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(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

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