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(Circulation. 2005;111:1738-1746.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Mouse Model of SCN5A-Linked Hereditary Lenègre’s Disease

Age-Related Conduction Slowing and Myocardial Fibrosis

Anne Royer, PhD^*; Toon A.B. van Veen, PhD^*; Sabrina Le Bouter, PhD; Céline Marionneau, MSc; Violaine Griol-Charhbili, MSc; Anne-Laure Léoni, DVM; Marja Steenman, PhD; Harold V.M. van Rijen, PhD; Sophie Demolombe, PhD; Catharine A. Goddard, PhD; Christine Richer, PharmD, PhD; Brigitte Escoubet, MD, PhD; Thérèse Jarry-Guichard, PhD; William H. Colledge, PhD; Daniel Gros, PhD; Jacques M.T. de Bakker, PhD; Andrew A. Grace, PhD, FRCP; Denis Escande, MD, PhD; Flavien Charpentier, PhD

From l’Institut du Thorax, INSERM U533 (A.R., S.L.B., C.M., A.-L.L., M.S., S.D., D.E., F.C.), Faculté de Médecine, Nantes, France; the Department of Medical Physiology (T.A.B.v.V., H.V.M.v.R.), University Medical Center, Utrecht, the Netherlands; the Experimental and Molecular Cardiology Group (J.M.T.d.B.), Academic Medical Center, Amsterdam, the Netherlands; the Section of Cardiovascular Biology (C.A.G., W.H.C., A.A.G.), Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK; the Département de Pharmacologie (V.G.-C., C.R.), Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France; INSERM U426, CEFI IFR02 (B.E.), Université Paris 7, Paris, France; and CNRS UMR 6545, Institut de Biologie du Développement de Marseille (T.J.-G., D.G.), Université de la Méditerranée, Marseille, France.

Correspondence to Flavien Charpentier, PhD, INSERM U533, Institut du Thorax, Faculté de Médecine, 1 rue G. Veil, 44035 Nantes cedex, France. E-mail flavien.charpentier{at}nantes.inserm.fr

Received September 21, 2004; revision received November 30, 2004; accepted December 1, 2004.

Background— We have previously linked hereditary progressive cardiac conduction defect (hereditary Lenègre’s disease) to a loss-of-function mutation in the gene encoding the main cardiac Na⁺ channel, SCN5A. In the present study, we investigated heterozygous Scn5a-knockout mice (Scn5a^+/– mice) as a model for hereditary Lenègre’s disease.

Methods and Results— In Scn5a^+/– mice, surface ECG recordings showed age-related lengthening of the P-wave and PR- and QRS-interval duration, coinciding with previous observations in patients with Lenègre’s disease. Old but not young Scn5a^+/– mice showed extensive fibrosis of their ventricular myocardium, a feature not seen in wild-type animals. In old Scn5a^+/– mice, fibrosis was accompanied by heterogeneous expression of connexin 43 and upregulation of hypertrophic markers, including ß-MHC and skeletal -actin. Global connexin 43 expression as assessed with Western blots was similar to wild-type mice. Decreased connexin 40 expression was seen in the atria. Using pangenomic microarrays and real-time PCR, we identified in Scn5a^+/– mice an age-related upregulation of genes encoding Atf3 and Egr1 transcription factors. Echocardiography and hemodynamic investigations demonstrated conserved cardiac function with aging and lack of ventricular hypertrophy.

Conclusions— We conclude that Scn5a^+/– mice convincingly recapitulate the Lenègre’s disease phenotype, including progressive impairment with aging of atrial and ventricular conduction associated with myocardial rearrangements and fibrosis. Our work provides the first demonstration that a monogenic ion channel defect can progressively lead to myocardial structural anomalies.

Key Words: conduction • ion channels • remodeling

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