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

内科学 医学 赫尔格 短QT综合征 QT间期 室性心动过速 心脏病学 心室颤动 奎尼丁 后去极化 复极 长QT综合征 内分泌学 电生理学 钾通道
作者
Katja E. Odening,Ilona Bódi,Gerlind Franke,Raphaela Rieke,Anna Ryan de Medeiros,Stefanie Perez‐Feliz,Hannah E. Fürniss,Lea Mettke,Konstantin Michaelides,Corinna N. Lang,Johannes Steinfurt,Naga Deepa Pantulu,David Ziupa,Marius Menza,Manfred Zehender,Heiko Bugger,Rémi Peyronnet,Jan C. Behrends,Zoltán Doleschall,Axel zur Hausen,Christoph Bode,Geneviève Jolivet,Michael Brunner
出处
期刊:European Heart Journal [Oxford University Press]
卷期号:40 (10): 842-853 被引量:42
标识
DOI:10.1093/eurheartj/ehy761
摘要

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.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.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.
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