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Transgenic upregulation of IK1 in the mouse heart is proarrhythmic

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An Erratum to this article was published on 05 June 2007

Abstract

The role of the cardiac current Ik1 in arrhythmogenesis remains highly controversal. To gain further insights into the mechanisms of IK1 involvement in cardiac excitability, we studied the susceptibility of transgenic mice with altered IK1 to arrhythmia during various pharmacological and physiological challenges.Arrhythmogenesis was studied in transgenic mice expressing either dominant negative Kir2.1-AAA or wild type Kir2.1 subunits in the heart, models of IK1 suppression (AAA-TG) and up-regulation (WT-TG), respectively. Under normal conditions, both anesthetized wild type (WT) and AAA-TG mice did not display any spontaneous arrhythmias. In contrast,WT-TG mice displayed numerous arrhythmias of various types. In isolated hearts, the threshold concentration for halothane-induced ventricular tachycardias (VT) was increased to 170 % in the AAA-TG and decreased to 55 % in WT-TG hearts when compared to WT hearts. The number of PVCs induced by AV node ablation combined with hypokalemia was reduced in AAA-TG hearts and increased in WT-TG mice.After AV node ablation AAA-TG hearts were more tolerant, and WT-TG less tolerant to isoproterenol- induced arrhythmias than WT hearts. Analysis of monophasic action potentials in isolated hearts shows a significant reduction in the dispersion of action potential repolarization in mice with suppressed IK1. The data strongly support the hypothesis that in the mouse heart upregulation of IK1 is proarrhythmic, and that under certain conditions IK1 blockade in cardiac myocytes may be a potentially useful antiarrhythmic strategy.

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Author notes

  1. J. Li*

    Present address: Dept. of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (Hubei Prov.), P. R. China

Authors and Affiliations

  1. Dept. of Molecular & Integrative Physiology, University of Michigan, Room 7812, Medical Science II, 1150 W Medical Center Drive, Ann Arbor (MI), 48109, USA

    L. Piao*, J. Li*, M. McLerie &  A. N. Lopatin

Authors
  1. L. Piao*
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  2. J. Li*
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  3. M. McLerie
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  4. A. N. Lopatin
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Corresponding author

Correspondence to A. N. Lopatin.

Additional information

This study was supported by RO1 HL69052 grant from NHBLI (AL). Part of this work was presented at the AHA Scientific Sessions 2003: Li J.,McLerie M. and Lopatin A. N. Transgenic Regulation of IK1 in the Mouse Heart Strongly Affects Drug-Induced Arrhythmias. Circulation 2003; 108(17): P. IV-87; Pos. 410.

*Both authors contributed equally to the work.

An erratum to this article is available at http://dx.doi.org/10.1007/s00395-007-0679-7.

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Piao*, L., Li*, J., McLerie, M. et al. Transgenic upregulation of IK1 in the mouse heart is proarrhythmic. Basic Res Cardiol 102, 416–428 (2007). https://doi.org/10.1007/s00395-007-0659-y

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  • DOI: https://doi.org/10.1007/s00395-007-0659-y

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