Arrhythmic substrate, slowed propagation and increased dispersion in conduction direction in the right ventricular outflow tract of murine Scn5a+/ − hearts

Aim To test a hypothesis attributing arrhythmia in Brugada Syndrome to right ventricular ( RV ) outflow tract ( RVOT ) conduction abnormalities arising from Na v 1.5 insufficiency and fibrotic change. Methods Arrhythmic properties of Langendorff‐perfused Scn5a +/− and wild‐type mouse hearts were correlated with ventricular effective refractory periods ( VERP s), multi‐electrode array ( MEA ) measurements of action potential ( AP ) conduction velocities and dispersions in conduction direction (CD), Na v 1.5 expression levels, and fibrotic change, as measured at the RVOT and RV . Two‐way anova was used to test for both independent and interacting effects of anatomical region and genotype on these parameters. Results Scn5a+/ − hearts showed greater arrhythmic frequencies during programmed electrical stimulation at the RVOT but not the RV . The Scn5a +/− genotype caused an independent increase of VERP regardless of whether the recording site was the RVOT or RV . Effective AP conduction velocities ( CV †s), derived from fitting regression planes to arrays of observed local activation times were reduced in Scn5a +/− hearts and at the RVOT independently. AP conduction velocity magnitudes derived by averaging MEA results from local vector analyses, CV *, were reduced by the Scn5a +/− genotype alone. In contrast, dispersions in conduction direction, were greater in the RVOT than the RV , when the atrioventricular node was used as the pacing site. The observed reductions in Na v 1.5 expression were attributable to Scn5a +/−, whereas increased levels of fibrosis were associated with the RVOT . Conclusions The Scn5a +/− RVOT recapitulates clinical findings of increased arrhythmogenicity through reduced CV † reflecting reduced CV * attributable to reduced Na v 1.5 expression and increased CD attributable to fibrosis.