Current cardiac safety assessment platforms (in vitro hERG-centric, APD, and/or in vivo animal
QT assays) are not fully predictive of drug-induced Torsades de Pointes (TdP) and do not address
other mechanism-based arrhythmia, including ventricular tachycardia or ventricular fibrillation, or cardiac
safety liabilities such as contractile and structural cardiotoxicity which are another growing safety
concerns. We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi;
http://csahi.org/en/) in 2013, based on the Japan Pharmaceutical Manufacturers Association (JPMA), to
verify the application of human iPS/ES cell-derived cardiomyocytes for drug safety evaluation. The
CSAHi HEART team focused on comprehensive screening strategies to predict a diverse range of cardiotoxicities
using recently introduced platforms such as the Multi-Electrode Array (MEA), cellular
impedance, Motion Field Imaging (MFI), and optical imaging of Ca transient to identify strengths and
weaknesses of each platform. Our study showed that hiPS-CMs used in these platforms could detect
pharmacological responses that were more relevant to humans compared to existing hERG, APD, or
Langendorff (MAPD/contraction) assays. Further, MEA and other methods such as impedance, MFI,
and Ca transient assays provided paradigm changes of platforms for predicting drug-induced QT risk
and/or arrhythmia or contractile dysfunctions. In contrast, since discordances such as overestimation
(false positive) of arrhythmogenicity, oversight, or opposite conclusions in positive inotropic and negative
chronotropic activities to some compounds were also confirmed, possibly due to their functional
immaturity of hiPS-CMs, hiPS-CMs should be used in these platforms for cardiac safety assessment
based upon their advantages and disadvantages.
Cardiac safety assessment with motion field imaging analysis of human iPS cell-derived cardiomyocytes is improved by an integrated evaluation with cardiac ion channel profiling