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BASIC SCIENCE

Electrical remodeling in hearts from a calcium-dependent mouse model of hypertrophy and failure

Complex nature of k⁺ current changes and action potential duration

Ilona Bodi, PhD, James N. Muth, PhD, Harvey S. Hahn, MD^*, Natasha N. Petrashevskaya, PhD, Marta Rubio, MPharm, Sheryl E. Koch, PhD, Gyula Varadi, PhD and Arnold Schwartz, PhD, FACC, FAHA^,*

^* Division of Cardiology, Department of Internal Medicine, Cincinnati, Ohio, USA
Institute of Molecular Pharmacology and Biophysics, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

Manuscript received September 13, 2002; revised manuscript received December 9, 2002, accepted December 18, 2002.

^* Reprint requests and correspondence: Dr. Arnold Schwartz, Institute of Molecular Pharmacology and Biophysics, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, Ohio, USA 45267-0828.
schwara{at}email.uc.edu

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 (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).

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: 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.

CONCLUSIONS: Contrary to accepted dogma, APD and I_to 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.

Abbreviations and Acronyms   APD90 or APD50 = action potential duration at 90% and 50% repolarization   Cm = cell membrane capacitance   EAD = early afterdepolarization   EP = electrophysiology   HF = heart failure   ICa = L-type calcium current   IK1 = inward rectifier potassium current   Isus = the current remaining at the end of the 680 ms pulse   Ito = transient outward potassium current (Ito,peak – Isus)   Ito,fast = rapidly inactivating and rapidly recovering component of Ito   Ito,peak = peak transient outward potassium current   Ito,slow = slowly inactivating and slowly recovering component of Ito   L-VDCC = L-type voltage-dependent calcium channel   NCX = Na+-Ca2+ exchanger   Ntg = nontransgenic   Tg = transgenic   fast = fast time constant of Ito inactivation or Ito recovery from inactivation   slow = slow time constant of Ito inactivation or Ito recovery from inactivation   %FS = percentage fractional shortening   4-AP = 4-aminopyridine

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