Effects of Flecainide and Quinidine on Arrhythmogenic Properties of Scn5a+/- Murine Hearts Modelling the Brugada Syndrome

Overview

Journal J Physiol

Specialty Physiology

Date 2007 Feb 17

PMID 17303635

Citations 38

Authors

Kate S Stokoe

Richard Balasubramaniam

Catharine A Goddard

William H Colledge

Andrew A Grace

Christopher L-H Huang

Affiliations

Soon will be listed here.

Abstract

Brugada syndrome (BrS) is associated with a loss of Na+ channel function and an increased incidence of rapid polymorphic ventricular tachycardia (VT) and sudden cardiac death. A programmed electrical stimulation (PES) technique assessed arrhythmic tendency in Langendorff-perfused wild-type (WT) and genetically modified (Scn5a+/-) 'loss-of-function' murine hearts in the presence and absence of flecainide and quinidine, and the extent to which Scn5a+/- hearts model the human BrS. Extra-stimuli (S2), applied to the right ventricular epicardium, followed trains of pacing stimuli (S1) at progressively reduced S1-S2 intervals. These triggered VT in 16 out of 29 untreated Scn5a+/- and zero out of 31 WT hearts. VT occurred in 11 out of 16 (10 microM) flecainide-treated WT and nine out of the 13 initially non-arrhythmogenic Scn5a+/- hearts treated with (1.0 microM) flecainide. Quinidine (10 microM) prevented VT in six out of six flecainide-treated WT and 13 out of the 16 arrhythmogenic Scn5a+/- hearts in parallel with its clinical effects. Paced electrogram fractionation analysis demonstrated increased electrogram durations, expressed as electrogram duration (EGD) ratios, with shortening S1-S2 intervals in arrhythmogenic Scn5a+/- hearts, and prolonged ventricular effective refractory periods (VERPs) in non-arrhythmogenic Scn5a+/- hearts. Flecainide increased EGD ratios in WT (at 10 microM) and non-arrhythmogenic Scn5a+/- hearts (at 1.0 microM), whereas quinidine (10 microM) reduced EGD ratios and prolonged VERPs in WT and arrhythmogenic Scn5a+/- hearts. However, epicardial and endocardial monophasic action potential recordings consistently demonstrated positive gradients of repolarization in WT, arrhythmogenic and non-arrhythmogenic Scn5a+/- hearts under all pharmacological conditions. Together, these findings demonstrate proarrhythmic effects of flecainide in WT and Scn5a+/- murine hearts that recapitulate its clinical effects. They further attribute the arrhythmogenic phenomena observed here to re-entrant substrates resulting from delayed epicardial activation despite an absence of transmural heterogeneities of repolarization, in sharp contrast to recent characterizations in 'gain-of-function' Scn5a+/Delta murine hearts modelling the long-QT(3) syndrome.

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References

Belhassen B, Glick A, Viskin S . Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation. 2004; 110(13):1731-7. DOI: 10.1161/01.CIR.0000143159.30585.90. View

Locati E, Zareba W, MOSS A, Schwartz P, Vincent G, Lehmann M . Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation. 1998; 97(22):2237-44. DOI: 10.1161/01.cir.97.22.2237. View

Bauman J, Bauernfeind R, Hoff J, Strasberg B, Swiryn S, Rosen K . Torsade de pointes due to quinidine: observations in 31 patients. Am Heart J. 1984; 107(3):425-30. DOI: 10.1016/0002-8703(84)90081-4. View

. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989; 321(6):406-12. DOI: 10.1056/NEJM198908103210629. View

Yan G, Antzelevitch C . Cellular basis for the electrocardiographic J wave. Circulation. 1996; 93(2):372-9. DOI: 10.1161/01.cir.93.2.372. View

