Published Online
on December 4, 2006

A more recent version of this article appeared on December 12, 2006

This Article Full Text (PDF) Data Supplement All Versions of this Article: 114/24/2584    most recent CIRCULATIONAHA.106.653949v1 Alert me when this article is cited Alert me if a correction is posted 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 Remme, C. A. Articles by Bezzina, C. R. Search for Related Content PubMed PubMed Citation Articles by Remme, C. A. Articles by Bezzina, C. R. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Medline Plus Health Information Arrhythmia Related Collections Animal models of human disease Arrythmias-basic studies

Submitted on July 26, 2006
Revised on October 10, 2006
Accepted on October 13, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: c.a.remme{at}amc.uva.nl.

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.

Key words: conduction • death, sudden • electrophysiology • genetics • ion channels • long-QT syndrome • sodium

This article has been cited by other articles:

				K. Pilichou, C. A. Remme, C. Basso, M. E. Campian, S. Rizzo, P. Barnett, B. P. Scicluna, B. Bauce, M. J.B. van den Hoff, J. M.T. de Bakker, et al. Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2-related arrhythmogenic right ventricular cardiomyopathy J. Exp. Med., August 3, 2009; 206(8): 1787 - 1802. [Abstract] [Full Text] [PDF]

				M. Stein, T. A.B. van Veen, C. A. Remme, M. Boulaksil, M. Noorman, L. van Stuijvenberg, R. van der Nagel, C. R. Bezzina, R. N.W. Hauer, J. M.T. de Bakker, et al. Combined reduction of intercellular coupling and membrane excitability differentially affects transverse and longitudinal cardiac conduction Cardiovasc Res, July 1, 2009; 83(1): 52 - 60. [Abstract] [Full Text] [PDF]

				A. L. George Jr Genetic Modulation of Impaired Cardiac Conduction: Sodium Channel {beta}4 Subunit Missing in Action Circ. Res., June 5, 2009; 104(11): 1238 - 1239. [Full Text] [PDF]

				C. A. Remme, B. P. Scicluna, A. O. Verkerk, A. S. Amin, S. van Brunschot, L. Beekman, V. H.M. Deneer, C. Chevalier, F. Oyama, H. Miyazaki, et al. Genetically Determined Differences in Sodium Current Characteristics Modulate Conduction Disease Severity in Mice With Cardiac Sodium Channelopathy Circ. Res., June 5, 2009; 104(11): 1283 - 1292. [Abstract] [Full Text] [PDF]

				J. M. van Opstal, P. G.A. Volders, and H. J.G.M. Crijns Provocation of silence Europace, March 1, 2009; 11(3): 385 - 387. [Abstract] [Full Text] [PDF]

				M. Eijgelsheim, A. L.H.J. Aarnoudse, F. Rivadeneira, J. A. Kors, J. C. M. Witteman, A. Hofman, C. M. van Duijn, A. G. Uitterlinden, and B. H.C. Stricker Identification of a common variant at the NOS1AP locus strongly associated to QT-interval duration Hum. Mol. Genet., January 15, 2009; 18(2): 347 - 357. [Abstract] [Full Text] [PDF]

				B. J.D. Boukens, V. M. Christoffels, R. Coronel, and A. F.M. Moorman Developmental Basis for Electrophysiological Heterogeneity in the Ventricular and Outflow Tract Myocardium As a Substrate for Life-Threatening Ventricular Arrhythmias Circ. Res., January 2, 2009; 104(1): 19 - 31. [Abstract] [Full Text] [PDF]

				S. Casini, A. O. Verkerk, M. M.G.J. van Borren, A. C.G. van Ginneken, M. W. Veldkamp, J. M.T. de Bakker, and H. L. Tan Intracellular calcium modulation of voltage-gated sodium channels in ventricular myocytes Cardiovasc Res, January 1, 2009; 81(1): 72 - 81. [Abstract] [Full Text] [PDF]

				R. Shi, Y. Zhang, C. Yang, C. Huang, X. Zhou, H. Qiang, A. A. Grace, C. L.-H. Huang, and A. Ma The cardiac sodium channel mutation delQKP 1507-1509 is associated with the expanding phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy, and high incidence of youth sudden death Europace, November 1, 2008; 10(11): 1329 - 1335. [Abstract] [Full Text] [PDF]

				C. A. Remme and A. A.M. Wilde SCN5A overlap syndromes: no end to disease complexity? Europace, November 1, 2008; 10(11): 1253 - 1255. [Full Text] [PDF]

				U. Lisewski, Y. Shi, U. Wrackmeyer, R. Fischer, C. Chen, A. Schirdewan, R. Juttner, F. Rathjen, W. Poller, M. H. Radke, et al. The tight junction protein CAR regulates cardiac conduction and cell-cell communication J. Exp. Med., September 29, 2008; 205(10): 2369 - 2379. [Abstract] [Full Text] [PDF]

				N. Kalcheva, J. Qu, N. Sandeep, L. Garcia, J. Zhang, Z. Wang, P. D. Lampe, S. O. Suadicani, D. C. Spray, and G. I. Fishman Gap junction remodeling and cardiac arrhythmogenesis in a murine model of oculodentodigital dysplasia PNAS, December 18, 2007; 104(51): 20512 - 20516. [Abstract] [Full Text] [PDF]

				H. Abriel Roles and regulation of the cardiac sodium channel Nav1.5: Recent insights from experimental studies Cardiovasc Res, December 1, 2007; 76(3): 381 - 389. [Abstract] [Full Text] [PDF]

				M. Lei, H. Zhang, A. A. Grace, and C. L.-H. Huang SCN5A and sinoatrial node pacemaker function Cardiovasc Res, June 1, 2007; 74(3): 356 - 365. [Abstract] [Full Text] [PDF]