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

Abstract

The atrial-specific ultrarapid delayed rectifier K þ 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 I Kur 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.

In Silico Assessment of Efficacy and Safety of IKur Inhibitors in Chronic Atrial Fibrillation: Role of Kinetics and State-Dependence of Drug Binding

“…This is a favorable drug property to avoid harmful AP prolongation (which is also limited by the reduced basal APD) if AF is terminated. Similar to Aguilar et al ( 2017 ), our results suggest that the APD- (and ERP)-prolonging effect of I Kur block is not affected by I Kur downregulation.…”

“…Thus, the consequences of I Kur inhibition, including the extent of AP and ERP prolongation, depend not only on I Kur magnitude (i.e., maximal conductance), but also on other fluxes affected by AF-induced remodeling, which affect E m and thus E m -dependent properties of I Kur (Figure 7 ). For example, our group and others have hypothesized that the extent of AP and ERP prolongation due to I Kur blockade depends on the AF-induced remodeling of other K + currents (Lagrutta et al, 2006 ; Morotti et al, 2016a ; Aguilar et al, 2017 ; Colman et al, 2017 ), and relative strengths of I CaL and I Kur (Wettwer et al, 2004 ; Grandi and Maleckar, 2016 ). Our sensitivity analysis (Figure 1C and Figures S1 – S6 ) revealed that APD 90 and ERP are more sensitive to changes in G Kur at fast vs. slow pacing rates.…”

“…Our sensitivity analysis (Figure 1C and Figures S1 – S6 ) revealed that APD 90 and ERP are more sensitive to changes in G Kur at fast vs. slow pacing rates. Aguilar et al recently determined that 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 (Aguilar et al, 2017 ). Our results concur with these findings, as our sensitivity analysis shows that APD 90 and ERP are less sensitive to changes in G Kr at 3-Hz pacing as compared to 1-Hz pacing in nSR conditions (Figures S2 , S3 ).…”

“…In their simulation study, Aguilar et al concluded that the ability of (simple pore) I Kur block to terminate simulated AF was greatly attenuated by remodeling, because the block-induced AP prolongation was insufficient to counteract the strong effects of cAF-induced remodeling (Aguilar et al, 2017 ). Notably, here we show that depending on the drug-binding kinetics, certain I Kur inhibitors can markedly counteract the effect of cAF-associated remodeling, and bring AP and ERP parameters close to nSR values, i.e., have a greater effect than simple pore blockers.…”

Mapping of the electrical activity of human atria. Multiscale modelling and simulations

“…Sánchez et al 143 reported a systematic characterization of the importance of transmembrane ionic currents in modulating the electrophysiological properties and reentrant activity in 2D simulations of human atrial isotropic and homogeneous tissue. Aguilar et al 144 used 2D simulations to study the rate-dependent role of I Kur and the effect of blocking it on the atrial AP. Keller et al 145 used a 3D isotropic planar patch of myocardium to stablish a model for acute ablation lesions in order to study the changes in the EGMs during radio-frequency ablation procedures.…”