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Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a +/Δ murine hearts modelling long QT syndrome 3
Author(s) -
Stokoe Kate S.,
Thomas Glyn,
Goddard Catharine A.,
Colledge William H.,
Grace Andrew A.,
Huang Christopher L.H.
Publication year - 2007
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2006.117945
Subject(s) - flecainide , quinidine , medicine , repolarization , cardiology , long qt syndrome , brugada syndrome , short qt syndrome , ventricular tachycardia , electrophysiology , proarrhythmia , qt interval , atrial fibrillation
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 +/Δ) 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 +/Δ and zero out of 12 WT hearts. Paced electrogram fractionation analysis then demonstrated increased electrogram durations (EGD), expressed as EGD ratios, in arrhythmogenic Scn5a +/Δ hearts, and prolonged ventricular effective refractory periods in initially non‐arrhythmogenic Scn5a +/Δ hearts. Nevertheless, comparisons of epicardial and endocardial monophasic action potential recordings demonstrated negative transmural repolarization gradients in both groups, giving ΔAPD 90 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 +/Δ hearts, reducing EGD ratio and restoring ΔAPD 90 to + 7.55 ± 2.24 ms ( n = 9) ( P < 0.05). VT occurred in four out of eight non‐arrhythmogenic Scn5a +/Δ hearts in the presence of quinidine, which increased EGD ratio but left ΔAPD 90 unchanged. In contrast ( P < 0.05), WT hearts had positive ΔAPD 90 values (+ 11.72 ± 2.17 ms) ( n = 20). Flecainide then increased arrhythmic tendency and EGD ratio but conserved ΔAPD 90 ; reduced EGD ratios and unaltered ΔAPD 90 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 ΔAPD 90 in Scn5a +/Δ hearts. This is consistent with a hypothesis in which incomplete Na + channel inactivation in Scn5a +/Δ 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.