Divergent action potential morphology in human atrial cells compared with tissue: Underlying ionic mechanisms

This study aimed to elucidate the mechanisms underlying the divergent action potential (AP) morphology observed in human atrial cells vs. tissue, with simulations employing computational models. Two modifications were introduced to the cell model, based on conditions inherent to in vitro AP measurements. First, we accounted for the loss of hERG ion channels, which mediate the rapid delayed rectifier potassium current (I_Kr), due to the standard enzymatic cell isolation protocol. Second, the effect of adding a intracellular calcium buffer (EGTA), which is typically used in patch clamp measurements of APs, was also considered. The reduced I_Kr conductance slowed repolarization (AP phases 2 and 3) significantly, while initial repolarization (AP phase 1) remained largely unaffected. Whereas, addition of the EGTA buffer in silico affected both the initial and later phases AP repolarization. Simulation results show that changes in AP morphology depend rather dramatically on the chosen mathematical formulation of calcium and potassium currents. Accordingly, it is important to consider this divergence in electrophysiological properties when, for example, extrapolating pharmacological effects simulated or measured in single cells to intact cardiac tissue.