| First Author | Royer A | Year | 2005 |
| Journal | Circulation | Volume | 111 |
| Issue | 14 | Pages | 1738-46 |
| PubMed ID | 15809371 | Mgi Jnum | J:109689 |
| Mgi Id | MGI:3629469 | Doi | 10.1161/01.CIR.0000160853.19867.61 |
| Citation | Royer A, et al. (2005) Mouse model of SCN5A-linked hereditary Lenegre's disease: age-related conduction slowing and myocardial fibrosis. Circulation 111(14):1738-46 |
| abstractText | 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. |
