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

Zhang, Y, Guzadhur, L, Jeevaratnam, K, Salvage, SC, Matthews, GD, Lammers, WJ, Lei, M, Huang, CL and Fraser, JA (2014) Arrhythmic substrate, slowed propagation and increased dispersion in conduction direction in the right ventricular outflow tract of murine Scn5a+/- hearts. Acta Physiol (Oxf), 211 (4). pp. 559-573.

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Abstract

AIM: To test a hypothesis attributing arrhythmia in Brugada Syndrome to right ventricular (RV) outflow tract (RVOT) conduction abnormalities arising from Nav 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 (VERPs), multi-electrode array (MEA) measurements of action potential (AP) conduction velocities and dispersions in conduction direction (CD), Nav 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 Nav 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 Nav 1.5 expression and increased CD attributable to fibrosis.

Item Type: Article
Authors :
NameEmailORCID
Zhang, YUNSPECIFIEDUNSPECIFIED
Guzadhur, LUNSPECIFIEDUNSPECIFIED
Jeevaratnam, Kk.jeevaratnam@surrey.ac.ukUNSPECIFIED
Salvage, SCUNSPECIFIEDUNSPECIFIED
Matthews, GDUNSPECIFIEDUNSPECIFIED
Lammers, WJUNSPECIFIEDUNSPECIFIED
Lei, MUNSPECIFIEDUNSPECIFIED
Huang, CLUNSPECIFIEDUNSPECIFIED
Fraser, JAUNSPECIFIEDUNSPECIFIED
Date : August 2014
Identification Number : https://doi.org/10.1111/apha.12324
Uncontrolled Keywords : Brugada Syndrome, Na+ channel, conduction velocity, right ventricular outflow tract, Action Potentials, Animals, Arrhythmias, Cardiac, Blotting, Western, Brugada Syndrome, Disease Models, Animal, Electrophysiology, Female, Heart, Heart Conduction System, Male, Mice, Mice, Mutant Strains, NAV1.5 Voltage-Gated Sodium Channel, Organ Culture Techniques
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:27
Last Modified : 17 May 2017 14:49
URI: http://epubs.surrey.ac.uk/id/eprint/827838

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