Mechano-electric regulations (MER) play an important role in the maintenance of cardiac performance. Mechano-calcium and mechano-electric feedback (MCF and MEF) pathways adjust the cardiomyocyte contractile force according to mechanical perturbations and affects electro-mechanical coupling. MER integrates all these regulations in one unit resulting in a complex phenomenon. Computational modelling is a useful tool to accelerate the mechanistic understanding of complex experimental phenomena. We have developed a novel model that integrates the MER loop for human atrial cardiomyocytes with proper consideration of feedforward and feedback pathways. The model couples a modified version of the action potential (AP) Koivumäki model with the contraction model by Quarteroni group. The model simulates iso-sarcometric and isometric twitches and the feedback effects on AP and Ca2+ -handling. The model showed a biphasic response of Ca2+ transient (CaT) peak to increasing pacing rates and highlights the possible mechanisms involved. The model has shown a shift of the threshold for AP and CaT alternans from 4.6 to 4 Hz under post-operative atrial fibrillation, induced by depressed SERCA activity. The alternans incidence was dependent on a chain of mechanisms including RyRs availability time, MCF coupling, CaMKII phosphorylation, and the stretch levels. As a result, the model predicted a 10% slowdown of conduction velocity for a 20% stretch, suggesting a role of stretch in creation of substrate formation for atrial fibrillation. Overall, we conclude that the developed model provides a physiological CaT followed by a physiological twitch. This model can open pathways for the future studies of human atrial electromechanics. KEY POINTS: With the availability of human atrial cellular data, interest in atrial-specific model integration has been enhanced. We have developed a detailed mathematical model of human atrial cardiomyocytes including the mechano-electric regulatory loop. The model has gone through calibration and evaluation phases against a wide collection of available human in-vitro data. The usefulness of the model for analysing clinical problems has been preliminaryly tested by simulating the increased incidence of Ca2+ transient and action potential alternans at high rates in post-operative atrial fibrillation condition. The model determines the possible role of mechano-electric feedback in alternans incidence, which can increase vulnerability to atrial arrhythmias by varying stretch levels. We found that our physiologically accurate description of Ca2+ handling can reproduce many experimental phenomena and can help to gain insights into the underlying pathophysiological mechanisms.

A detailed mathematical model of the human atrial cardiomyocyte: integration of electrophysiology and cardiomechanics

Regazzoni, Francesco;Dede', Luca;Quarteroni, Alfio;Severi, Stefano
2023-01-01

Abstract

Mechano-electric regulations (MER) play an important role in the maintenance of cardiac performance. Mechano-calcium and mechano-electric feedback (MCF and MEF) pathways adjust the cardiomyocyte contractile force according to mechanical perturbations and affects electro-mechanical coupling. MER integrates all these regulations in one unit resulting in a complex phenomenon. Computational modelling is a useful tool to accelerate the mechanistic understanding of complex experimental phenomena. We have developed a novel model that integrates the MER loop for human atrial cardiomyocytes with proper consideration of feedforward and feedback pathways. The model couples a modified version of the action potential (AP) Koivumäki model with the contraction model by Quarteroni group. The model simulates iso-sarcometric and isometric twitches and the feedback effects on AP and Ca2+ -handling. The model showed a biphasic response of Ca2+ transient (CaT) peak to increasing pacing rates and highlights the possible mechanisms involved. The model has shown a shift of the threshold for AP and CaT alternans from 4.6 to 4 Hz under post-operative atrial fibrillation, induced by depressed SERCA activity. The alternans incidence was dependent on a chain of mechanisms including RyRs availability time, MCF coupling, CaMKII phosphorylation, and the stretch levels. As a result, the model predicted a 10% slowdown of conduction velocity for a 20% stretch, suggesting a role of stretch in creation of substrate formation for atrial fibrillation. Overall, we conclude that the developed model provides a physiological CaT followed by a physiological twitch. This model can open pathways for the future studies of human atrial electromechanics. KEY POINTS: With the availability of human atrial cellular data, interest in atrial-specific model integration has been enhanced. We have developed a detailed mathematical model of human atrial cardiomyocytes including the mechano-electric regulatory loop. The model has gone through calibration and evaluation phases against a wide collection of available human in-vitro data. The usefulness of the model for analysing clinical problems has been preliminaryly tested by simulating the increased incidence of Ca2+ transient and action potential alternans at high rates in post-operative atrial fibrillation condition. The model determines the possible role of mechano-electric feedback in alternans incidence, which can increase vulnerability to atrial arrhythmias by varying stretch levels. We found that our physiologically accurate description of Ca2+ handling can reproduce many experimental phenomena and can help to gain insights into the underlying pathophysiological mechanisms.
2023
Ca2+-handling
cardiomechanics
computational modelling
contractility
coupling
human atrial cells
rate adaptation
stretch activated currents
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11311/1257904
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