Abstract

AimTo test a hypothesis attributing arrhythmia in Brugada Syndrome to right ventricular (RV) outflow tract (RVOT) conduction abnormalities arising from Nav1.5 insufficiency and fibrotic change.MethodsArrhythmic properties of Langendorff-perfused Scn5a+/− and wild-type mouse hearts were correlated with ventricular effective refractory periods (VERPs), multi-electrode array (MEA) measurements of action potential (AP) conduction velocities and dispersions in conduction direction (CD), Nav1.5 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.ResultsScn5a+/− 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 Nav1.5 expression were attributable to Scn5a+/−, whereas increased levels of fibrosis were associated with the RVOT.ConclusionsThe Scn5a+/− RVOT recapitulates clinical findings of increased arrhythmogenicity through reduced CV† reflecting reduced CV* attributable to reduced Nav1.5 expression and increased CD attributable to fibrosis.

Highlights

  • An occurrence of ventricular tachycardia (VT) was defined as a period containing three or more consecutive ectopic beats detected by epicardial recording

  • Application of two successive runs of PES provoked arrhythmia with greater frequency in Scn5a+/À compared to WT hearts

  • They compare observations resulting from stimulation applied to the RV outflow tract (RVOT) (c) and right ventricular (RV) (d) of WT and Scn5a+/À hearts respectively

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Summary

Objectives

To test a hypothesis attributing arrhythmia in Brugada Syndrome to right ventricular (RV) outflow tract (RVOT) conduction abnormalities arising from Nav1.5 insufficiency and fibrotic change

Methods
Results
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