Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model

Balakina-Vikulova, Nathalie; Panfilov, Alexander; Solovyova, Olga; Katsnelson, Leonid B.

doi:10.1101/855890

Cited by 3 publications

(10 citation statements)

References 105 publications

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“…In all cases, the initial length of the cardiomyocyte is shown to influence the time course of the AP, the Ca 2+ transient and the isometric force developed. These changes are based on the mechanisms of MCF and MEF, as we have shown earlier (Balakina-Vikulova et al, 2020). Increasing both ɡ gap and n results in a decrease in peak of Ca 2+ transients and a significant decrease in peak active isometric force at all lengths.…”

Section: Contribution Of Mechanical Coupling To the Interaction Durin...supporting

confidence: 56%

“…Here we apply our mathematical model of electromechanical activity for the human cardiomyocyte, the TP + M model (Balakina-Vikulova et al, 2020), based on the ten Tusscher-Panfilov model (TP06) (ten Tusscher and Panfilov, 2006) and our earlier model of the myocardial mechanical activity and Ca 2+ handling (Sulman et al, 2008). Figures 1, 2 schematically represent the electrophysiological and mechanical modules of the combined TP + M model (dashed boxes).…”

Section: Methodsmentioning

confidence: 99%

“…Figures 1, 2 schematically represent the electrophysiological and mechanical modules of the combined TP + M model (dashed boxes). This model simulates both mechanical and electrical behavior of the cardiomyocyte during isometric and afterloaded contractions (Balakina-Vikulova et al, 2020).…”

Section: Methodsmentioning

confidence: 99%

“…Attachment of Xbs during the contractile cycle is regulated by Ca 2+ ions via their binding to troponin C located along the thin filament. An important feature of this model is the mathematical description of cooperativity mechanisms (Sulman et al, 2008) that make the kinetics of CaTnC complexes dependent on the number of attached forcegenerating Xbs and allow us to simulate and explain a wide range of mechano-calcium and mechanoelectric feedback (MCF and MEF) loops in the cardiomyocyte (Balakina-Vikulova et al, 2020).…”

Section: Methodsmentioning

confidence: 99%

“…Model 1 is an extension of the MacCannell model (MacCannell et al, 2007). As is well known, the cardiomyocyte in the MacCannell model is represented by the electrical TNNP model (ten Tusscher et al, 2004), whereas in model 1 we replaced the TNNP model with our electromechanical TP + M model that combines the TP06 model (a further development of the TNNP model) and a module for simulation of cardiomyocyte mechanics (Balakina-Vikulova et al, 2020). This allowed us to analyze some aspects not only the electrical but also the mechanical response of a cardiomyocyte to electrical interaction with fibroblasts in model 1.…”

Section: Mef In the Model Of Cardiomyocyte Electrically Connected Wit...mentioning

confidence: 99%

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In silico analysis of the contribution of cardiomyocyte-fibroblast electromechanical interaction to the arrhythmia

Kursanov

Balakina-Vikulova²,

Solovyova³

et al. 2023

Front. Physiol.

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Although fibroblasts are about 5–10 times smaller than cardiomyocytes, their number in the ventricle is about twice that of cardiomyocytes. The high density of fibroblasts in myocardial tissue leads to a noticeable effect of their electromechanical interaction with cardiomyocytes on the electrical and mechanical functions of the latter. Our work focuses on the analysis of the mechanisms of spontaneous electrical and mechanical activity of the fibroblast-coupled cardiomyocyte during its calcium overload, which occurs in a variety of pathologies, including acute ischemia. For this study, we developed a mathematical model of the electromechanical interaction between cardiomyocyte and fibroblasts and used it to simulate the impact of overloading cardiomyocytes. In contrast to modeling only the electrical interaction between cardiomyocyte and fibroblasts, the following new features emerge in simulations with the model that accounts for both electrical and mechanical coupling and mechano-electrical feedback loops in the interacting cells. First, the activity of mechanosensitive ion channels in the coupled fibroblasts depolarizes their resting potential. Second, this additional depolarization increases the resting potential of the coupled myocyte, thus augmenting its susceptibility to triggered activity. The triggered activity associated with the cardiomyocyte calcium overload manifests itself in the model either as early afterdepolarizations or as extrasystoles, i.e., extra action potentials and extra contractions. Analysis of the model simulations showed that mechanics contribute significantly to the proarrhythmic effects in the cardiomyocyte overloaded with calcium and coupled with fibroblasts, and that mechano-electrical feedback loops in both the cardiomyocyte and fibroblasts play a key role in this phenomenon.

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Section: Contribution Of Mechanical Coupling To the Interaction Durin...supporting

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Mef In the Model Of Cardiomyocyte Electrically Connected Wit...mentioning

confidence: 99%

See 3 more Smart Citations

In silico analysis of the contribution of cardiomyocyte-fibroblast electromechanical interaction to the arrhythmia

Kursanov

Balakina-Vikulova²,

Solovyova³

et al. 2023

Front. Physiol.

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A Population Modelling Approach to Studying Age-Related Effects on Excitation-Contraction Coupling in Human Cardiomyocytes

Dokuchaev

Khamzin

Solovyova

2019

Preprint

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Ageing is the dominant risk factor for cardiovascular diseases. A great body of experimental data has been gathered on cellular remodelling in the Ageing myocardium from animals. Very few experimental data are available on age-related changes in the human cardiomyocyte. We have used our combined electromechanical model of the human cardiomyocyte and the population modelling approach to investigate the variability in the response of cardiomyocytes to age-related changes in the model parameters. To generate the model population, we varied nine model parameters and excluded model samples with biomarkers falling outside of the physiological ranges. We evaluated the response to age-related changes in four electrophysiological model parameters reported in the literature: reduction in the density of the K + transient outward current, maximal velocity of SERCA, and an increase in the density of NaCa exchange current and CaL-type current. The sensitivity of the action potential biomarkers to individual parameter variations was assessed. Each parameter modulation caused an increase in APD, while the sensitivity of the model to changes in G CaL and V max_up was much higher than to those in the effects of G to and K NaCa . Then 60 age-related sets of the four parameters were randomly generated and each set was applied to every model in the control population. We calculated the frequency of model samples with repolarisation anomalies (RA) and the shortening of the electro-mechanical window in the ageing model populations as an arrhythmogenic ageing score. The linear dependence of the score on the deviation of the parameters showed a high determination coefficient with the most significant impact due to the age-related change in the CaL current. The population-based approach allowed us to classify models with low and high risk of age-related RA and to predict risks based on the control biomarkers.

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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

et al. 2023

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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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Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model

Cited by 3 publications

References 105 publications

In silico analysis of the contribution of cardiomyocyte-fibroblast electromechanical interaction to the arrhythmia

In silico analysis of the contribution of cardiomyocyte-fibroblast electromechanical interaction to the arrhythmia

A Population Modelling Approach to Studying Age-Related Effects on Excitation-Contraction Coupling in Human Cardiomyocytes

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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