The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes
Электронный научный архив УРФУ
Информация об архиве | Просмотр оригинала| Поле | Значение | |
| Заглавие |
The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes
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| Автор |
Dokuchaev, A.
Kursanov, A. Balakina-Vikulova, N. A. Katsnelson, L. B. Solovyova, O. |
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| Тематика |
CARDIAC ELECTROPHYSIOLOGY
DRUG TESTING HUMAN VENTRICULAR CARDIOMYOCYTE MATHEMATICAL MODELS MECHANICAL FUNCTION REPOLARIZATION ABNORMALITIES ADENOSINE TRIPHOSPHATASE (POTASSIUM SODIUM) CALCIUM DOFETILIDE POTASSIUM SODIUM SODIUM CALCIUM EXCHANGE PROTEIN VERAPAMIL ACTION POTENTIAL ALGORITHM APD90 ARTICLE CARDIAC MUSCLE CELL CD50 (CYTOTOXIC DOSE) ELECTROMECHANICAL MODEL HEART ARRHYTHMIA HEART CONTRACTION HEART ELECTROPHYSIOLOGY HEART FUNCTION HUMAN IC50 ION CURRENT MECHANICAL TEST MEMBRANE STEADY POTENTIAL MODEL PATCH CLAMP TECHNIQUE QT INTERVAL SARCOMERE LENGTH |
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| Описание |
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. Copyright © 2023 Dokuchaev, Kursanov, Balakina-Vikulova, Katsnelson and Solovyova.
Russian Science Foundation, RSF: 19-14-00134 This work was supported by Russian Science Foundation grant No. 19-14-00134. |
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| Дата |
2024-04-05T16:26:13Z
2024-04-05T16:26:13Z 2023 |
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| Тип |
Article
Journal article (info:eu-repo/semantics/article) |info:eu-repo/semantics/publishedVersion |
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| Идентификатор |
Dokuchaev, A, Kursanov, A, Balakina-Vikulova, NA, Katsnelson, LB & Solovyova, O 2023, 'The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes', Frontiers in Physiology, Том. 14, 1187956. https://doi.org/10.3389/fphys.2023.1187956
Dokuchaev, A., Kursanov, A., Balakina-Vikulova, N. A., Katsnelson, L. B., & Solovyova, O. (2023). The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes. Frontiers in Physiology, 14, [1187956]. https://doi.org/10.3389/fphys.2023.1187956 1664-042X Final All Open Access, Gold, Green https://www.scopus.com/inward/record.uri?eid=2-s2.0-85162692140&doi=10.3389%2ffphys.2023.1187956&partnerID=40&md5=11a23978e3f97bc3a42ddd99544cc007 https://www.frontiersin.org/articles/10.3389/fphys.2023.1187956/pdf http://elar.urfu.ru/handle/10995/130565 10.3389/fphys.2023.1187956 85162692140 001014999200001 |
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| Язык |
en
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| Связанные ресурсы |
info:eu-repo/grantAgreement/RSF//19-14-00134
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| Права |
Open access (info:eu-repo/semantics/openAccess)
cc-by https://creativecommons.org/licenses/by/4.0/ |
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| Формат |
application/pdf
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| Издатель |
Frontiers Media SA
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| Источник |
Frontiers in Physiology
Frontiers in Physiology |
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