Aims Short QT syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in human-ether-a-go-go (HERG) underlying the rapid delayed-rectifier K+ current (IKr), leading to QT-shortening, ventricular arrhythmias, and sudden cardiac death. Data on efficient pharmacotherapy for SQT1 are scarce. In patients with primary carnitine-deficiency, acquired-short QT syndrome (SQTS) has been observed and rescued by carnitine supplementation. Here, we assessed whether carnitine exerts direct beneficial (prolonging) effects on cardiac repolarization in genetic SQTS. Methods and results Adult wild-type (WT) and transgenic SQT1 rabbits (HERG-N588K, gain of IKr) were used. In vivo electrocardiograms (ECGs), ex vivo monophasic action potentials (APs) in Langendorff-perfused hearts, and cellular ventricular APs and ion currents were assessed at baseline and during L-Carnitine/C16-Carnitine-perfusion. Two-dimensional computer simulations were performed to assess re-entry-based ventricular tachycardia-inducibility. L-Carnitine/C16-Carnitine prolonged QT-intervals in WT and SQT1, leading to QT-normalization in SQT1. Similarly, monophasic and cellular AP duration (APD) was prolonged by L-Carnitine/C16-Carnitine in WT and SQT1. As underlying mechanisms, we identified acute effects on the main repolarizing ion currents: IKr-steady, which is pathologically increased in SQT1, was reduced by L-Carnitine/C16-Carnitine and deactivation kinetics were accelerated. Moreover, L-Carnitine/C16-Carnitine decreased IKs-steady and IK1. In silico modelling identified IKr changes as the main factor for L-Carnitine/C16-Carnitine-induced APD-prolongation. 2D simulations revealed increased sustained re-entry-based arrhythmia formation in SQT1 compared to WT, which was decreased to the WT-level when adding carnitine-induced ion current changes. Conclusion L-Carnitine/C16-Carnitine prolong/normalize QT and whole-heart/cellular APD in SQT1 rabbits. These beneficial effects are mediated by acute effects on IKr. L-Carnitine may serve as a potential future QT-normalizing, anti-arrhythmic therapy in SQT1.

中文翻译：

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转基因短 QT 综合征 1 型兔模型中肉碱心脏复极的有益正常化


目的 1 型短 QT 综合征 （SQT1） 是一种遗传性离子通道病，由快速延迟整流器 K+ 电流 （IKr） 背后的人 ether-a-go-go （HERG） 功能获得性变异引起，导致 QT 缩短、室性心律失常和心源性猝死。关于 SQT1 有效药物治疗的数据很少。在原发性肉碱缺乏症患者中，已观察到获得性短 QT 综合征 （SQTS） 并通过补充肉碱来挽救。在这里，我们评估了肉碱是否对遗传 SQTS 中的心脏复极产生直接有益（延长）影响。方法和结果 使用成年野生型 （WT） 和转基因 SQT1 兔 （HERG-N588K，IKr 增益）。在基线和 L-肉碱/C16-肉碱灌注期间评估体内心电图 （ECG） 、Langendorff 灌注心脏中的离体单相动作电位 （AP） 以及细胞心室 AP 和离子电流。进行二维计算机模拟以评估基于折返的室性心动过速诱发性。左旋肉碱/C16-肉碱延长了 WT 和 SQT1 的 QT 间期，导致 SQT1 的 QT 正常化。同样，左旋肉碱/C16-肉碱在 WT 和 SQT1 中延长了单相和细胞 AP 持续时间 （APD）。作为潜在机制，我们确定了对主要复极化离子电流的急性影响： SQT1 中病理性增加的 IKr-steady 被左旋肉碱/C16-肉碱降低，失活动力学加速。此外，左旋肉碱/C16-肉碱降低 IKs-steady 和 IK1。计算机建模确定 IKr 变化是左旋肉碱/C16-肉碱诱导的 APD 延长的主要因素。 2D 模拟显示，与 WT 相比，SQT1 中基于持续折返的心律失常形成增加，当添加肉碱诱导的离子电流变化时，这种情况降低到 WT 水平。结论 左旋肉碱/C16-肉碱延长/正常化 SQT1 兔的 QT 和全心/细胞 APD。这些有益作用是由对 IKr 的急性作用介导的。左旋肉碱可能作为 SQT1 中潜在的未来 QT 正常化抗心律失常疗法。