Computationally informed point of departure evaluation for proarrhythmic cardiotoxicity assessment using 3D engineered cardiac microtissues from human iPSC-derived cardiomyocytes

Research Overview

Human iPSC-derived cardiomyocytes are promising for proarrhythmia testing, but batch variation and non-linear drug responses make it hard to pin down the concentration at which risk begins. This study paired a computational human action-potential model of hERG channel block with experimental data from 3D iPSC-cardiomyocyte engineered microtissues to sharpen point-of-departure estimates for action-potential-duration prolongation.

Simulations predicted that APD prolongation follows a logistic curve and that more than 81% hERG block triggers early afterdepolarizations, which markedly shift the response curve. Curve fitting was most accurate before that onset — practical guidance for deriving defensible cardiotoxicity thresholds from 3D microtissue data.