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The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes

Background: Populations of in silico electrophysiological models of human cardiomyocytes represent natural variability in cell activity and are thoroughly calibrated and validated using experimental data from the human heart. The models have been shown to predict the effects of drugs and their pro-a...

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Autores principales: Dokuchaev, Arsenii, Kursanov, Alexander, Balakina-Vikulova, Nathalie A., Katsnelson, Leonid B., Solovyova, Olga
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10285544/
https://www.ncbi.nlm.nih.gov/pubmed/37362439
http://dx.doi.org/10.3389/fphys.2023.1187956
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author Dokuchaev, Arsenii
Kursanov, Alexander
Balakina-Vikulova, Nathalie A.
Katsnelson, Leonid B.
Solovyova, Olga
author_facet Dokuchaev, Arsenii
Kursanov, Alexander
Balakina-Vikulova, Nathalie A.
Katsnelson, Leonid B.
Solovyova, Olga
author_sort Dokuchaev, Arsenii
collection PubMed
description Background: Populations of in silico electrophysiological models of human cardiomyocytes represent natural variability in cell activity and are thoroughly calibrated and validated using experimental data from the human heart. The models have been shown to predict the effects of drugs and their pro-arrhythmic risks. However, excitation and contraction are known to be tightly coupled in the myocardium, with mechanical loads and stretching affecting both mechanics and excitation through mechanisms of mechano-calcium-electrical feedback. However, these couplings are not currently a focus of populations of cell models. Aim: We investigated the role of cardiomyocyte mechanical activity under different mechanical conditions in the generation, calibration, and validation of a population of electro-mechanical models of human cardiomyocytes. Methods: To generate a population, we assumed 11 input parameters of ionic currents and calcium dynamics in our recently developed TP + M model as varying within a wide range. A History matching algorithm was used to generate a non-implausible parameter space by calibrating the action potential and calcium transient biomarkers against experimental data and rejecting models with excitation abnormalities. The population was further calibrated using experimental data on human myocardial force characteristics and mechanical tests involving variations in preload and afterload. Models that passed the mechanical tests were validated with additional experimental data, including the effects of drugs with high or low pro-arrhythmic risk. Results: More than 10% of the models calibrated on electrophysiological data failed mechanical tests and were rejected from the population due to excitation abnormalities at reduced preload or afterload for cell contraction. The final population of accepted models yielded action potential, calcium transient, and force/shortening outputs consistent with experimental data. In agreement with experimental and clinical data, the models demonstrated a high frequency of excitation abnormalities in simulations of Dofetilide action on the ionic currents, in contrast to Verapamil. However, Verapamil showed a high frequency of failed contractions at high concentrations. Conclusion: Our results highlight the importance of considering mechanoelectric coupling in silico cardiomyocyte models. Mechanical tests allow a more thorough assessment of the effects of interventions on cardiac function, including drug testing.
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spelling pubmed-102855442023-06-23 The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes Dokuchaev, Arsenii Kursanov, Alexander Balakina-Vikulova, Nathalie A. Katsnelson, Leonid B. Solovyova, Olga Front Physiol Physiology Background: Populations of in silico electrophysiological models of human cardiomyocytes represent natural variability in cell activity and are thoroughly calibrated and validated using experimental data from the human heart. The models have been shown to predict the effects of drugs and their pro-arrhythmic risks. However, excitation and contraction are known to be tightly coupled in the myocardium, with mechanical loads and stretching affecting both mechanics and excitation through mechanisms of mechano-calcium-electrical feedback. However, these couplings are not currently a focus of populations of cell models. Aim: We investigated the role of cardiomyocyte mechanical activity under different mechanical conditions in the generation, calibration, and validation of a population of electro-mechanical models of human cardiomyocytes. Methods: To generate a population, we assumed 11 input parameters of ionic currents and calcium dynamics in our recently developed TP + M model as varying within a wide range. A History matching algorithm was used to generate a non-implausible parameter space by calibrating the action potential and calcium transient biomarkers against experimental data and rejecting models with excitation abnormalities. The population was further calibrated using experimental data on human myocardial force characteristics and mechanical tests involving variations in preload and afterload. Models that passed the mechanical tests were validated with additional experimental data, including the effects of drugs with high or low pro-arrhythmic risk. Results: More than 10% of the models calibrated on electrophysiological data failed mechanical tests and were rejected from the population due to excitation abnormalities at reduced preload or afterload for cell contraction. The final population of accepted models yielded action potential, calcium transient, and force/shortening outputs consistent with experimental data. In agreement with experimental and clinical data, the models demonstrated a high frequency of excitation abnormalities in simulations of Dofetilide action on the ionic currents, in contrast to Verapamil. However, Verapamil showed a high frequency of failed contractions at high concentrations. Conclusion: Our results highlight the importance of considering mechanoelectric coupling in silico cardiomyocyte models. Mechanical tests allow a more thorough assessment of the effects of interventions on cardiac function, including drug testing. Frontiers Media S.A. 2023-06-08 /pmc/articles/PMC10285544/ /pubmed/37362439 http://dx.doi.org/10.3389/fphys.2023.1187956 Text en Copyright © 2023 Dokuchaev, Kursanov, Balakina-Vikulova, Katsnelson and Solovyova. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Dokuchaev, Arsenii
Kursanov, Alexander
Balakina-Vikulova, Nathalie A.
Katsnelson, Leonid B.
Solovyova, Olga
The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes
title The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes
title_full The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes
title_fullStr The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes
title_full_unstemmed The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes
title_short The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes
title_sort importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10285544/
https://www.ncbi.nlm.nih.gov/pubmed/37362439
http://dx.doi.org/10.3389/fphys.2023.1187956
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