Downregulation of Ventricular K+ Channel-Interacting Protein 2 Expression Reduces Arrhythmia Vulnerability in Mice with Heart Failure

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<h3>Background</h3> Abnormal ventricular repolarization in ion channelopathies and heart disease are major causes of ventricular arrhythmias and sudden cardiac death. The level of K⁺ channel-interacting protein 2 (KChIP2) is significantly reduced in human heart failure (HF), contributing to a loss of transient outward K⁺ current (I_to). We have previously shown that the structural development of HF in wild-type (WT) and KChIP2^–/– mice have similar time-courses. Here, we explore the impact of both reduced and complete absence of KChIP2 on proarrhythmia. <h3>Methods</h3> Transverse aortic constriction (TAC) and sham operations were performed in WT and KChIP2^–/– mice. Echocardiography was used to monitor functional changes of the left ventricle (LV). Programmed electrical stimulation of the LV with up to 6 coupled extrastimuli was performed <i>in vivo</i> and arrhythmia vulnerability evaluated by logistic regression analysis. Action potentials were recorded <i>ex vivo</i> in intact perfused hearts using floating microelectrodes. <h3>Results</h3> The presence of HF in the TAC operated WT mice was documented by reduced ejection fraction (29 ± 3% in TAC vs 53 ± 2% in sham-operated mice, <i>P</i> <.05). Moreover, ventricular KChIP2 expression was reduced by 70 ± 6% (<i>P</i> <.05). Ventricular effective refractory period (VERP) was longer in mice with TAC compared to sham-operated WT mice (47 ± 2 vs 34 ± 2 ms, <i>P</i> <.05). Ejection fraction and VERP in KChIP2^–/– mice with and without TAC were comparable to those in WT mice. Pacing-induced VT was observed in 5/10 sham-operated WT mice compared with 2/10 TAC-operated WT mice (<i>P</i> >.05). Surprisingly, sham-operated KChIP2^–/– mice were more resistant to pacing-induced VT resulting in only 1/9 inducible mice (vs WT sham-operated mice, <i>P</i> <.05). KChIP2^–/– with TAC mice had similar vulnerability to inducible VT. Additionally, KChIP2^–/– mice showed slower ventricular repolarization than WT mice (APD₉₀: 57 ± 5 vs 40 ± 3 ms, <i>P</i> <.05). <h3>Conclusions</h3> In our hands, the absence of KChIP2 prolongs APD and reduces inducibility of VT without affecting the VERP in mice with normal LV function. In HF, ventricular KChIP2 protein levels and inducibility of VT are reduced. Thus, downregulation of KChIP2 expression in HF reduces arrhythmia vulnerability in mice.