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Safety Research Laboratories, Ono Pharmaceutical Co., Ltd., Fukui, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ando
authors.affiliation: Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Drug Safety Research Laboratories, Astellas Pharma Inc., Osaka, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kazusa
authors.affiliation: Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Discovery Research, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kitaguchi
authors.affiliation: Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kunimatsu
authors.affiliation: Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Pharmacokinetics and Non-Clinical Safety Dept., Nippon Boehringer Ingelheim Co., Ltd., Hyogo, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Japan Pharmaceutical Manufacturers Association Drug Evaluation Committee, Non-Clinical Evaluation Expert Committee, TF2, Japan; Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Japan; Biopharmaceutical Assessments Core Function Unit Medicine Development Center Eisai Co., Ltd., Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Miyamoto
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D066126:Cardiotoxicity; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000502:physiology; D008839:Microelectrodes; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D004364:Pharmaceutical Preparations / Q000008:administration & dosage
chemical_list: D004364:Pharmaceutical Preparations
keywords: CSAHi; Ca transient; Cardiac liability; Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs); Impedance; Motion field imaging; Multi-electrode arrays; Multi-parametric; Simulation; Stem cell