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(Circulation. 2006;114:2584-2594.)
© 2006 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Overlap Syndrome of Cardiac Sodium Channel Disease in Mice Carrying the Equivalent Mutation of Human SCN5A-1795insD

Carol Ann Remme, MD, PhD; Arie O. Verkerk, PhD; Dieter Nuyens, MD, PhD; Antoni C. G. van Ginneken, PhD; Sandra van Brunschot, MSc; Charly N. W. Belterman, RA; Ronald Wilders, PhD; Marian A. van Roon, PhD; Hanno L. Tan, MD, PhD; Arthur A. M. Wilde, MD, PhD; Peter Carmeliet, MD, PhD; Jacques M. T. de Bakker, PhD; Marieke W. Veldkamp, PhD; Connie R. Bezzina, PhD

Experimental and Molecular Cardiology Group, Department of Cardiology (C.A.R., A.O.V., A.C.G.v.G., S.v.B., C.N.W.B., H.L.T., A.A.M.W., J.M.T.d.B., M.W.V., C.R.B.), Department of Physiology (A.O.V., A.C.G.v.G., R.W.), Facility for Genetically Modified Mice (M.A.v.R.), and Department of Clinical Genetics (C.R.B.), Academic Medical Center, University of Amsterdam, the Netherlands; The Center for Transgene Technology and Gene Therapy (D.N., P.C.), Flanders, Interuniversity Institute for Biotechnology, University of Leuven, Belgium; and Interuniversity Cardiology Institute of the Netherlands (J.M.T.d.B.), Utrecht, the Netherlands.

Correspondence to Dr Carol Ann Remme, MD, PhD, Department of Experimental Cardiology, Academic Medical Center, Room K2-110, PO Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail c.a.remme{at}amc.uva.nl

Received July 26, 2006; revision received October 10, 2006; accepted October 13, 2006.

Background— Patients carrying the cardiac sodium channel (SCN5A) mutation 1795insD show sudden nocturnal death and signs of multiple arrhythmia syndromes including bradycardia, conduction delay, QT prolongation, and right precordial ST-elevation. We investigated the electrophysiological characteristics of a transgenic model of the murine equivalent mutation 1798insD.

Methods and Results— On 24-hour continuous telemetry and surface ECG recordings, Scn5a^1798insD/+ heterozygous mice showed significantly lower heart rates, more bradycardic episodes (pauses 500 ms), and increased PQ interval, QRS duration, and QTc interval compared with wild-type mice. The sodium channel blocker flecainide induced marked sinus bradycardia and/or sinus arrest in the majority of Scn5a^1798insD/+ mice, but not in wild-type mice. Epicardial mapping using a multielectrode grid on excised, Langendorff-perfused hearts showed preferential conduction slowing in the right ventricle of Scn5a^1798insD/+ hearts. On whole-cell patch-clamp analysis, ventricular myocytes isolated from Scn5a^1798insD/+ hearts displayed action potential prolongation, a 39% reduction in peak sodium current density and a similar reduction in action potential upstroke velocity. Scn5a^1798insD/+ myocytes displayed a slower time course of sodium current decay without significant differences in voltage-dependence of activation and steady-state inactivation, slow inactivation, or recovery from inactivation. Furthermore, Scn5a^1798insD/+ myocytes showed a larger tetrodotoxin-sensitive persistent inward current compared with wild-type myocytes.

Conclusions— Mice carrying the murine equivalent of the SCN5A-1795insD mutation display bradycardia, right ventricular conduction slowing, and QT prolongation, similar to the human phenotype. These results demonstrate that the presence of a single SCN5A mutation is indeed sufficient to cause an overlap syndrome of cardiac sodium channel disease.

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