56-03: Increased arrhythmia vulnerability in KChIP2 knock-out mice is explained by different spatial dispersion of ventricular repolarization and location of cardiac stimulation

Abstract

Purpose of the study: Downregulation of ventricular K+ channel-interacting protein 2 (KChIP2) and loss of the transient outward K+ current (Ito), is observed in failing hearts. In this study, we investigate the impact of KChIP2 and heart failure (HF) on action potential duration (APD) and repolarization time (RT) in mouse hearts. We hypothese that a dispersion of RT will provoke arrhythmias if cardiac pacing is performed from the region with the shortest RT. Method used: HF in WT and KChIP2-/- mice was induced by transverse aortic constriction and verified by echocardiography. Regional activation time (AT), APD and RT (=AT + APD) were subsequently measured in isolated, perfused and apically paced hearts using floating microelectrodes. Finally, in-vivo intracardiac pacing of the right ventricle tested arrhythmia vulnerability. Summary of results: Within the left ventricle, APD is longer at the base in KChIP2-/- hearts (n = 6) when compared to WT (n = 6) (APD90: 52.4 ± 5.3 vs. 37.6 ± 3.8 ms, p < 0.05). However, including the AT, the apico-basal dispersion of RT in KChIP2-/- hearts is not different from WT. KChIP2-/- hearts have a larger interventricular dispersion of APD (Δ-APD90: 18.7 ± 4.8 vs. 6.1 ± 1.5 ms, p < 0.05), which translates into a larger left-to-right ventricular dispersion of RT compared to WT hearts (Δ-RT: 22.7 ± 6.7 vs. 5.0 ± 1.5 ms, p < 0.05). HF prolongs AT and APD in WT and KChIP2-/- hearts, and makes spatial dispersion of RT comparable. Pacing the right ventricle of KChIP2-/- control mice to test if pacing from a region with a shorter RT will provoke arrhythmias revealed significant increased arrhythmia vulnerability in these mice. Conclusion: Absence of KChIP2 leads to a prolongation of the left ventricular action potential and an increased interventricular dispersion of RT. HF alters the APD gradients, but reduces the differences in spatial dispersion of RT between WT and KChIP2-/- hearts. Finally, the location of cardiac pacing is crucial when evaluating arrhythmia vulnerability.