Background: Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in the Long-QT Syndrome Type 3 (LQT3). Previous studies suggest that narrowing the perinexus within the intercalated disc, leading to rapid sodium depletion, attenuates LQT3-associated action potential duration (APD) prolongation. However, it remains unknown whether extracellular sodium concentration modulates APD prolongation during sodium channel gain-of-function. We hypothesized that elevated extracellular sodium concentration and widened perinexus synergistically prolong APD in LQT3. Methods and Results: LQT3 was induced with anemone toxin type II (ATXII) in Langendorff-perfused guinea pig hearts (n=20). Sodium concentration was increased from 145 to 160 mM. Perinexal expansion was induced with mannitol or the sodium channel β1-subunit adhesion domain antagonist (βadp1). Epicardial ventricular action potentials were optically mapped. Individual and combined effects of varying clefts and sodium concentrations were simulated in a computational model. With ATXII, both mannitol and βadp1 significantly widened the perinexus and prolonged APD, respectively. The elevated sodium concentration alone significantly prolonged APD as well. Importantly, the combination of elevated sodium concentration and perinexal widening synergistically prolonged APD. Computational modeling results were consistent with animal experiments. Conclusions: Concurrently elevating extracellular sodium and increasing intercalated disc edema prolongs repolarization more than the individual interventions alone in the LQT3. This synergistic effect suggests an important clinical implication that hypernatremia in the presence of cardiac edema can markedly increase LQT3-associated APD prolongation. Therefore, this is the first study to provide evidence of a tractable and effective strategy to mitigate LQT3 phenotype by managing patient sodium levels and preventing cardiac edema.

中文翻译：

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高钠血症和椎间盘水肿协同加重长 QT 综合征 3 型表型

背景：心脏电压门控钠通道功能增益可延长 3 型长 QT 综合征 (LQT3) 的复极化。以前的研究表明，在椎间盘内缩小 perinexus，导致钠快速消耗，减弱 LQT3 相关动作电位持续时间 (APD) 的延长。然而，细胞外钠浓度是否在钠通道功能获得过程中调节 APD 延长仍然未知。我们假设升高的细胞外钠浓度和扩大的 perinexus 协同延长 LQT3 中的 APD。方法和结果：在 Langendorff 灌注的豚鼠心脏 (n=20) 中，用 II 型海葵毒素 (ATXII) 诱导 LQT3。钠浓度从 145 增加到 160 mM。用甘露醇或钠通道 β1-亚基粘附结构域拮抗剂 (βadp1) 诱导外膜扩张。心外膜心室动作电位被光学映射。在计算模型中模拟了不同裂缝和钠浓度的单独和组合效应。对于 ATXII，甘露醇和 βadp1 分别显着扩大了会阴部和延长了 APD。单独升高的钠浓度也会显着延长 APD。重要的是，升高的钠浓度和外周增宽相结合可协同延长 APD。计算建模结果与动物实验一致。结论：在 LQT3 中，同时升高细胞外钠和增加椎间盘水肿比单独干预更能延长复极化。这种协同效应表明一个重要的临床意义，即在存在心脏水肿的情况下高钠血症可以显着增加 LQT3 相关的 APD 延长。因此，这是第一项提供证据证明通过管理患者钠水平和预防心脏水肿来减轻 LQT3 表型的易处理且有效策略的研究。