Electrical remodeling in hearts from a calcium-dependent mouse model of hypertrophy and failure -: Complex nature of K+ current changes and action potential duration

OBJECTIVES This study was designed to identify possible electrical remodeling (ER) in transgenic (Tg) mice with over-expressed L-type Ca2+ channels. Transient outward K+ current (It.) and action potential duration (APD) were studied in 2-, 4-, 8-, and 9- to 12-month-old mice to determine linkage to ventricular remodeling (VR), ER, and heart failure (HF). BACKGROUND Prolongation of APD and reduction in current density of I-to. are thought to be hallmarks of VR and HF. Mechanisms are not understood. METHODS Patch-clamp, perfused hearts, echocardiography, and Western blots were employed using 2-, 4-, 8-, and 9- to 12-month-old Tg mice. RESULTS Transgen'ic mice developed slow VR statistically manifesting at four months and continuing through death at 12 to 14 months, despite a slight up-regulation of I-to. A slight decrease or no change in APD was observed up to eight months; however, at 9 to 12 months, a small increase in APD was detected. Early after depolarizations were observed after application of 4-aminopyridine in Tg mice. No change was detected in protein of. Kv4.3 and Kv4.2 up to eight months. At 9 to 12 months, Tg mice showed a slight decrease (41.4 +/- 6.9%, p < 0.05) in Kv4.2, consistent with a decrease in I-to. Surprisingly, Kv1.4 (the "fetal" K+-channel form) was up-regulated, and restitution of I-to. was slowed. Echocardiography revealed cardiac enlargement with impaired chamber function in hearts that were taken from the older animals. CONCLUSIONS Contrary to accepted dogma, APD and It in a mouse model of hypertrophy and HF are not hallmarks of pathophysiology. We suggest that [Ca2+](i) (i.e., [Ca2+] concentration) is the primary factor in triggering cardiac enlargement and arrhythmogenesis. (C) 2003 by the American College of Cardiology Foundation.