Modulation of Action Potential Alternans by IKs in Myocardial Infarction

Abstract

Background: Patients with post myocardial infarction (MI) have increased incidence of ventricular arrhythmias. The slowly activating K+ channels (IKs) has been reported to be downregulated consistently but in different degrees in the post-MI hearts. The role of downregulation of IKs in arrhythmogenesis in post MI remains to be defined.Hypothesis: We hypothesize that significant suppression of IKs in post MI impairs the rate-dependent and Ca2+-dependent augmentation of repolarization reserve resulting in increased alternans and thereby arrhythmias.Methods: We evaluated the effect of IKs on alternans in post MI using transgenic rabbit model of Long QT Type 1 (LQT1) lacking IKs. LQT1 and littermate control (LMC) rabbits underwent MI procedures and optical mapping was performed to record Vm and Ca2+ simultaneously from the 3 week post-MI hearts (n=9 LQT1-MI, 4 LQT-MI Sham, 10 LMC-MI, 9 LMC-Sham hearts).Results: The dispersion of APD was enhanced in LQT1-MI compared to LQT1-Sham and LMC-MI (αAPDmax-min = 28±4 ms vs. 20±3 ms and 27±6 ms). APD alternans was more pronounced in LQT1-MI, accompanied with large amplitude Ca2+ alternans, and often spatially discordant (see traces and restitution curves in panel A&B). Spatially discordant alternans in LQT1-MI was highly dynamic, preceded by sudden appearance of Ca2+ nodal lines near the MI border zone (panel C, dark lines), associated with high VF induction (n=9/9 LQT1-MI vs. 1/4 LQT1-sham and 7/10 LMC-MI).Conclusion: Our results demonstrate the importance of IKs as a repolarization reserve in MI and that significant downregulation of IKs may promote spatially discordant Ca2+ and APD alternans and VF induction.