Validating the Arrhythmogenic Potential of High-, Intermediate-, and Low-Risk Drugs in a Human-Induced Pluripotent Stem Cell-Derived Cardiac Microphysiological System

Abstract

Evaluation of arrhythmogenic drugs is required by regulatory agencies before any new compound can obtain market approval. Despite rigorous review, cardiac disorders remain the second most common cause for safety-related market withdrawal. On the other hand, false-positive preclinical findings prohibit potentially beneficial candidates from moving forward in the development pipeline. Complex in vitro models using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CM) have been identified as a useful tool that allows for rapid and cost-efficient screening of proarrhythmic drug risk. Currently available hiPSC-CM models employ simple two-dimensional (2D) culture formats with limited structural and functional relevance to the human heart muscle. Here, we present the use of our 3D cardiac microphysiological system (MPS), composed of a hiPSC-derived heart micromuscle, as a platform for arrhythmia risk assessment. We employed two different hiPSC lines and tested seven drugs with known ion channel effects and known clinical risk: dofetilide and bepridil (high risk); amiodarone and terfenadine (intermediate risk); and nifedipine, mexiletine, and lidocaine (low risk). The cardiac MPS successfully predicted drug cardiotoxicity risks based on changes in action potential duration, beat waveform (i.e., shape), and occurrence of proarrhythmic events of healthy patient hiPSC lines in the absence of risk cofactors. We showcase examples where the cardiac MPS outperformed existing hiPSC-CM 2D models.

The simplified Kirchhoff network model (SKNM): a cell-based reaction–diffusion model of excitable tissue

“…Several mathematical models have been developed to describe the action potential of hiPSC-CMs, see, e.g., Kernik et al 57 , Paci et al 58 , and Jæger et al 58 , 59 Additionally, the issue of modeling hiPSC-CMs as interconnected tissue has been addressed using the BD framework 6 , 60 , 61 . Within an MPS, the quantity of cardiomyocytes is typically relatively modest, ranging from thousands to millions 52 , 55 , 62 . The task of simulating these cells aligns well with the capabilities of KNM and SKNM.…”

Predicting individual-specific cardiotoxicity responses induced by tyrosine kinase inhibitors

“…An important improvement that needs to be made in this area, however, is the more widespread adoption of engineered cell culture systems exhibiting a reproducible and mature phenotype, as drug responses in these systems are more likely to mimic those seen in adult patients. Efforts to improve maturity of the cellular system ( Charwat et al, 2022 ; Huebsch et al, 2022 ) can be combined with computational approaches to translate drug responses across cells with different properties ( Gong and Sobie, 2018 ; Tveito et al, 2018 ; Jaeger et al, 2019 ), thereby providing additional confidence in the results.…”

Do calcium channel blockers applied to cardiomyocytes cause increased channel expression resulting in reduced efficacy?

“…Cardiac microtissues were generated based on a refined version of our previously published cardiac microtissue platform [17, 18]. In brief, microtissues were created in 384 well plates (206384; GraceBioLabs) with custom substrates (COC TPE E140; Stratec) featuring 4 tissue formation chambers per well (1400x200x150 μ m length×width×depth) using 35000 iPSC-derived cardiomyocytes (C1056; Fujifilm CDI) per well.…”