Abstract 17778: Cellular and Functional Defects Contributing to Dilated Cardiomyopathy in SCN5A D1275N Mice

Background: The D1275N SCN5A mutation is associated with dilated cardiomyopathy (DCM) in humans. We have previously reported that in 12 week old mice carrying humanized SCN5A alleles, DCM is evident by echo in those homozygous for D1275N (DN/DN) compared to those homozygous for the wild-type allele (H/H), with striking conduction slowing and disorganization by ECG and mapping. Here we compared cellular structure, expression of sodium channel partners, and calcium handling in young (3-week) DN/DN versus H/H mice to identify early changes and thereby illuminate mechanisms for DCM in this model. Methods and Results: By 3 weeks, QRS duration was markedly prolonged and disorganized in DN/DN mice (HH, n=11, 9.8 ± 0.2; DN/DN, n=9, 22.3 ± 2.2 P ratio ) and SR calcium stores (H/H, 0.85±0.08; DN/DN, 0.92±0.07, F ratio ) were not statistically significantly different in DN/DN compared to H/H, arguing against aberrant calcium handling as a primary driver of DCM in these mice. Similarly, there were no differences in alpha-actinin or ryanodine receptor expression patterns by immunofluorescence. Expression of the sodium channel partners (and DCM associated genes) dystrophin and syntrophin were identical between H/H and DN/DN by immunostaining and Western blotting. Conclusions: Our present results support the hypothesis that slow, abnormal conduction detected by ECG at 3 weeks of age is a primary factor underlying DCM development.