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

The atrial-specific ultrarapid delayed rectifier K+ current (I-Kur) inactivates slowly but completely at depolarized voltages. The consequences for I-Kur rate-dependence have not been analyzed in detail and currently available mathematical action-potential (AP) models do not take into account experimentally observed I-Kur inactivation dynamics. Here, we developed an updated formulation of I-Kur inactivation that accurately reproduces time-, voltage-, and frequency-dependent inactivation. We then modified the human atrial 'cardiomyocyte Courtemanche AP model to incorporate realistic I-Kur 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-Kur 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-Kur magnitude decreases at higher rates because of AP changes that reduce IKur activation. Nevertheless, the relative contribution of I-Kur to AP repolarization increases at higher frequencies because of reduced activation of the rapid delayed-rectifier current I-Kr Consequently, I-Kur 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-Kur block. Our results explain a range of experimental observations, including recently reported positive rate-dependent I-Kur-blocking effects on human atrial APs, and provide insights relevant to the potential value of I-Kur as an antiarrhythmic target for the treatment of AF.