Electrical remodeling in hearts from a calcium-dependent mouse model of hypertrophy and failure: complex nature of K+...

This study was designed to identify possible electrical remodeling (ER) in transgenic (Tg) mice with over-expressed L-type Ca(2+) channels. Transient outward K(+) current (I(to)) 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).

Prolongation of APD and reduction in current density of I(to) are thought to be hallmarks of VR and HF. Mechanisms are not understood.

Patch-clamp, perfused hearts, echocardiography, and Western blots were employed using 2-, 4-, 8-, and 9- to 12-month-old Tg mice.

Transgenic 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 afterdepolarizations 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.

Contrary to accepted dogma, APD and I(to) in a mouse model of hypertrophy and HF are not hallmarks of pathophysiology. We suggest that [Ca(2+)](i) (i.e., [Ca(2+)] concentration) is the primary factor in triggering cardiac enlargement and arrhythmogenesis.