This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 97/1/62    most recent 01.RES.0000173047.42236.88v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Temple, J. Articles by Roden, D. M. Search for Related Content PubMed PubMed Citation Articles by Temple, J. Articles by Roden, D. M. Related Collections Arrythmias-basic studies Arrhythmias, clinical electrophysiology, drugs

(Circulation Research. 2005;97:62.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Atrial Fibrillation in KCNE1-Null Mice

Joel Temple, Patricio Frias, Jeffrey Rottman, Tao Yang, Yuejin Wu, E. Etienne Verheijck, Wei Zhang, Chanthaphaychith Siprachanh, Hideaki Kanki, James B. Atkinson, Paul King, Mark E. Anderson, Sabina Kupershmidt, Dan M. Roden

From the Departments of Medicine (J.R., T.Y., Y.W., M.E.A., D.M.R.), Pharmacology (W.Z., C.S., H.K., M.E.A., S.K., D.M.R.), Pediatrics (J.T., P.F.), Pathology (J.B.A.), and Biomedical Engineering (P.K.), Vanderbilt University School of Medicine, Nashville, Tenn; and the Academic Medical Center (E.E.V.), University of Amsterdam, Task Force Heart Failure and Aging, Department of Physiology, The Netherlands.

Correspondence to Dr Dan M. Roden, Director, Oates Institute for Experimental Therapeutics, Vanderbilt University, 532C Robinson Research Bldg I, Nashville, TN 37232-6602. E-mail dan.roden{at}vanderbilt.edu

Although atrial fibrillation is the most common serious cardiac arrhythmia, the fundamental molecular pathways remain undefined. Mutations in KCNQ1, one component of a sympathetically activated cardiac potassium channel complex, cause familial atrial fibrillation, although the mechanisms in vivo are unknown. We show here that mice with deletion of the KCNQ1 protein partner KCNE1 have spontaneous episodes of atrial fibrillation despite normal atrial size and structure. Isoproterenol abolishes these abnormalities, but vagomimetic interventions have no effect. Whereas loss of KCNE1 function prolongs ventricular action potentials in humans, KCNE1^–/– mice displayed unexpectedly shortened atrial action potentials, and multiple potential mechanisms were identified: (1) K⁺ currents (total and those sensitive to the KCNQ1 blocker chromanol 293B) were significantly increased in atrial cells from KCNE1^–/– mice compared with controls, and (2) when CHO cells expressing KCNQ1 and KCNE1 were pulsed very rapidly (at rates comparable to the normal mouse heart and to human atrial fibrillation), the sigmoidicity of I_Ks activation prevented current accumulation, whereas cells expressing KCNQ1 alone displayed marked current accumulation at these very rapid rates. Thus, KCNE1 deletion in mice unexpectedly leads to increased outward current in atrial myocytes, shortens atrial action potentials, and enhances susceptibility to atrial fibrillation.

Key Words: arrhythmia • atrial fibrillation • cardiac electrophysiology • mouse • potassium channels

This article has been cited by other articles:

				K. Nishida, G. Michael, D. Dobrev, and S. Nattel Animal models for atrial fibrillation: clinical insights and scientific opportunities Europace, February 1, 2010; 12(2): 160 - 172. [Abstract] [Full Text] [PDF]

				L. Pretorius, X.-J. Du, E. A. Woodcock, H. Kiriazis, R. C.Y. Lin, S. Marasco, R. L. Medcalf, Z. Ming, G. A. Head, J. W. Tan, et al. Reduced Phosphoinositide 3-Kinase (p110{alpha}) Activation Increases the Susceptibility to Atrial Fibrillation Am. J. Pathol., September 1, 2009; 175(3): 998 - 1009. [Abstract] [Full Text] [PDF]

				Y. Etzion, M. Mor, A. Shalev, S. Dror, O. Etzion, A. Dagan, O. Beharier, A. Moran, and A. Katz New insights into the atrial electrophysiology of rodents using a novel modality: the miniature-bipolar hook electrode Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1460 - H1469. [Abstract] [Full Text] [PDF]

				C.-T. Tsai, L.-P. Lai, J.-J. Hwang, J.-L. Lin, and F.-T. Chiang Molecular Genetics of Atrial Fibrillation J. Am. Coll. Cardiol., July 22, 2008; 52(4): 241 - 250. [Abstract] [Full Text] [PDF]

				M. E. Mangoni and J. Nargeot Genesis and Regulation of the Heart Automaticity Physiol Rev, July 1, 2008; 88(3): 919 - 982. [Abstract] [Full Text] [PDF]

				B. London An irregularly irregular inheritance. J. Am. Coll. Cardiol., March 18, 2008; 51(11): 1090 - 1091. [Full Text] [PDF]

				K. J. Sampson, C. Terrenoire, D. O. Cervantes, R. A. Kaba, N. S. Peters, and R. S. Kass Adrenergic regulation of a key cardiac potassium channel can contribute to atrial fibrillation: evidence from an IKs transgenic mouse J. Physiol., January 15, 2008; 586(2): 627 - 637. [Abstract] [Full Text] [PDF]

				V. E. Bondarenko and R. L. Rasmusson Simulations of propagated mouse ventricular action potentials: effects of molecular heterogeneity Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1816 - H1832. [Abstract] [Full Text] [PDF]

				O. Adam, G. Frost, F. Custodis, M. A. Sussman, H.-J. Schafers, M. Bohm, and U. Laufs Role of Rac1 GTPase Activation in Atrial Fibrillation J. Am. Coll. Cardiol., July 24, 2007; 50(4): 359 - 367. [Abstract] [Full Text] [PDF]

				G. Thomas, M. J. Killeen, I. S. Gurung, P. Hakim, R. Balasubramaniam, C. A. Goddard, A. A. Grace, and C. L.-H. Huang Mechanisms of ventricular arrhythmogenesis in mice following targeted disruption of KCNE1 modelling long QT syndrome 5 J. Physiol., January 1, 2007; 578(1): 99 - 114. [Abstract] [Full Text] [PDF]

				Z. Mustapha, L. Pang, and S. Nattel Characterization of the cardiac KCNE1 gene promoter Cardiovasc Res, January 1, 2007; 73(1): 82 - 91. [Abstract] [Full Text] [PDF]

				D. Dobrev and U. Ravens Do genetics help to better understand the underlying mechanisms of atrial fibrillation? Eur. Heart J., July 2, 2006; 27(14): 1640 - 1641. [Full Text] [PDF]