Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8401801 | Progress in Biophysics and Molecular Biology | 2008 | 14 Pages |
Abstract
The gain-of-function Scn5a+/ÎKPQ mutation in the cardiac Na+ channel causes human long QT type 3 syndrome (LQT3) associated with ventricular arrhythmogenesis. The KATP channel-opener nicorandil (20 μM) significantly reduced arrhythmic incidence in Langendorff-perfused Scn5a+/Î hearts during programmed electrical stimulation; wild-types (WTs) showed a total absence of arrhythmogenicity. These observations precisely correlated with alterations in recently established criteria for re-entrant excitation reflected in: (1) shortened left-ventricular epicardial but not endocardial monophasic action potential durations at 90% repolarization (APD90) that (2) restored transmural repolarization gradients, ÎAPD90. Scn5a+/Î hearts showed longer epicardial but not endocardial APD90s, giving shorter ÎAPD90s than WT hearts. Nicorandil reduced epicardial APD90 in both Scn5a+/Î and WT hearts thereby increasing ÎAPD90. (3) Reduced epicardial critical intervals for re-excitation; Scn5a+/Î hearts showed greater differences between APD90 and ventricular effective refractory period than WT hearts that were reduced by nicorandil. (4) Reduced APD90 alternans. Scn5a+/Î hearts showed greater epicardial and endocardial alternans than WTs, which increased with pacing rate. Nicorandil reduced these in Scn5a+/Î hearts to levels indistinguishable from untreated WTs. (5) Flattened restitution curves. Scn5a+/Î hearts showed larger epicardial and endocardial critical diastolic intervals than WT hearts. Nicorandil decreased these in Scn5a+/Î and WT hearts. The presence or absence of arrhythmogenesis in Scn5a+/Î and WT hearts thus agreed with previously established criteria for re-entrant excitation, and alterations in these precisely correlated with the corresponding antiarrhythmic effects of nicorandil. Together these findings implicate spatial and temporal re-entrant mechanisms in arrhythmogenesis in LQT3 and their reversal by nicorandil.
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Authors
Sandeep S. Hothi, Stephen W. Booth, Ian N. Sabir, Matthew J. Killeen, Fergus Simpson, Yanmin Zhang, Andrew A. Grace, Christopher L.-H. Huang,