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

Y. Zhang, L. Guzadhur, K. Jeevaratnam, S. C. Salvage, G. D.K. Matthews, W. J. Lammers, M. Lei, C. L.H. Huang, J. A. Fraser

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Aim: 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: Arrhythmic 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. 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 Nav1.5 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 Nav1.5 expression and increased CD attributable to fibrosis.

Original languageEnglish
Pages (from-to)559-573
Number of pages15
JournalActa Physiologica
Volume211
Issue number4
DOIs
Publication statusPublished - Aug 2014

Keywords

  • Brugada Syndrome
  • Conduction velocity
  • Right ventricular outflow tract

ASJC Scopus subject areas

  • Physiology

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