Revealing the Concealed Nature of Long-QT Type 3 Syndrome.
Revealing the Concealed Nature of Long-QT Type 3 Syndrome.
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DOI：
10.1161/circep.116.004400
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发表时间：
2017-02
期刊：
影响因子：
--
通讯作者：
Weinberg SH
中科院分区：
文献类型：
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作者：
Greer-Short A;George SA;Poelzing S;Weinberg SH
电压门控钠通道（Nav1.5）的功能获得突变与长QT-3 （LQT3）综合征有关。Nav1.5密集地表达在嵌入的圆盘上，狭窄的细胞间分离可以通过细胞外电场和局部钠离子纳米结构域的耗尽来调节细胞间的偶联。模型预测细胞间隙宽度的显著减少会减缓传导，这是由于钠电流驱动力的减少，称为“自衰减”。我们验证了新的假设，即自衰减可以通过减少产生早期后去极化（EADs）的驱动力和晚期钠电流来“掩盖”LQT3表型。在离体豚鼠心脏实验中，采用急性间质水肿（AIE）增加细胞间隙宽度。在药物诱导的LQT3模型中，AIE加重动作电位持续时间延长并产生EADs，特别是在慢起搏速率下。在一个包含细胞外电场耦合、细胞间隙钠纳米结构域和lqt3相关突变通道的心脏组织计算模型中，心肌细胞在宽的细胞间隙中产生EADs，而在窄的细胞间隙中，EADs被抑制。无论是宽裂还是窄裂，突变体通道都不完全失活。然而，对于窄间隙，后期钠电流通过自衰减减少，保护性负反馈机制，掩盖了EADs。我们展示了一种在LQT3模型中导致EADs隐藏和暴露的新机制。模拟预测这种机制可能独立于特定突变而起作用，这表明未来的治疗可能针对细胞间隙分离作为钠通道的补充或替代。
Gain-of-function mutations in the voltage-gated sodium channel (Nav1.5) are associated with the long QT-3 (LQT3) syndrome. Nav1.5 is densely expressed at the intercalated disk, and narrow intercellular separation can modulate cell-to-cell coupling via extracellular electric fields and depletion of local sodium ion nanodomains. Models predict that significantly decreasing intercellular cleft widths slows conduction due to reduced sodium current driving force, termed “self-attenuation.” We tested the novel hypothesis that self-attenuation can “mask” the LQT3 phenotype by reducing the driving force and late sodium current that produces early afterdepolarizations (EADs). Acute interstitial edema (AIE) was used to increase intercellular cleft width in isolated guinea pig heart experiments. In a drug-induced LQT3 model, AIE exacerbated action potential duration prolongation and produced EADs, in particular at slow pacing rates. In a computational cardiac tissue model incorporating extracellular electric field coupling, intercellular cleft sodium nanodomains, and LQT3-associated mutant channels, myocytes produced EADs for wide intercellular clefts, while for narrow clefts, EADs were suppressed. For both wide and narrow clefts, mutant channels were incompletely inactivated. However, for narrow clefts, late sodium current was reduced via self-attenuation, a protective negative feedback mechanism, masking EADs. We demonstrated a novel mechanism leading to the concealing and revealing of EADs in LQT3 models. Simulations predict that this mechanism may operate independent of the specific mutation, suggesting that future therapies could target intercellular cleft separation as a compliment or alternative to sodium channels.