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

Abstract

AbstractMechano‐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. imageKey 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.