Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent
Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent
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DOI：
10.1161/01.res.85.9.803
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发表时间：
1999-10-29
影响因子：
20.1
通讯作者：
Antzelevitch, C
中科院分区：
文献类型：
--
作者：
Dumaine, R;Towbin, JA;Antzelevitch, C
Brugada综合征是猝死的主要原因，特别是在东南亚和日本血统的年轻男性中。该综合征的心电图特征为V1至V3的ST段抬高和可退化为心室颤动的快速多形性室性心动过速。我们的研究小组最近将这种疾病与SCN 5A的突变联系起来，SCN 5A是编码心脏钠通道cu亚基的基因。当在青蛙卵母细胞中异源表达时，从Thr1620Met错义突变体记录的电生理数据未能充分解释心电图表型。因此，我们试图进一步表征该突变体的电生理学。我们假设，在更多的生理温度下，错义突变可能会改变钠通道的门控，使净外向电流在右心室动作电位的早期阶段显着增加。在本研究中，我们通过在哺乳动物细胞系中表达Thr1620Met来验证这一假设，使用膜片钳技术研究32 ℃下的电流。我们的结果表明，Thr1620Met电流衰减动力学在32 ℃时比野生型更快。失活的恢复是缓慢的Thr1620Met在32摄氏度，和稳态激活显着转移。我们的研究结果解释了Brugada患者的心电图特征，首次说明了心脏钠通道突变，其致炎性仅在接近生理范围的温度下才显示，并表明某些患者在发热状态下可能更危险。
The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in SCN5A, the gene encoding for the cu subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32 degrees C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32 degrees C. Recovery from inactivation was slower for Thr1620Met at 32 degrees C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states.