K+ Channel-Interacting Protein 2 Deficient mice have a Rate Dependent Prolongation of Left Ventricular CA2+ Transients

Abstract

In the heart, K+ channel-interacting protein 2 (KChIP2) stabilizes Kv4 channels in the membrane resulting in larger transient outward potassium currents (Ito). Recently it has been demonstrated that KChIP2 also enhances Cav1.2 and that the KChIP2-/- mouse has reduced inward L-type Ca2+ current. In this study, we test the impact of KChIP2-/- on cardiac contraction and on underlying Ca2+ transients.Through ultrasound examination, we found comparable left ventricular ejection fraction and fractional shortening in the heart of wild-type (WT) and KChIP2-/- mice, indicating that the function of the left ventricle was not impaired despite reduced L-type Ca2+ current. Confocal line scan Ca2+ imaging was performed using the Cal-520TM fluorophore. Whole-cell Ca2+ transients were recorded from disaggregated left ventricular cardiomyocytes at 37°C, field stimulated at cycle lengths between 80 and 1000 ms. A decrease in the relative peak of the Ca2+ transient was found in KChIP2-/- versus WT (0.58±0.06 vs. 0.71±0.07 F/F0, P<0.05) and the time to 50% decay of the transient was prolonged (133±5 vs. 121±3 ms, P<0.05). These differences were rate-dependent and diminished at cycle lengths shorter than 1000 ms. However, at the fastest pacing rate more cardiomyocytes were alternating in KChIP2-/- compared with WT (cycle length: 80 ms; WT: 12/18, KChIP2-/-: 23/23). The fractional Ca2+ release was not different between the two genotypes, suggesting that the differences in Ca2+ transients are not a result of differential SR load.In conclusion, although cardiac contraction is not impaired in the KChIP2-/- mouse, some abnormal Ca2+ handling is apparent in individual KChIP2-/- cardiomyocytes, including a higher propensity to develop Ca2+ transient alternans. If this is manifested significantly at the tissue level, it could contribute to the development of repolarization gradients across the myocardium.