Referenced in: none

Automatically associated channels: Nav1.5 , Slo1

Title: Mouse model of SCN5A-linked hereditary Lenègre's disease: age-related conduction slowing and myocardial fibrosis.

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

Journal, date & volume: Circulation, 2005 Apr 12 , 111, 1738-46

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/15809371

Abstract
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.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.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.