PDF(Pubmed)
Abstract：
SCN5A mutations are associated with various cardiac phenotypes, including long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), and cardiac conduction disease (CCD). Certain mutations, such as SCN5A-1795insD, lead to an overlap syndrome, with patients exhibiting both features of BrS/CCD [decreased sodium current (INa)] and LQT3 (increased late INa). The sodium channel blocker mexiletine may acutely decrease LQT3-associated late INa and chronically increase peak INa associated with SCN5A loss-of-function mutations. However, most studies have so far employed heterologous expression systems and high mexiletine concentrations. We here investigated the effects of a therapeutic dose of mexiletine on the mixed phenotype associated with the SCN5A-1795insD mutation in HEK293A cells and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
To assess only the chronic effects on trafficking, HEK293A cells transfected with wild-type (WT) SCN5A or SCN5A-1795insD were incubated for 48 h with 10 µm mexiletine followed by wash-out, which resulted in an increased peak INa for both SCN5A-WT and SCN5A-1795insD and an increased late INa for SCN5A-1795insD. Acute re-exposure of HEK293A cells to 10 µm mexiletine did not impact on peak INa but significantly decreased SCN5A-1795insD late INa. Chronic incubation of SCN5A-1795insD hiPSC-CMs with mexiletine followed by wash-out increased peak INa, action potential (AP) upstroke velocity, and AP duration. Acute re-exposure did not impact on peak INa or AP upstroke velocity, but significantly decreased AP duration.
These findings demonstrate for the first time the therapeutic benefit of mexiletine in a human cardiomyocyte model of SCN5A overlap syndrome.
To assess only the chronic effects on trafficking, HEK293A cells transfected with wild-type (WT) SCN5A or SCN5A-1795insD were incubated for 48 h with 10 µm mexiletine followed by wash-out, which resulted in an increased peak INa for both SCN5A-WT and SCN5A-1795insD and an increased late INa for SCN5A-1795insD. Acute re-exposure of HEK293A cells to 10 µm mexiletine did not impact on peak INa but significantly decreased SCN5A-1795insD late INa. Chronic incubation of SCN5A-1795insD hiPSC-CMs with mexiletine followed by wash-out increased peak INa, action potential (AP) upstroke velocity, and AP duration. Acute re-exposure did not impact on peak INa or AP upstroke velocity, but significantly decreased AP duration.
These findings demonstrate for the first time the therapeutic benefit of mexiletine in a human cardiomyocyte model of SCN5A overlap syndrome.
摘要：
目的：SCN5A突变与各种心脏表型相关，包括长QT综合征3型（LQT3），Brugada综合征（BrS），和心脏传导疾病（CCD）。某些突变,如SCN5A-1795insD，导致重叠综合征,患者同时表现出BrS/CCD[钠电流（INa）降低]和LQT3（晚期INa增加）的特征。钠通道阻断剂美西律可急性降低与LQT3相关的晚期INa，并慢性增加与SCN5A功能丧失突变相关的INa峰。然而,到目前为止，大多数研究都采用了异源表达系统和高浓度的美西律。我们在这里研究了治疗剂量的美西律对HEK293A细胞和人诱导的多能干细胞衍生的心肌细胞（hiPSC-CM）中与SCN5A-1795insD突变相关的混合表型的影响。
结果：为了仅评估对贩运的慢性影响，用野生型（WT）SCN5A或SCN5A-1795insD转染的HEK293A细胞与10μm美西律孵育48小时，然后洗出，这导致SCN5A-WT和SCN5A-1795insD的INa峰值增加，SCN5A-1795insD的INa晚期增加。HEK293A细胞急性再暴露于10µm美西律对INa峰值没有影响，但显着降低了SCN5A-1795insD晚期INa。SCN5A-1795insDhiPSC-CM与美西律的慢性孵育，随后洗脱峰值INa增加，动作电位（AP）上行程速度，和AP持续时间。急性再暴露对峰值INa或AP上冲程速度没有影响，但显着减少AP持续时间。
结论：这些发现首次证明了美西律在SCN5A重叠综合征的人心肌细胞模型中的治疗益处。
结果：为了仅评估对贩运的慢性影响，用野生型（WT）SCN5A或SCN5A-1795insD转染的HEK293A细胞与10μm美西律孵育48小时，然后洗出，这导致SCN5A-WT和SCN5A-1795insD的INa峰值增加，SCN5A-1795insD的INa晚期增加。HEK293A细胞急性再暴露于10µm美西律对INa峰值没有影响，但显着降低了SCN5A-1795insD晚期INa。SCN5A-1795insDhiPSC-CM与美西律的慢性孵育，随后洗脱峰值INa增加，动作电位（AP）上行程速度，和AP持续时间。急性再暴露对峰值INa或AP上冲程速度没有影响，但显着减少AP持续时间。
结论：这些发现首次证明了美西律在SCN5A重叠综合征的人心肌细胞模型中的治疗益处。
