16 Delayed conduction and its implications in murine SCN5a+/− hearts: independent and interacting effects of genotype, age and sex

SCN5A haploinsufficiencies are implicated in clinical arrhythmic conditions associated with cardiac conduction disorders. We examined myocardial conduction and its dispersion, and relationships between them, in murine Scn5a+/– hearts modelling such clinical conditions. A 64- channel, multi-electrode array of electrode spacing 0.55-mm compared patterns of right ventricular activation in intrinsically beating Langendorff-perfused, male and female, and young (3 months) and old (>12-month-old), Scn5a+/− and WT hearts, from which monophasic action potentials were also obtained. Mean ventricular activation times (T*MEAN), spatial dispersions (D*S) between recording channels within a given cardiac cycle, and maximum activation times (T*MAX) representing the slowest possible conduction in any given heart were all higher in old male Scn5a+/– compared to young male and old female Scn5a+/– and old male WT. Temporal dispersions (D*T) of ventricular activation times at given recording channels were similarly higher in old male Scn5a+/– compared to old male WT. In contrast, T*MEAN, D*T, D*S and T*MAX were indistinguishable between all WT groups. All groupings of D*T, D*S and T*MAX gave linear correlations with T*MEAN, each with indistinguishable slopes. In contrast, measures of monophasic action potential duration were indistinguishable between all groups. Genotype, age and sex thus exert significant (p<0.05) independent and/or interacting effects on both myocardial conduction and its dispersion. These variates appeared to influence D*T, D*S and T*MAX through actions on T*MEAN. Effects on both myocardial conduction and dispersion were greatest in old male Scn5a+/– in direct parallel with features of the corresponding clinical arrhythmogenecity in Brugada Syndrome.