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¹ Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK
² Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK

Long QT(3) (LQT3) syndrome is associated with incomplete Na⁺ channel inactivation, abnormal repolarization kinetics and prolonged cardiac action potential duration (APD). Electrophysiological effects of flecainide and quinidine were compared in Langendorff-perfused wild-type (WT), and genetically modified (Scn5a+/) murine hearts modelling LQT3. Extra stimuli (S2) following trains of pacing stimuli (S1) applied to the right ventricular epicardium triggered ventricular tachycardia (VT) in 16 out of 28 untreated Scn5a+/ and zero out of 12 WT hearts. Paced electrogram fractionation analysis then demonstrated increased electrogram durations (EGD), expressed as EGD ratios, in arrhythmogenic Scn5a+/ hearts, and prolonged ventricular effective refractory periods in initially non-arrhythmogenic Scn5a+/ hearts. Nevertheless, comparisons of epicardial and endocardial monophasic action potential recordings demonstrated negative transmural repolarization gradients in both groups, giving APD₉₀ values at 90% repolarization of –20.88 ± 1.93 ms (n = 11) and –16.91 ± 1.43 ms (n = 23), respectively. Flecainide prevented initiation of VT in 13 out of 16 arrhythmogenic Scn5a+/ hearts, reducing EGD ratio and restoring APD₉₀ to + 7.55 ± 2.24 ms (n = 9) (P < 0.05). VT occurred in four out of eight non-arrhythmogenic Scn5a+/ hearts in the presence of quinidine, which increased EGD ratio but left APD₉₀ unchanged. In contrast (P < 0.05), WT hearts had positive APD₉₀ values (+ 11.72 ± 2.17 ms) (n = 20). Flecainide then increased arrhythmic tendency and EGD ratio but conserved APD₉₀; reduced EGD ratios and unaltered APD₉₀ values accompanied the lower arrhythmogenicity associated with quinidine treatment. In addition to the changes in EGD ratio shown by WT hearts, these findings attribute arrhythmogenesis and its modification by flecainide and quinidine to alterations in APD₉₀ in Scn5a+/ hearts. This is consistent with a hypothesis in which incomplete Na⁺ channel inactivation in Scn5a+/ hearts generates functional substrates dependent on altered refractoriness that cause abnormalities in activation and conduction of subsequent cardiac impulses. Any spatial heterogeneities between the epicardial and endocardial layers would thus cause fragmentation of the activation wavefront and contribute to electrogram spreading.

(Received 27 July 2006; accepted after revision 3 October 2006; first published online 5 October 2006)
Corresponding author C. L.-H. Huang: Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. Email: clh11{at}cam.ac.uk

This article has been cited by other articles:

				K. S. Stokoe, R. Balasubramaniam, C. A. Goddard, W. H. Colledge, A. A. Grace, and C. L.-H. Huang Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/ murine hearts modelling the Brugada syndrome J. Physiol., May 15, 2007; 581(1): 255 - 275. [Abstract] [Full Text] [PDF]