Agladze, K. | Search bioRxiv

bioRxiv2024

Advanced Cardiovascular Toxicity Screening: Integrating Human iPSC-Derived Cardiomyocytes with In Silico Models

The pharmaceutical industry is evolving with the use of hiPSC-derived cardiomyocytes (hiPSC-CM) for in vitro cardiac safety screening. Traditional reliance on QT interval prolongation as a main cardiotoxicity marker is being challenged. In addition, Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative recommends using computer modeling and in silico platforms as more comprehensive approach for cardiotoxicity testing in conjunction with hiPSC-CM in vitro screening. Our study presents such an innovative platform that integrates in vitro hiPSC-CM propagation test with in silico models to assess cardiotoxicity. Utilizing the electrophysiological and morphological characteristics of hiPSC-CM, we offer a thorough evaluation of potential drug-induced cardiac risks by computer modelling. We show, using the example of lidocaine and other antiarrhythmics, that using a integrative experimental and computer platform, the possibility to correctly display the clinical manifestations of side effects in advance.

pharmacology and toxicology↗

bioRxiv2019

The Use of iPSC-Derived Cardiomyocytes and Optical Mapping for Erythromycin Arrhythmogenicity Testing

Erythromycin is an antibiotic that prolongs the QT-interval and causes Torsade de Pointes (TdP) by blocking the rapid delayed rectifying potassium current (IKr) without affecting either the slow delayed rectifying potassium current (IKs) or inward rectifying potassium current (IK1). Erythromycin exerts this effect in the range of 1.5 M-100 M. However, the mechanism of action underlying its cardiotoxic effect and its role in the induction of arrhythmias, especially in multicellular cardiac experimental models, remain unclear. In this study the re-entry formation, conduction velocity, and maximum capture rate were investigated in a monolayer of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a healthy donor and in a neonatal rat ventricular myocyte (NRVM) monolayer using the optical mapping method under erythromycin concentrations of 15, 30, and 45 M. In the monolayer of human iPSC-derived cardiomyocytes, the conduction velocity (CV) varied up to 12{+/-}9% at concentrations of 15-45 M as compared with that of the control, whereas the maximum capture rate (MCR) declined substantially up to 28{+/-}12% (p < 0.05). In contrast, the tests on the NRVM monolayer showed no significant effect on the MCR. The results of the arrhythmogenicity test provided evidence for a \"window\" of concentrations of the drug (15 to 30 M) at which the probability of re-entry increased.

biophysics↗