Rate-Dependent Role of I in Human Atrial Repolarization and Atrial Fibrillation Maintenance.

The atrial-specific ultrarapid delayed rectifier K current (I) inactivates slowly but completely at depolarized voltages. The consequences for I rate-dependence have not been analyzed in detail and currently available mathematical action-potential (AP) models do not take into account experimentally observed I inactivation dynamics. Here, we developed an updated formulation of I inactivation that accurately reproduces time-, voltage-, and frequency-dependent inactivation. We then modified the human atrial cardiomyocyte Courtemanche AP model to incorporate realistic I inactivation properties. Despite markedly different inactivation dynamics, there was no difference in AP parameters across a wide range of stimulation frequencies between the original and updated models. Using the updated model, we showed that, under physiological stimulation conditions, I does not inactivate significantly even at high atrial rates because the transmembrane potential spends little time at voltages associated with inactivation. Thus, channel dynamics are determined principally by activation kinetics. I magnitude decreases at higher rates because of AP changes that reduce I activation. Nevertheless, the relative contribution of I to AP repolarization increases at higher frequencies because of reduced activation of the rapid delayed-rectifier current I. Consequently, I block produces dose-dependent termination of simulated atrial fibrillation (AF) in the absence of AF-induced electrical remodeling. The inclusion of AF-related ionic remodeling stabilizes simulated AF and greatly reduces the predicted antiarrhythmic efficacy of I block. Our results explain a range of experimental observations, including recently reported positive rate-dependent I-blocking effects on human atrial APs, and provide insights relevant to the potential value of I as an antiarrhythmic target for the treatment of AF.