Regional variations in action potential alternans in isolated murine Scn5a+/- hearts during dynamic pacing

Matthews, G. D.K. ORCID:, Martin, C. A., Grace, A. A., Zhang, Y. and Huang, C. L.H. (2010) Regional variations in action potential alternans in isolated murine Scn5a+/- hearts during dynamic pacing. Acta Physiologica, 200 (2). pp. 129-146. ISSN 1748-1708

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Aim: Clinical observations suggest that alternans in action potential (AP) characteristics presages breakdown of normal ordered cardiac electrical activity culminating in ventricular arrhythmogenesis. We compared such temporal nonuniformities in monophasic action potential (MAP) waveforms in left (LV) and right ventricular (RV) epicardia and endocardia of Langendorff-perfused murine wild-type (WT), and Scn5a+/- hearts modelling Brugada syndrome (BrS) for the first time. Methods: A dynamic pacing protocol imposed successively incremented steady pacing rates between 5.5 and 33 Hz. A signal analysis algorithm detected sequences of >10 beats showing alternans. Results were compared before and following the introduction of flecainide (10 μm) and quinidine (5 μm) known to exert pro- and anti-arrhythmic effects in BrS. Results: Sustained and transient amplitude and duration alternans were both frequently followed by ventricular ectopic beats and ventricular tachycardia or fibrillation. Diastolic intervals (DIs) that coincided with onsets of transient (tr) or sustained (ss) alternans in MAP duration (DI*) and amplitude (DI′) were determined. Kruskal-Wallis tests followed by Bonferroni-corrected Mann-Whitney U-tests were applied to these DI results sorted by recording site, pharmacological conditions or experimental populations. WT hearts showed no significant heterogeneities in any DI. Untreated Scn5a+/- hearts showed earlier onsets of transient but not sustained duration alternans in LV endocardium compared with RV endocardium or LV epicardium. Flecainide administration caused earlier onsets of both transient and sustained duration alternans selectively in the RV epicardium in the Scn5a+/- hearts. Conclusion: These findings in a genetic model thus implicate RV epicardial changes in the arrhythmogenicity produced by flecainide challenge in previously asymptomatic clinical BrS.

Item Type: Article
Uncontrolled Keywords: alternans,arrhythmogenesis,na channel,scn5a,physiology ,/dk/atira/pure/subjectarea/asjc/1300/1314
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 10 Nov 2022 13:31
Last Modified: 10 Nov 2022 13:31
DOI: 10.1111/j.1748-1716.2010.02138.x

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