We have previously linked hereditary progressive cardiac conduction defect (hereditary Lenègre's disease) to 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 EKG recordings showed age-related lengthening of P wave, 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. Using pangenomic-microarrays, we identified in Scn5a+/- mice an age-related up-regulation of genes encoding Atf3 and Egr1 transcription factors. Echocardiography and hemodynamic investigations demonstrated conserved cardiac function with aging and lack of ventricular hypertrophy. Our work provides the first demonstration that a monogenic ion channel defect can progressively lead to myocardial structural anomalies. Finally, inbred Scn5a+/- mice show similar phenotype heterogeneity as Lenègre disease patients. Mice with a severe phenotype at a young age are more prone to develop ventricular arrhythmias.