Electrogram prolongation and nifedipine-suppressible ventricular arrhythmias in mice following targeted disruption of KCNE1
Electrogram prolongation and nifedipine-suppressible ventricular arrhythmias in mice following targeted disruption of KCNE1
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DOI：
10.1113/jphysiol.2003.048249
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发表时间：
2003-10-15
影响因子：
5.5
通讯作者：
Huang, CLH
中科院分区：
文献类型：
--
作者：
Balasubramaniam, R;Grace, AA;Huang, CLH
KCNE 1是编码缓慢激活的延迟整流钾电流（I-Ks）通道蛋白的1，8亚基的基因，其突变可能导致长QT综合征（LQTS），这是一种与增强的心肌梗死相关的疾病。KCNE 1编码序列纯合缺失的小鼠具有与相应人类条件中所见惊人相似的内耳缺陷。本研究证明并评估了与同龄野生型小鼠相比，纯合子KCNE 1-/-小鼠Langendorff灌注全心脏制备物中室性心律失常的机制。在实验系统中，首次使用起搏电描记图分段分析技术评估和量化了从基底右心室心外膜表面递减起搏的程控电刺激对从基底左心室记录的电描记图波形的影响。所有KCNE 1-/-（n = 10），但不是野生型（n = 14）小鼠心脏经验性地表现出明显的起搏诱导的心室致心律失常性。这与电描记图离散度的显著增加相关，与传导速度的更广泛分布一致，与钾通道突变的LQTS患者的临床结果平行。相反，在起搏过程中，100 nM异丙肾上腺素的引入诱导KCNE 1-/-（n = 7）和野生型（n = 6）心脏的促心律失常性。此外，用1 μ M硝苯地平预处理在KCNE 1-/-心脏（n = 12）中产生强的抗心律失常作用，即使在100 nM异丙肾上腺素（n = 6）存在下也持续存在。我们的研究结果将KCNE 1-/-与一种致瘤表型相关联，该表型显示传导速度的分散增加，并且其启动被硝苯地平阻止，这一发现反过来可能在LQTS等疾病中具有治疗应用。
Mutations in KCNE1, the gene encoding the,8 subunit of the slowly activating delayed rectifier potassium current (I-Ks) channel protein, may lead to the long QT syndrome (LQTS), a condition associated with enhanced arrhythmogenesis. Mice with homozygous deletion of the coding sequence of KCNE1 have inner ear defects strikingly similar to those seen in the corresponding human condition. The present study demonstrated and assessed the mechanism of ventricular arrhythmias in Langendorff-perfused whole heart preparations from homozygous KCNE1-/- mice compared to wild-type mice of the same age. The effects of programmed electrical stimulation with decremental pacing from the basal right ventricular epicardial surface upon electrogram waveforms recorded from the basal left ventricle were assessed and quantified using techniques of paced electrogram fractionation analysis for the first time in an experimental system. All KCNE1-/-(n = 10) but not wild-type (n = 14) mouse hearts empirically demonstrated marked pacing-induced ventricular arrhythmogenicity. This correlated with significant increases in electrogram dispersion, consistent with a wider spread in conduction velocities, in parallel with clinical findings from LQTS patients with potassium channel mutations. In contrast, introduction of 100 nM isoprenaline induced arrhythmogenicity in both KCNE1-/- (n = 7) and wild-type (n = 6) hearts during pacing. Furthermore, pretreatment with I muM nifedipine exerted a strong anti-arrhythmic effect in the KCNE1-/- hearts (n = 12) that persisted even in the presence of 100 nM isoprenaline (n = 6). Our findings associate KCNE1-/- with an arrhythmogenic phenotype that shows an increased dispersion of conduction velocities, and whose initiation is prevented by nifedipine, a finding that in turn may have therapeutic applications in conditions such as LQTS.