Mouse model of SCN5A-linked hereditary Lenegre's disease -: Age-related conduction slowing and myocardial fibrosis

Background-We have previously linked hereditary progressive cardiac conduction defect (hereditary Lenegre'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 Lenegre'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 Lenegre'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 Lenegre'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.