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Cardiovascular Research 2005 65(1):128-137; doi:10.1016/j.cardiores.2004.09.030
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Copyright © 2004, European Society of Cardiology

Expression of human ERG K+ channels in the mouse heart exerts anti-arrhythmic activity

Anne Royera,1, Sophie Demolombea,1, Aziza El Harchia, Khaï Le Quanga, Julien Pirona, Gilles Toumaniantza, David Mazuraisa, Chloé Bellocqa, Gilles Landea, Cécile Terrenoireb, Howard K. Motoikeb, Jean-Christophe Chevalliera, Gildas Loussouarna, Colleen E. Clancyc, Denis Escandea and Flavien Charpentiera,*

aINSERM U533, Institut du Thorax, Faculté de Médecine, 1 rue G. Veil, 44035 Nantes cedex, France
bDepartment of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
cDepartment of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY 10021, USA

* Corresponding author. Tel.: +33 240 41 28 44; fax: +33 240 41 29 50. Email address: flavien.charpentier{at}nantes.inserm.fr

Objective: The K+ channel encoded by the human ether-à-go-go-related gene (HERG) is crucial for repolarization in the human heart. In order to investigate the impact of HERG current (IKr) on the incidence of cardiac arrhythmias, we generated a transgenic mouse expressing HERG specifically in the heart.

Methods and results: ECG recordings at baseline showed no obvious difference between transgenic and wild-type (WT) mice with the exception of the T wave, which was more negative in transgenic mice than in WT mice. E4031 (20 mg/kg) prolonged the QTc interval and flattened the T wave in transgenic mice, but not in WT mice. Injection of BaCl2 (25 mg/kg) induced short runs of ventricular tachycardia in 9/10 WT mice, but not in transgenic animals. Atrial pacing reproducibly induced atrial tachyarrhythmias in 11/15 WT mice. In contrast, atrial arrhythmia was inducible in only 2/11 transgenic mice. When pretreated with dofetilide (10 mg/kg), transgenic mice were as sensitive to experimental arrhythmias as WT mice. Microelectrode studies showed that atrial action potentials have a steeper slope of duration-rate adaptation in WT than in transgenic mice. Transgenic mice were also characterized by a post-repolarization refractoriness, which could result from the substantial amount of IKr subsisting after repolarization as assessed with action potential-clamp experiments and simulations with a model of the transgenic mouse action potential.

Conclusion: HERG expression in the mouse heart can protect against experimental induction of arrhythmias. This is the first report of such a protective effect of HERG in vivo.

KEYWORDS Arrhythmia; Repolarization; K+ channel; Transgenic animal models

1 Contributed equally to this work.

Time for primary review 17 days


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