Differences in sino-atrial and atrio-ventricular function with age and sex attributable to the Scn5a⁺/⁻ mutation in a murine cardiac model

To investigate the interacting effects of age and sex on electrocardiographic (ECG) features of Scn5a⁺/⁻ mice modelling Brugada syndrome. Recordings were performed on anaesthetized wild-type (WT) and Scn5a⁺/⁻ mice and differences attributable to these risk factors statistically stratified. Scn5a⁺/⁻ exerted sex-dependent effects upon sino-atrial function that only became apparent with age. RR intervals were greater in old male than in old female Scn5a⁺/⁻. Atrio-ventricular (AV) conduction was slower in young female mice, whether WT and Scn5a⁺/⁻, than the corresponding young male WT and Scn5a⁺/⁻. However, PR intervals lengthened with age in male but not in female Scn5a⁺/⁻ giving the greatest PR intervals in old male Scn5a⁺/⁻ compared with either old male WT or young male Scn5a⁺/⁻ mice. In contrast, PR intervals were similar in old female Scn5a⁺/⁻ and in old female WT. QTc was prolonged in Scn5a⁺/⁻ compared with WT, and female Scn5a⁺/⁻ compared with female WT. Age-dependent alterations in durations of ventricular repolarization relative to WT affected male but not female Scn5a⁺/⁻. Thus, T-wave durations were greater in old male Scn5a⁺/⁻ compared with old male WT, but indistinguishable between old female Scn5a⁺/⁻ and old female WT. Finally, analysis for combined interactions of genotype, age and sex demonstrated no effects on P wave and QRS durations and QTc intervals. We demonstrate for the first time that age, sex and genotype exert both independent and interacting ECG effects. The latter suggest alterations in cardiac pacemaker function, atrio-ventricular conduction and ventricular repolarization greatest in ageing male Scn5a⁺/⁻.