Effect of Blocking IKur on the Genesis of Repolarisation Alternans in Canine Atrium

Na Zhao1, Qince Li1, Kuanquan Wang1, Runnan He1, Yongfeng Yuan1, Henggui Zhang2
1Harbin Institute of Technology, 2University of Manchester


Aims: This study aimed to investigate the effects of blocking the ultra-rapid delayed rectifier K+ current (IKur) on the genesis of repolarisation alter-nans which was associated with arrhythmogenesis. Methods: The canine atrial cell model developed by Ramirez et al. was used to examine the effects of blocking IKur by various percentages on the action potential (AP). The action potential duration at 90% repolarization (APD90) restitution curves were calculated using the dynamic pacing protocol and the standard S1-S2 protocol respectively to analyse the genesis of re-polarisation alternans under control and IKur block conditions. In addition, effective refractory period (ERP) restitution curves were also calculated using the combination of the two protocols described above. Furthermore, changes in the intracellular Ca2+ transient amplitude (CaTamp) and decay time (CaTD) were evaluated in the two conditions. Results: Simulation results demonstrated that the APD90 was prolonged by 7.0 ms to 84.0 ms, the CaTamp increased by 8.5 nM to 162.9 nM, and the CaTD increased by 3.2 ms to 57.5 ms when IKur was blocked from 10% to 90% at 2 Hz pacing rate. APD and Ca2+ transient alternans occurred when IKur was blocked by 40% to 90%. Genesis of alternans was considered when the beat-to-beat variation > 10 ms in APD90, ERP and CaTD or 10 nM in CaTamp at the longest pacing cycle length (PCL) (details in Table 1). Further analysis demonstrated that blocking IKur promoted the genesis of APD alternans, via a mechanism of an increased APD that led to increased amplitude of Ca2+ transient and prolonged Ca2+ decay, which produced an increased Na+/Ca2+ exchange current, promoting the genesis of AP alternans. Conclusion: This study demonstrates that although prolonging the APD, blocking IKur may promote the genesis of AP alternans at a lower pacing fre-quency, indicating a latent pro-arrhythmic of IKur blocking.