Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel.
Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel.
复制标题
利多卡因诱导的布鲁格达综合征表型与心脏钠通道的新型双突变有关。
DOI：
10.1161/circresaha.108.172619
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发表时间：
2008-08-15
影响因子：
20.1
通讯作者：
Dumaine, Robert
中科院分区：
文献类型：
--
作者：
Barajas-Martinez, Hector M.;Hu, Dan;Cordeiro, Jonathan M.;Wu, Yuesheng;Kovacs, Richard J.;Meltser, Henry;Kui, Hong;Elena, Burashnikov;Brugada, Ramon;Antzelevitch, Charles;Dumaine, Robert
Brugada综合征与SCN 5A突变有关。与钠通道缓慢分离的药物，如氟卡尼和阿曲库铵，可暴露Brugada综合征心电图并诱发室性心动过速/室颤。利多卡因是一种具有快速解离动力学的药物，先前已证明对Brugada综合征患者无影响。我们描述了在利多卡因（1 mg/kg）诱导的Brugada综合征的罕见病例中发现的一种新的SCN 5A双突变（DI-S4中的V232 I + DIII-S4中的L1308 F）。我们使用膜片钳技术研究了利多卡因阻断野生型和V232 I + L1308 F突变型哺乳动物TSA 201细胞中表达的心脏钠通道产生的INa。尽管V232 I + L1308 F和野生型钠电流之间的稳态门控参数在基线时无显著差异，但V232 I + L1308 F中利多卡因对INa的使用依赖性抑制比野生型更明显（在10 Hz下测量的10 μmol/L时分别为73.0±0.1%和18.23±0.04%）。与野生型相比，10 μmol/L利多卡因也导致V232 I + L1308 F的稳态失活负移（分别为-14.1 0. 3 mV和-4.8 0. 3 mV）。单个突变产生的影响要小得多。我们报告了第一例利多卡因诱发的Brugada心电图表型。SCN 5A、V232 I和L1308 F中的双突变改变了心脏钠通道对利多卡因的亲和力，使得药物呈现IC类特征，具有强效的钠通道使用依赖性阻滞。我们的研究结果表明，2个错义突变的叠加效应使钠通道对利多卡因敏感。这些发现表明，在使用I类抗肿瘤药物治疗携带此类遗传变异的患者时应谨慎。
Brugada syndrome has been linked to mutations in SCN5A. Agents that dissociate slowly from the sodium channel such as flecainide and ajmaline unmask the Brugada syndrome electrocardiogram and precipitate ventricular tachycardia/fibrillation. Lidocaine, an agent with rapid dissociation kinetics, has previously been shown to exert no effect in patients with Brugada syndrome. We characterized a novel double mutation of SCN5A (V232I in DI-S4+L1308F in DIII-S4) identified in a rare case of lidocaine (1 mg/kg)-induced Brugada syndrome. We studied lidocaine blockade of INa generated by wild-type and V232I+L1308F mutant cardiac sodium channels expressed in mammalian TSA201 cells using patch clamp techniques. Despite no significant difference in steady-state gating parameters between V232I+L1308F and wild-type sodium currents at baseline, use-dependent inhibition of INa by lidocaine was more pronounced in V232I+L1308F versus wild-type (73.0±0.1% versus 18.23±0.04% at 10 μmol/L measured at 10 Hz, respectively). A dose of 10 μmol/L lidocaine also caused a more negative shift of steady-state inactivation in V232I+L1308F versus wild-type (-14.1±0.3 mV and -4.8±0.3 mV, respectively). The individual mutations produced a much less accentuated effect. We report the first case of lidocaine-induced Brugada electrocardiogram phenotype. The double mutation in SCN5A, V232I, and L1308F alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes Class IC characteristics with potent use-dependent block of the sodium channel. Our results demonstrate an additive effect of the 2 missense mutations to sensitize the sodium channel to lidocaine. These findings suggest caution when treating patients carrying such genetic variations with Class I antiarrhythmic drugs.