Biology subjects

Slotvitsky, M.

Publications and source records attributed to Slotvitsky, M..

3 recordsLinked to original sources

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↗

bioRxiv2023

Human sodium current voltage-dependence at physiological temperature measured by coupling patch-clamp experiment to a mathematical model.

Voltage-gated sodium channels are crucial to action potential propagation in excitable tissues. Voltage-clamp measurements of sodium current are very challenging and are usually performed at room temperature due to the high amplitude and fast activation of the current. In this study, we measured sodium currents voltage dependence in stem-cell-derived cardiomyocytes at physiological temperature. Although apparent activation and inactivation curves measured as the sodium current amplitude dependence on voltage step is within the range reported in previous studies, we demonstrate a systematic error in our measurements that is due to deviation of membrane potential from the command potential of the amplifier. We show how this artifact can be accounted for by the computer simulation of the patch-clamp experiment. This patch-clamp model optimization technique yields a surprising result: -11.5 mV half-activation and -87 mV half-inactivation of the sodium current. Although the half-activation is strikingly different from what was previously believed to be typical for the cardiac sodium current, we show that this estimate explains conduction velocity dependence on extracellular potassium in hyperkalemic conditions. Key pointsO_LIVoltage gated sodium currents play a crucial role in excitable tissues including neurons, cardiac and skeletal muscles. C_LIO_LIMeasurement of sodium current is challenging because of its high amplitude and rapid kinetics, especially at physiological temperature. C_LIO_LIWe have used the patch-clamp technique to measure human sodium current voltage-dependence in human induced pluripotent stem cell-derived cardiomyocytes. C_LIO_LIThe patch-clamp data was processed by optimization of the model accounting for voltage-clamp experiment artifacts, revealing a large difference between apparent parameters of sodium current and the results of the optimization. C_LIO_LIWe conclude that actual sodium current activation is extremely depolarized in comparison to previous studies. C_LIO_LIThe new sodium current model provides a better understanding of action potential propagation, we demonstrate that it explains propagation in hyperkalemic conditions. C_LI

biophysics↗

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↗