Knock-in gain-of-function sodium channel mutation prolongs atrial action potentials and alters atrial vulnerability
Knock-in gain-of-function sodium channel mutation prolongs atrial action potentials and alters atrial vulnerability
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DOI：
10.1016/j.hrthm.2010.08.016
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发表时间：
2010-12-01
期刊：
影响因子：
5.5
通讯作者：
Fabritz, Larissa
中科院分区：
文献类型：
--
作者：
Blana, Andreas;Kaese, Sven;Fabritz, Larissa
长QT综合征（LQTS）患者不仅室性心律失常的风险增加，而且心房病变（包括房颤（AF））的风险也增加。一些“孤立性”房颤患者携带Na+通道突变。目的本研究的目的是确定LQTS心房病理学的潜在机制。方法在具有心脏Na+通道的杂合敲入型长QT综合征3型（LQT 3）突变的小鼠中，（Delta KPQ-SCN 5A）和野生型（WT）同窝仔，心房大小，功能，结果心房肌动作电位时程、有效不应期、周期长度、心房肌电生理参数Delta KPQ-SCN 5A心脏的PQ和PQ间期延长（均P < .05）。氟卡尼（1 μ M）逆转心房动作电位时程延长和诱导的复极后不应性（P <0.05）。在WT和Delta KPQ-SCN 5A中，心律失常在规则快速心房率期间都不常见，但在40只Delta KPQ-SCN 5A中的15只（38%）和28只WT小鼠中的8只（29%）中，在额外刺激后可诱导心律失常。在9只Delta KPQ-SCN 5A小鼠中，产生频率快速变化的起搏方案引起房性期前收缩和心律失常的发生率为666%，而在6只WT小鼠中，引起房性期前收缩和心律失常的发生率为0（P <0.05）。在5月龄以上的Delta KPQ-SCN 5A小鼠中，心房直径增加了近10%，而纤维化组织没有增加。结论携带LQT 3突变的小鼠心脏显示心房电生理异常和心房尺寸的微妙变化，包括心房致炎表型。这些结果支持表明LQTS突变可引起心房病理学和心房肌生成的临床数据，并表明鼠钠通道LQTS模型可用于探索潜在机制。
BACKGROUND Patients with long QT syndrome (LQTS) are at increased risk not only for ventricular arrhythmias but also for atrial pathology including atrial fibrillation (AF). Some patients with "lone" AF carry Na+-channel mutations.OBJECTIVE The purpose of this study was to determine the mechanisms underlying atrial pathology in LQTS.METHODS In mice with a heterozygous knock-in long QT syndrome type 3 (LQT3) mutant of the cardiac Na+ channel (Delta KPQ-SCN5A) and wild-type (WT) littermates, atrial size, function, and electrophysiologic parameters were measured in intact Langendorff-perfused hearts, and histologic analysis was performed.RESULTS Atrial action potential duration, effective refractory period, cycle length, and PQ interval were prolonged in Delta KPQ-SCN5A hearts (all P < .05). Flecainide (1 mu M) reversed atrial action potential duration prolongation and induced postrepolarization refractoriness (P < .05). Arrhythmias were infrequent during regular rapid atrial rate in both WT and Delta KPQ-SCN5A but were inducible in 15 (38%) of 40 Delta KPQ-SCN5A and 8 (29%) of 28 WT mice upon extrastimulation. Pacing protocols generating rapid alterations in rate provoked atrial extrasystoles and arrhythmias in 6 66%) of 9 Delta KPQ-SCN5A but in 0 (0%) of 6 WT mice (P < .05). Atrial diameter was increased by nearly 10% in Delta KPQ-SCN5A mice > 5 months old without increase in fibrotic tissue.CONCLUSION Murine hearts bearing an LQT3 mutation show abnormalities in atrial electrophysiology and subtle changes in atrial dimension, including an atrial arrhythmogenic phenotype on provocation. These results support clinical data suggesting that LQTS mutations can cause atrial pathology and arrhythmogenesis and indicate that murine sodium channel LQTS models may be useful for exploring underlying mechanisms.