UNIVERSITY OF BUCHAREST
FACULTY OF PHYSICS

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2022-07-01 17:17

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Conference: Bucharest University Faculty of Physics 2019 Meeting


Section: Biophysics; Medical Physics


Title:
Analysis of proarrhythmogenic risk predictors using advanced cardiomyocyte electrophysiology models combined with experimental pharmacology data on human cardiac ion channels in heterologous expression systems and induced pluripotent stem cell-derived cardiomyocytes


Authors:
Bogdan AMUZESCU (1), Pauline LE GOC (2), Razvan AIRINI (1), Florin Bogdan EPUREANU (1), Alexandru Florian DEFTU (1), Antonia Teona DEFTU (1), Beatrice RADU (1), Dan Florin MIHAILESCU (1)


*
Affiliation:
1) Dept. Biophysics&Physiology, Faculty of Biology, University of Bucharest,

Romania

2) Université de La Rochelle, France



E-mail
bogdan@biologie.kappa.ro


Keywords:
Cardiac safety pharmacology, comprehensive in vitro proarrhythmia assay (CiPA), cardiomyocyte, action potential (AP), early afterdepolarization (EAD), patch-clamp, human ether-à-go-go related gene (hERG), Markov model, Hodgkin-Huxley type model, O'Hara-R


Abstract:
Some large-scale in vitro proarrhythmogenic risk assessment studies of drug candidates proposed linear logistic regression models with leave-one-out cross-validation tests (Kramer J. et al. 2013 Sci. Rep. 3:2100; Blinova K. et al. 2018 Cell Rep. 24:3582-92). The comprehensive in vitro pro-arrhythmia assay (CiPA) in silico working group developed a computational assay for proarrhythmogenic risk prediction based on numeric integration runs of the O’Hara-Rudy 2011 human ventricular cardiomyocyte mathematical model (with default parameters for subendocardic cardiomyocytes, type = 0), with a Markov model for hERG channels (human ether-à-go-go related gene) that passes the rapid delayed rectifier K+ current (IKr), the main contributor of ventricular repolarisation (named ORd-IKr dynamic model, Li et al. 2017 Circ. Arrhythm. Electrophysiol. 10(2):e004628). A subsequent study (Dutta et al. 2017 Front. Physiol. 8:616) used the ORd-IKr dynamic model with pharmacological inhibition data for a panel of 12 drugs with low, intermediate, and high proarrhythmogenic risk to assess the effectiveness of multiple proarrhythmogenic risk predictors based on action potential (AP) and intracellular calcium dynamics during AP, as well as the newly defined predictors cQinward and Qnet, concluding that Qnet represents the most reliable predictor. We reproduced these simulations for the 12-compound panel based on published pharmacological inhibition data using the ORd model with default parameters for midmyocardial cardiomyocytes (type = 2). Using the classical (Hodgkin-Huxley-type) IKr model, we found good predictability of EAD development (their detection can be itself a good predictor), while with the Markov IKr model no EADs were detected in the range 1 to 25x Cmax (maximal plasma therapeutic concentration), except for dofetilide. Therefore, we modified the hERG blocking and unblocking rates for cisapride according to our own experimental pharmacology results in whole-cell patch-clamp experiments on HEK293 cells stably transfected with hERG1, applying an onset-of-block kinetics analysis, obtaining direct EAD generation for cisapride with the ORd-IKr dynamic model.


Acknowledgement:
The study was funded from Competitiveness Operational Programme 2014-2020 project P_37_675 (146/2016), Priority Axis 1, Action 1.1.4, co-financed by the European Funds for Regional Development and Romanian Government.