Individual Contributions of Cardiac Ion Channels on Atrial Repolarization and Reentrant Waves: A Multiscale In-Silico...

The excitation, contraction, and relaxation of an atrial cardiomyocyte are maintained by the activation and inactivation of numerous cardiac ion channels. Their collaborative efforts cause time-dependent changes of membrane potential, generating an action potential (AP), which is a surrogate marker of atrial arrhythmias. Recently, computational models of atrial electrophysiology emerged as a modality to investigate arrhythmia mechanisms and to predict the outcome of antiarrhythmic therapies. However, the individual contribution of atrial ion channels on atrial action potential and reentrant arrhythmia is not yet fully understood. Thus, in this multiscale in-silico study, perturbations of individual atrial ionic currents (I_Na, I_to, I_CaL, I_Kur, I_Kr, I_Ks, I_K1, I_NCX and I_NaK) in two in-silico models of human atrial cardiomyocyte (i.e., Courtemanche-1998 and Grandi-2011) were performed at both cellular and tissue levels. The results show that the inhibition of I_CaL and I_NCX resulted in AP shortening, while the inhibition of I_Kur, I_Kr, I_Ks, I_K1 and I_NaK prolonged AP duration (APD). Particularly, in-silico perturbations (inhibition and upregulation) of I_Kr and I_Ks only minorly affected atrial repolarization in the Grandi model. In contrast, in the Courtemanche model, the inhibition of I_Kr and I_Ks significantly prolonged APD and vice versa. Additionally, a 50% reduction of I_to density abbreviated APD in the Courtemanche model, while the same perturbation prolonged APD in the Grandi model. Similarly, a strong model dependence was also observed at tissue scale, with an observable I_K1-mediated reentry stabilizing effect in the Courtemanche model but not in the Grandi atrial model. Moreover, the Grandi model was highly sensitive to a change on intracellular Ca²⁺ concentration, promoting a repolarization failure in I_CaL upregulation above 150% and facilitating reentrant spiral waves stabilization by I_CaL inhibition. Finally, by incorporating the previously published atrial fibrillation (AF)-associated ionic remodeling in the Courtemanche atrial model, in-silico modeling revealed the antiarrhythmic effect of I_Kr inhibition in both acute and chronic settings. Overall, our multiscale computational study highlights the strong model-dependent effects of ionic perturbations which could affect the model's accuracy, interpretability, and prediction. This observation also suggests the need for a careful selection of in-silico models of atrial electrophysiology to achieve specific research aims.