Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility
Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility
复制标题
转基因短 QT 综合征 1 兔模仿人类疾病表型，心房和心室 QT/动作电位持续时间缩短，室性心动过速/心室颤动诱发性增加
作者：
K. Odening;I. Bódi;G. Franke;Raphaela Rieke;Anna Ryan de Medeiros;Stefanie Perez;H. Fürniss;Lea Mettke;Konstantinos Michaelides;C. Lang;J. Steinfurt;N. D. Pantulu;D. Ziupa;M. Menza;M. Zehender;H. Bugger;R. Peyronnet;J. Behrends;Z. Doleschall;A. zur Hausen;C. Bode;G. Jolivet;M. Brunner
目标
短QT综合征1(SQT1)是一种遗传性通道病，由于HERG/IKR的功能获得而加速复极。患者出现房颤、室性心动过速(VT)和心脏性猝死，其表型存在明显的个体差异。我们制备并鉴定了转基因的SQT1兔，并研究了电重构。
方法和结果
通过卵母细胞显微注射β-myosin-heavy-chain-promoter-KCNH2/HERG-N588K构建物产生转基因兔。对短QT综合征1和野生型(WT)仔鼠进行了体内心电图、电生理、磁共振成像和体外动作电位(AP)测量。用膜片钳、实时定量聚合酶链式反应和蛋白质印迹检测细胞的电重构。我们产生了三个SQT1创始人。QT间期缩短，QT/RR斜率低于WT组(Qt，147.8 ± 2 ms vs 166.4 ± 3，P <； 0.0001)。房室不应性和AP间期明显缩短(vAPD90,118.6 ± 5 ms vs 154.4 ± 2，P <； 0.0001)。室性心动过速/室颤(VT/VF)的诱发率在SQT1时增加。SQT1组心脏收缩功能无明显变化，但舒张期功能增强。随着SQT1失活的减弱，IKR-STRATE增加，而IKR-Tail减少。奎尼丁通过降低IKR延长/正常化SQT1兔的QT和动作电位时程。观察到了不同的电重构：在SQT1中，Ik1减少-部分逆转了表型-而Iks的少量增加可能部分导致了表型的加重。
结论
短QT综合征1兔在所有水平上模拟人类疾病的表型，QT/APD值缩短，VT/VF诱导性增加，并对奎尼丁表现出类似的有益反应，表明它们在阐明心律失常发生机制和识别新的抗心律失常策略方面具有价值。
AIMS
Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/IKr. Patients develop atrial fibrillation, ventricular tachycardia (VT), and sudden cardiac death with pronounced inter-individual variability in phenotype. We generated and characterized transgenic SQT1 rabbits and investigated electrical remodelling.
METHODS AND RESULTS
Transgenic rabbits were generated by oocyte-microinjection of β-myosin-heavy-chain-promoter-KCNH2/HERG-N588K constructs. Short-QT syndrome 1 and wild type (WT) littermates were subjected to in vivo ECG, electrophysiological studies, magnetic resonance imaging, and ex vivo action potential (AP) measurements. Electrical remodelling was assessed using patch clamp, real-time PCR, and western blot. We generated three SQT1 founders. QT interval was shorter and QT/RR slope was shallower in SQT1 than in WT (QT, 147.8 ± 2 ms vs. 166.4 ± 3, P < 0.0001). Atrial and ventricular refractoriness and AP duration were shortened in SQT1 (vAPD90, 118.6 ± 5 ms vs. 154.4 ± 2, P < 0.0001). Ventricular tachycardia/fibrillation (VT/VF) inducibility was increased in SQT1. Systolic function was unaltered but diastolic relaxation was enhanced in SQT1. IKr-steady was increased with impaired inactivation in SQT1, while IKr-tail was reduced. Quinidine prolonged/normalized QT and action potential duration (APD) in SQT1 rabbits by reducing IKr. Diverse electrical remodelling was observed: in SQT1, IK1 was decreased-partially reversing the phenotype-while a small increase in IKs may partly contribute to an accentuation of the phenotype.
CONCLUSION
Short-QT syndrome 1 rabbits mimic the human disease phenotype on all levels with shortened QT/APD and increased VT/VF-inducibility and show similar beneficial responses to quinidine, indicating their value for elucidation of arrhythmogenic mechanisms and identification of novel anti-arrhythmic strategies.
影响因子：
15.9
作者：
Brunner, Michael;Peng, Xuwen;Koren, Gideon
通讯作者：
Koren, Gideon