Proarrhythmia risk prediction using human induced pluripotent stem cell-derived cardiomyocytes

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to become a useful tool for proarrhythmia risk prediction in the non-clinical drug development phase. Several features including electrophysiological properties, ion channel expression profile and drug responses were investigated using commercially available hiPSC-CMs, such as iCell-CMs and Cor.4U-CMs. Although drug-induced arrhythmia has been extensively examined by microelectrode array (MEA) assays in iCell-CMs, it has not been fully understood an availability of Cor.4U-CMs for proarrhythmia risk. Here, we evaluated the predictivity of proarrhythmia risk using Cor.4U-CMs. MEA assay revealed linear regression between inter-spike interval and field potential duration (FPD). The hERG inhibitor E-4031 induced reverse-use dependent FPD prolongation. We next evaluated the proarrhythmia risk prediction by a two-dimensional map, which we have previously proposed. We determined the relative torsade de pointes risk score, based on the extent of FPD with Fridericia's correction (FPDcF) change and early afterdepolarization occurrence, and calculated the margins normalized to free effective therapeutic plasma concentrations. The drugs were classified into three risk groups using the two-dimensional map. This risk-categorization system showed high concordance with the torsadogenic information obtained by a public database CredibleMeds. Taken together, these results indicate that Cor.4U-CMs can be used for drug-induced proarrhythmia risk prediction.

Development of a Human iPSC Cardiomyocyte-Based Scoring System for Cardiac Hazard Identification in Early Drug Safety De-risking

“…The scoring system can be applied not only to various calcium-imaging-based assays but also to different detection technologies and experimental models. Using the same principal (i.e., design of the scoring matrix and the hazard labeling), the scoring system could be developed for technologies based on multi-electrode arrays (Yamazaki et al., 2018), voltage-sensitive dyes (Blinova et al., 2017, Lu et al., 2017), impedance (Zhang et al., 2016), and video motion imaging (Kopljar et al., 2017) to comprehensively account (indirectly) for APD-like parameters as well as other pharmacological responses such as BR, beat stop, and EAD-like events. Similarly, different cardiomyocyte models (primary or stem cell-derived) can be used.…”

Intensive care for human hearts in pluripotent stem cell models

“…Two further initiatives with hPSC-CMs for safety pharmacology are the Japan iPS Cardiac Safety Assessment (JiCSA) 46,47 and the CRACK IT InPulse Challenge [48][49][50] . Key lessons from JiCSA, which likewise is focused on arrhythmic risk, have included fidelity of the relationship between MEA-measured field potential duration and interspike interval in hPSC-CMs to the QT-RR relation deduced from clinical electrocardiograms in the Framingham Heart Study 46 .…”

“…Two further initiatives with hPSC-CMs for safety pharmacology are the Japan iPS Cardiac Safety Assessment (JiCSA) 46,47 and the CRACK IT InPulse Challenge [48][49][50] . Key lessons from JiCSA, which likewise is focused on arrhythmic risk, have included fidelity of the relationship between MEA-measured field potential duration and interspike interval in hPSC-CMs to the QT-RR relation deduced from clinical electrocardiograms in the Framingham Heart Study 46 . Human-relevant characteristics included repolarization delay at slow beating rates, reverse use-dependency, categorical analyses as potential indices of risk, and a threshold field potential duration that predicts early afterdepolarizations (EADs) and triggered activity, useful as a potential marker of risk for the onset of human Torsade de pointes 46 .…”

“…Key lessons from JiCSA, which likewise is focused on arrhythmic risk, have included fidelity of the relationship between MEA-measured field potential duration and interspike interval in hPSC-CMs to the QT-RR relation deduced from clinical electrocardiograms in the Framingham Heart Study 46 . Human-relevant characteristics included repolarization delay at slow beating rates, reverse use-dependency, categorical analyses as potential indices of risk, and a threshold field potential duration that predicts early afterdepolarizations (EADs) and triggered activity, useful as a potential marker of risk for the onset of human Torsade de pointes 46 . A subsequent large-scale validation study of 60 compounds' torsadogenic risk markedly expanded the conclusions available from CiPA 32 , though not yet in blinded fashion.…”

A greedy classifier optimization strategy to assess ion channel blocking activity and pro-arrhythmia in hiPSC-cardiomyocytes

“…The Comprehensive in vitro Proarrhythmia Assay (CiPA) is an initiative for a new paradigm in safety pharmacology to redefine the non-clinical evaluation of Torsade de Pointes (TdP) [ 1 – 3 ].…”