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.
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。