Dynamics of human atrial cell models: Restitution, memory, and intracellular calcium dynamics in single cells

Abstract

Mathematical models of cardiac cells have become important tools for investigating the electrophysiological properties and behavior of the heart. As the number of published models increases, it becomes more difficult to choose a model appropriate for the conditions to be studied, especially when multiple models describing the species and region of the heart of interest are available. In this paper, we will review and compare two detailed ionic models of human atrial myocytes, the Nygren et al. model (NM) and the Courtemanche et al. model (CM). Although both models include the same transmembrane currents and are largely based on the same experimental data from human atrial cells, the two models exhibit vastly different properties, especially in their dynamical behavior, including restitution and memory effects. The CM produces pronounced rate adaptation of action potential duration (APD) with limited memory effects, while the NM exhibits strong rate dependence of resting membrane potential (RMP), limited APD restitution, and stronger memory, as well as delayed afterdepolarizations and auto-oscillatory behavior upon cessation of rapid pacing. Channel conductance modifications based on experimentally measured changes during atrial fibrillation modify rate adaptation and memory in both models, but do not change the primary rate-dependent properties of APD and RMP for the CM and NM, respectively. Two sets of proposed changes to the NM that yield a spike-and-dome action potential morphology qualitatively similar to the CM at slow pacing rates similarly do not change the underlying dynamics of the model. Moreover, interchanging the formulations of all transmembrane currents between the two models while leaving calcium handling and ionic concentrations intact indicates that the currents strongly influence memory and the rate adaptation of RMP, while intracellular calcium dynamics primarily determine APD rate adaptation. Our results suggest that differences in intracellular calcium handling between the two human atrial myocyte models are responsible for marked dynamical differences and may prevent reconciliation between the models by straightforward channel conductance modifications.

The Na+/K+ pump is an important modulator of refractoriness and rotor dynamics in human atrial tissue

“…Single cell simulations were conducted using the forward Euler method with time step of 0.02 ms. Figure 1 shows the time course of the steady-state AP and the main underlying ionic currents in control and AFER atrial cardiomyocytes, using the MGGT model (left) and the CRN model (right). In both models, AFER results in shortening of APD 90 and slight RMP hyperpolarization, consistent with previous experimental and theoretical human atrial studies (6,12,50). Steady-state APD 90 shortens from 200 ms in control to 115.8 ms in AFER in simulations using the MGGT model and from 252 ms to 115.5 ms using the CRN model.…”

“…Finally, a few recent studies have focused on the comparison of different AP models aiming at targeting similar cell type and mammalian species and have highlighted differences in dynamics because of differences in the model equations and parameters (7,11,12,13,58,59). The results of this study should be interpreted with caution since there could be different combinations of changes in the model parameters leading to similar results (62).…”

“…A large number of studies have provided insights into the ionic basis of atrial electrophysiology (12,13,18,50,60,65,66). Research has focused primarily on the role of either sodium or potassium channel block in modulating atrial electrophysiology (8,48) and has often been performed in different animal species, usually either before or after AFER (68,74).…”

Influence of left atrial geometry on rotor core trajectories in a model of atrial fibrillation

“…For each pacing location, an S1-S2 extra stimulus protocol was applied. A wide-area S1 stimulus of 50µΑ/mm 3 was followed 315 ms later by a second smaller S2 stimulus of strength 100µΑ/mm 3 on the boundary of the S1 stimulus to initiate two counter-rotating spiral waves. The area of the S1 Figure 2.…”

“…A rotor is defined as a high frequency curved wavefront, which meets the wavetail at a single point and is characterised by the absence of refractory tissue at the centre [2]. Until recently, the presence of rotors was only observed in animal experimental studies [3], but localized and stable rotors in human AF have now been identified [4,5]. This progress may increase the efficacy of targeted left atrial ablation therapy.…”