Zhang Z, Tranquillo J, Neplioueva V, Bursac N, Grant A . Sodium channel kinetic changes that produce Brugada syndrome or progressive cardiac conduction system disease. Am J Physiol Heart Circ Physiol. 2006; 292(1):H399-407. DOI: 10.1152/ajpheart.01025.2005. View

Saumarez R, Chojnowska L, Derksen R, Pytkowski M, Sterlinski M, Huang C . Sudden death in noncoronary heart disease is associated with delayed paced ventricular activation. Circulation. 2003; 107(20):2595-600. DOI: 10.1161/01.CIR.0000068342.96569.A1. View

Benhorin J, TAUB R, Goldmit M, Kerem B, Kass R, WINDMAN I . Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome?. Circulation. 2000; 101(14):1698-706. DOI: 10.1161/01.cir.101.14.1698. View

Vaidya D, Morley G, Samie F, Jalife J . Reentry and fibrillation in the mouse heart. A challenge to the critical mass hypothesis. Circ Res. 1999; 85(2):174-81. DOI: 10.1161/01.res.85.2.174. View

10.

Lei M, Honjo H, Kodama I, Boyett M . Characterisation of the transient outward K+ current in rabbit sinoatrial node cells. Cardiovasc Res. 2000; 46(3):433-41. DOI: 10.1016/s0008-6363(00)00036-5. View

11.

Fabritz L, Kirchhof P, Franz M, Nuyens D, Rossenbacker T, Ottenhof A . Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice. Cardiovasc Res. 2003; 57(4):1085-93. DOI: 10.1016/s0008-6363(02)00839-8. View

12.

Antzelevitch C, Brugada P, Brugada J, Brugada R, Shimizu W, Gussak I . Brugada syndrome: a decade of progress. Circ Res. 2002; 91(12):1114-8. DOI: 10.1161/01.res.0000046046.53721.90. View

13.

Liu H, Clancy C, Cormier J, Kass R . Mutations in cardiac sodium channels: clinical implications. Am J Pharmacogenomics. 2003; 3(3):173-9. DOI: 10.2165/00129785-200303030-00003. View

14.

Alings M, Wilde A . "Brugada" syndrome: clinical data and suggested pathophysiological mechanism. Circulation. 1999; 99(5):666-73. DOI: 10.1161/01.cir.99.5.666. View

15.

Knollmann B, Tranquillo J, Sirenko S, Henriquez C, Franz M . Microelectrode study of the genesis of the monophasic action potential by contact electrode technique. J Cardiovasc Electrophysiol. 2003; 13(12):1246-52. DOI: 10.1046/j.1540-8167.2002.01246.x. View

16.

Krishnan S, Antzelevitch C . Flecainide-induced arrhythmia in canine ventricular epicardium. Phase 2 reentry?. Circulation. 1993; 87(2):562-72. DOI: 10.1161/01.cir.87.2.562. View

17.

Grant A, Carboni M, Neplioueva V, Starmer C, Memmi M, Napolitano C . Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J Clin Invest. 2002; 110(8):1201-9. PMC: 150793. DOI: 10.1172/JCI15570. View

18.

Fujiki A, Usui M, Nagasawa H, Mizumaki K, Hayashi H, Inoue H . ST segment elevation in the right precordial leads induced with class IC antiarrhythmic drugs: insight into the mechanism of Brugada syndrome. J Cardiovasc Electrophysiol. 1999; 10(2):214-8. DOI: 10.1111/j.1540-8167.1999.tb00662.x. View

19.

Viswanathan P, Bezzina C, George Jr A, Roden D, Wilde A, Balser J . Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes. Circulation. 2001; 104(10):1200-5. DOI: 10.1161/hc3501.093797. View

20.

Head C, Balasubramaniam R, Thomas G, Goddard C, Lei M, Colledge W . Paced electrogram fractionation analysis of arrhythmogenic tendency in DeltaKPQ Scn5a mice. J Cardiovasc Electrophysiol. 2006; 16(12):1329-40. DOI: 10.1111/j.1540-8167.2005.00200.x. View