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

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising new approach for in vitro proarrhythmic cardiotoxicity assessment. However, variation due to differentiation batch, individual sample variation, and non-linear responses to test drugs complicate prediction of proarrhythmic drug concentrations. This study combines a computational human action potential (AP) model of hERG channel block with experimental data from three-dimensional hiPSC-CM engineered microtissues to optimize point of departure (POD) estimation of drug-induced prolongation of AP duration (APD). Computer simulations predicted that APD prolongation from hERG block follows a logistic curve and that >81% hERG block induced early afterdepolarizations (EADs) which significantly shifted the APD response curve. Curve fitting of APD response by logistic, bilinear breakpoint, and maximal curvature was more accurate prior to EAD onset. Goodness-of-fit testing indicated that logistic regression w..., , # Computationally-informed point of departure evaluation for proarrhythmic cardiotoxicity assessment using 3D engineered cardiac microtissues from human iPSC-derived cardiomyocytes

Dataset DOI: [10.5061/dryad.wh70rxx15](10.5061/dryad.wh70rxx15)

## Description of the data and file structure

POD calculation and plotting from the human AP (ToRORd) population simulation data (APD90 or APDtriangulation) or experimental data

#### Simulation to generate data in simulation files:

The simulation was run with the Tomek et al. (PMID: 31868580) human action potential model. hERG block was represented as a gradient of IKr conductance from 100% to 0% (100 cells along the x axis), and cell population variability was represented by normally distributed random variation of INa, ICa, IKr, and IKs conductances (± 20%) (200 cells along the y axis). APD90 or APDtri were calculated for each cell in the matrix (see data files below).

## Data Files:

**Simulation data**

*Simul-population-APD90-vs-hERGbl...,