title: Mouse model of SCN5A-linked hereditary Lenègre's disease: age-related conduction slowing and myocardial fibrosis.
abstract: 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.
  
  
  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 beta-MHC and skeletal alpha-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.
authors.affiliation: INSERM U533, Institut du Thorax, Faculté de Médecine, Nantes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Royer
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
authors.forename: Sabrina
authors.initials: S
authors.lastname: Le Bouter
authors.forename: Céline
authors.initials: C
authors.lastname: Marionneau
authors.forename: Violaine
authors.initials: V
authors.lastname: Griol-Charhbili
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Léoni
authors.forename: Marja
authors.initials: M
authors.lastname: Steenman
authors.forename: Harold V M
authors.initials: HV
authors.lastname: van Rijen
authors.forename: Sophie
authors.initials: S
authors.lastname: Demolombe
authors.forename: Catharine A
authors.initials: CA
authors.lastname: Goddard
authors.forename: Christine
authors.initials: C
authors.lastname: Richer
authors.forename: Brigitte
authors.initials: B
authors.lastname: Escoubet
authors.forename: Thérèse
authors.initials: T
authors.lastname: Jarry-Guichard
authors.forename: William H
authors.initials: WH
authors.lastname: Colledge
authors.forename: Daniel
authors.initials: D
authors.lastname: Gros
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.forename: Denis
authors.initials: D
authors.lastname: Escande
authors.forename: Flavien
authors.initials: F
authors.lastname: Charpentier
mesh_terms: D000367:Age Factors; D000818:Animals; D006332:Cardiomegaly; D017630:Connexins / Q000032:analysis; D004195:Disease Models, Animal; D004562:Electrocardiography; D005355:Fibrosis / Q000235:genetics; D005786:Gene Expression Regulation; D030342:Genetic Diseases, Inborn; D006327:Heart Block / Q000209:etiology / Q000235:genetics*; D006329:Heart Conduction System / Q000503:physiopathology*; D006352:Heart Ventricles / Q000473:pathology; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics*; D014157:Transcription Factors / Q000032:analysis
chemical_list: D017630:Connexins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D014157:Transcription Factors