Arrhythmogenic substrate and its modification by nicorandil in a murine model of long QT type 3 syndrome

作者：Hothi Sandeep S^*; Booth Stephen W; Sabir Ian N; Killeen Matthew J; Simpson Fergus; Zhang Yanmin; Grace Andrew A; Huang Christopher L H

来源：Progress in Biophysics and Molecular Biology, 2008, 98(2-3): 267-280.

DOI：10.1016/j.pbiomolbio.2009.01.006

• Arrhythmia
• LQT3
• Mouse
• Nicorandil
• Ventricle

The gain-of-function Scn5a+/Delta KPQ mutation in the cardiac Na(+) channel Causes human long QT type 3 syndrome (LQT3) associated with ventricular arrhythmogenesis. The K(ATP) channel-opener nicorandil (20 mu M) significantly reduced arrhythmic incidence in Langendorff-perfused Scn5a+/Delta, 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 (APD(90)) that (2) restored transmural repolarization gradients, Delta APD(90). Scn5a+/Delta hearts showed longer epicardial but not endocardial APD(90)s, giving shorter Delta APD(90)s than WT hearts. Nicorandil reduced epicardial APD(90) in both Scn5a+/Delta and WT hearts thereby increasing Delta APD(90). (3) Reduced epicardial critical intervals for re-excitation: Scn5a+/Delta hearts showed greater differences between APD(90) and ventricular effective refractory period than WT hearts that were reduced by nicorandil. (4) Reduced APD(90) alternans. Scn5a+/Delta hearts showed greater epicardial and endocardial alternans than WTs, which increased with pacing rate. Nicorandil reduced these in Scn5a+/Delta hearts to levels indistinguishable from untreated WTs. (5) Flattened restitution curves. Scn5a+/Delta hearts showed larger epicardial and endocardial critical diastolic intervals than WT hearts. Nicorandil decreased these in Scn5a+/Delta, and WT hearts. The presence or absence of arrhythmogenesis in Scn5a+/Delta and WT hearth 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.

• 出版日期2008-11
• 单位西安交通大学