Frequency distribution analysis of activation times and regional fibrosis in murine Scn5a+/- hearts: the effects of ageing and sex

Abstract

Both Brugada Syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated respectively with diffuse and discrete alterations in conduction pathways affected by ageing and sex. This study assessed for contributions of such processes to the mechanism of conduction changes in Scn5a(+/-) and WT hearts stratified by age (3 and 12 months) and sex. In vivo electrocardiographic chest-lead assessment demonstrated greater incidences of bundle branch block in all Scn5a(+/-) mice compared to WT. Frequency analysis of right ventricular (RV) epicardial activation obtained from a 64-channel multi-electrode array demonstrated greater prominence of late conducting components in Scn5a(+/-) compared to WT male, and in male compared to female Scn5a(+/-) following stratification by genotype and sex. Similar differences were observed between old male Scn5a(+/-) and young male Scn5a(+/-), old female Scn5a(+/-), and old male WT, following stratification by genotype, age and sex. These findings directly correlated with histomorphometric assessment of regional fibrosis in both septa and free walls preferentially involving the RV. We demonstrate complex alterations in conduction distributions suggesting a conversion of normal to slow-conducting tissue, modulated by ageing and sex, coupled with fibrosis in Scn5a(+/-) hearts. These features suggest an overlap between pathophysiological processes related to BrS and PCCD in Scn5a(+/-) hearts.