Abstract 18898: Abnormal Conduction and Arrhythmias Precede the Development of Dilated Cardiomyopathy in D1275n Mutant 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. The present experiments were designed establish the time course of these defects to further understand the pathophysiology of D1275N-related DCM. 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<0.05) and optical mapping at 3 and 10 weeks showed slow, dyssynchronous conduction in DN/DN mice. However, at 3 weeks, there was no significant difference in ejection fraction or heart rate. Indices of calcium handling were also near-identical in DN/DN and H/H mice, and there were no differences in alpha-actinin, ryanodine receptor, dystrophin, and syntroph...