In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 111, No. 14 ( 2005-04-12), p. 1738-1746
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. 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 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 β-MHC and skeletal α-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.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/01.CIR.0000160853.19867.61
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2005
detail.hit.zdb_id:
1466401-X