Loss of K+ Currents in Heart Failure Is Accentuated in KChIP2 Deficient Mice

• Published in: Journal of cardiovascular electrophysiology Vol. 25; no. 8; pp. 896 - 904
• Main Authors: GRUBB, SØREN, SPEERSCHNEIDER, TOBIAS, OCCHIPINTI, DONA, FISET, CÉLINE, OLESEN, SØREN-PETER, THOMSEN, MORTEN B., CALLOE, KIRSTINE
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.08.2014; Wiley Subscription Services, Inc
• Subjects: Action Potentials; Animals; cardiac; Cardiac Pacing, Artificial; Disease Models, Animal; Down-Regulation; Genotype; Heart Conduction System - metabolism; Heart Conduction System - physiopathology; Heart failure; Heart Failure - genetics; Heart Failure - metabolism; Heart Failure - physiopathology; KChIP2; Kv Channel-Interacting Proteins - deficiency; Kv Channel-Interacting Proteins - genetics; Male; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac - metabolism; Phenotype; Potassium; Potassium - metabolism; potassium currents; repolarization; Rodents; Time Factors; transient outward potassium current; KChIP2; heart failure; potassium currents; action potentials; transient outward potassium current; repolarization; cardiac
• ISSN: 1045-3873; 1540-8167
• DOI: 10.1111/jce.12422

The Role of KChIP2 in Heart Failure Introduction KV4 together with KV Channel‐Interacting Protein 2 (KChIP2) mediate the fast recovering transient outward potassium current (Ito,f) in the heart. KChIP2 is downregulated in human heart failure (HF), potentially underlying the loss of Ito,f. We investigated remodeling associated with HF hypothesizing that KChIP2 plays a central role in the modulation of outward K+ currents in HF. Methods and Results HF was induced by aortic banding in wild‐type (WT) and KChIP2 deficient (KChIP2–/–) mice, evaluated by echocardiography. Action potentials were measured by floating microelectrodes in intact hearts. Ventricular cardiomyocytes were isolated and whole‐cell currents were recorded by patch clamp. Left ventricular action potentials in KChIP2–/– mice were prolonged in a rate dependent manner, consistent with patch‐clamp data showing loss of a fast recovering outward K+ current and upregulation of the slow recovering Ito,s and IKur. HF decreased all outward K+ currents in WT mice and did not change the relative contribution of Ito,f in WT mice. Compared to WT HF, KChIP2–/– HF had a larger reduction of K+‐current density. However, the relative APD prolongation caused by HF was shorter for KChIP2–/– compared with WT, and the APs of the 2 HF mouse types were indistinguishable. Conclusion Ito,f is just one of many K+ currents being downregulated in murine HF. The downregulation of repolarizing currents in HF is accentuated in KChIP2–/– mice. However, the prolongation of APs associated with HF is less in KChIP2–/– compared to WT, suggesting other compensatory mechanism(s) in the KChIP2–/– mouse.