Mechanisms of acquired Long QT syndrome in patients with propionic academia
Mechanisms of acquired Long QT syndrome in patients with propionic academia
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DOI：
10.1016/j.hrthm.2016.02.003
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发表时间：
2016-06-01
期刊：
影响因子：
5.5
通讯作者：
Odening, Katja E.
中科院分区：
文献类型：
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作者：
Bodi, Ilona;Gruenert, Sarah C.;Odening, Katja E.
背景技术丙酸血症(PROP)是一种罕见的代谢性疾病，由丙酰辅酶A羧化酶缺乏引起。 PROP 患者表现出与室性心动过速和晕厥相关的 QT 延长。导致这种获得性长 QT 综合征 (acqLQTS) 的机制尚不清楚。 目的 本研究的目的是研究 PROP 患者体内积累的代谢物对主要复极钾电流 (I-Ks 和 I-Kr) 及其通道亚基的急性和慢性影响。 方法 在 CHO-KCNQ1/KCNE1 或 HEK-KCNH2 细胞中进行电压阻尼研究，以确定丙酸 (PA; 1-10 mM)、丙酰肉碱 (PC；25 mu M-10 mM)、柠檬酸甲酯 (MC；25 mu M-10 mM)、0.2 M 磷酸盐缓冲液 (PB) 或 I-K 和 I-Kr 电流上的患者血清。在人诱导多能干细胞来源的心肌细胞 (hiPSC-CM) 中，以电流潮湿模式记录代谢对动作电位的影响。用蛋白质印迹法评估 I-Ks (KCNQ1/KCNE1) 和 I-Kr (KCNH2) 的 α 和 β 亚基的蛋白质表达。 结果 急性应用 PA、PC、MC 和患者血清对净 I-Kr 密度（和 KCNH2 表达）没有直接影响，尽管它改变了 I-Kr 门控动力学。相比之下，PA、PC、MC 和患者血清均降低 I-Ks 尾部 (-67% +/- 4.2%、-27% +/- 6.7%、-16% +/- 6.3%、-42.8% +/- 5.15；P < .001) 和 I-Ks 尾部脉冲电流。 PA 显着延长野生型 hiPSC-CM 的动作电位持续时间 (APD) 和 QT 间期，但在缺乏 I-K 的 LQT1 兔子中则不然。此外，PC 和 MC (1 mM) 降低了 KCNQ1 蛋白表达（相对密度：0.58 +/- 0.08 和 0.16 +/- 0.05；P < .01）。相反，长期暴露于 10 mM PA，由于蛋白质降解减少，KCNQ1 增加 5.4 倍 (P < .001)。 结论 PROP 代谢物引起的 I-K 急剧减少可能是在 PROP 患者中观察到的 APD 延长和 acqLQTS 的原因。
BACKGROUND Propionic acidemia (PROP) is a rare metabolic disorder caused by deficiency of propionyl-CoA carboxylase. PROP patients demonstrate QT prolongations associated with ventricular tachycardia and syncopes. Mechanisms responsible for this acquired long QT syndrome (acqLQTS) are unknown.OBJECTIVE The aim of the study was to investigate acute and chronic effects of metabolites accumulating in PROP patients on major repolarizing potassium currents (I-Ks and I-Kr) and their channel subunits.METHODS Voltage damp studies were performed in CHO-KCNQ1/KCNE1 or HEK-KCNH2 cells to determine effects of propionic acid (PA; 1-10 mM), propionylcarnitine (PC; 25 mu M-10 mM), methylcitrate (MC; 25 mu M-10 mM), 0.2 M phosphate buffer (PB), or patient serum on I-Ks and I-Kr currents. Metabolite effects on action potentials were recorded in current damp mode in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Protein expression of alpha- and beta-subunits of I-Ks (KCNQ1/KCNE1) and I-Kr (KCNH2) was evaluated with Western blots.RESULTS Acute application of PA, PC, MC, and patient serum had no direct effect on net I-Kr densities (and KCNH2 expression), although it changed I-Kr gating kinetics. In contrast, PA, PC, MC, and patient serum all reduced I-Ks-tail (-67% +/- 4.2%, -27% +/- 6.7%, -16% +/- 6.3%, -42.8% +/- 5.15; P < .001) and I-Ks-end pulse currents. PA significantly prolonged action potential duration (APD) in hiPSC-CM and QT interval in wild-type but not in LQT1 rabbits lacking I-Ks. Moreover, PC and MC (1 mM) decreased KCNQ1 protein expression (relative density: 0.58 +/- 0.08 and 0.16 +/- 0.05; P < .01). Chronic exposure to 10 mM PA, in contrast, increased KCNQ1 5.4-fold (P < .001) owing to decreased protein degradation.CONCLUSION Acute reduction of I-Ks by PROP metabolites may be responsible for APD prolongation and acqLQTS observed in PROP patients.