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

Katja E. Odening; Ilona Bodi; Gerlind Franke; Raphaela Rieke; Anna Ryan de Medeiros; Stefanie Perez-Feliz; Hannah Fuerniss; Lea Mettke; Konstantin Michaelides; Corinna N. Lang; Johannes Steinfurt; Naga Deepa Pantulu; David Ziupa; Marius Menza; Manfred Zehender; Heiko Bugger; Remi Peyronnet; Jan C. Behrends; Zoltan Doleschall; Axel Zur Hausen; Christoph Bode; Genevieve Jolivet; Michael Brunner

doi:10.1093/eurheartj/ehy761

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

Katja E. Odening^*, Ilona Bodi, Gerlind Franke, Raphaela Rieke, Anna Ryan de Medeiros, Stefanie Perez-Feliz, Hannah Fuerniss, Lea Mettke, Konstantin Michaelides, Corinna N. Lang, Johannes Steinfurt, Naga Deepa Pantulu, David Ziupa, Marius Menza, Manfred Zehender, Heiko Bugger, Remi Peyronnet, Jan C. Behrends, Zoltan Doleschall, Axel Zur HausenChristoph Bode, Genevieve Jolivet, Michael Brunner

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Aims Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/I-Kr. 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 -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, 147.82ms vs. 166.4 +/- 3, P

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.

Original language	English
Pages (from-to)	842-853
Number of pages	12
Journal	European Heart Journal
Volume	40
Issue number	10
DOIs	https://doi.org/10.1093/eurheartj/ehy761
Publication status	Published - 7 Mar 2019

Keywords

Short-QT syndrome
Animal models
Cardiac repolarization
Ion channels
Electrical remodelling
Arrhythmia
SUDDEN-DEATH
MUTATION

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10.1093/eurheartj/ehy761

Cite this

Odening, K. E., Bodi, I., Franke, G., Rieke, R., de Medeiros, A. R., Perez-Feliz, S., Fuerniss, H., Mettke, L., Michaelides, K., Lang, C. N., Steinfurt, J., Pantulu, N. D., Ziupa, D., Menza, M., Zehender, M., Bugger, H., Peyronnet, R., Behrends, J. C., Doleschall, Z., ... Brunner, M. (2019). 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. European Heart Journal, 40(10), 842-853. https://doi.org/10.1093/eurheartj/ehy761

@article{5ddc69fccb1b44c085c3a7cfc1aa1bc9,

title = "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",

abstract = "Aims Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/I-Kr. 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 -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, 147.82ms vs. 166.4 +/- 3, PConclusion 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.",

keywords = "Short-QT syndrome, Animal models, Cardiac repolarization, Ion channels, Electrical remodelling, Arrhythmia, SUDDEN-DEATH, MUTATION",

author = "Odening, {Katja E.} and Ilona Bodi and Gerlind Franke and Raphaela Rieke and {de Medeiros}, {Anna Ryan} and Stefanie Perez-Feliz and Hannah Fuerniss and Lea Mettke and Konstantin Michaelides and Lang, {Corinna N.} and Johannes Steinfurt and Pantulu, {Naga Deepa} and David Ziupa and Marius Menza and Manfred Zehender and Heiko Bugger and Remi Peyronnet and Behrends, {Jan C.} and Zoltan Doleschall and {Zur Hausen}, Axel and Christoph Bode and Genevieve Jolivet and Michael Brunner",

note = "Funding Information: This work was supported by the German Research Foundation (DFG-BR2107/4-1 to K.E.O. and M.B.) and the {\textquoteleft}Margarete-von-Wrangell-Program{\textquoteright} by the Ministry of Science and Research Baden Wuerttemberg (to K.E.O.). Publisher Copyright: {\textcopyright} 2019 Published on behalf of the European Society of Cardiology. All rights reserved.",

year = "2019",

month = mar,

day = "7",

doi = "10.1093/eurheartj/ehy761",

language = "English",

volume = "40",

pages = "842--853",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "10",

}

Odening, KE, Bodi, I, Franke, G, Rieke, R, de Medeiros, AR, Perez-Feliz, S, Fuerniss, H, Mettke, L, Michaelides, K, Lang, CN, Steinfurt, J, Pantulu, ND, Ziupa, D, Menza, M, Zehender, M, Bugger, H, Peyronnet, R, Behrends, JC, Doleschall, Z, Zur Hausen, A, Bode, C, Jolivet, G & Brunner, M 2019, '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', European Heart Journal, vol. 40, no. 10, pp. 842-853. https://doi.org/10.1093/eurheartj/ehy761

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. / Odening, Katja E.; Bodi, Ilona; Franke, Gerlind et al.
In: European Heart Journal, Vol. 40, No. 10, 07.03.2019, p. 842-853.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - 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

AU - Odening, Katja E.

AU - Bodi, Ilona

AU - Franke, Gerlind

AU - Rieke, Raphaela

AU - de Medeiros, Anna Ryan

AU - Perez-Feliz, Stefanie

AU - Fuerniss, Hannah

AU - Mettke, Lea

AU - Michaelides, Konstantin

AU - Lang, Corinna N.

AU - Steinfurt, Johannes

AU - Pantulu, Naga Deepa

AU - Ziupa, David

AU - Menza, Marius

AU - Zehender, Manfred

AU - Bugger, Heiko

AU - Peyronnet, Remi

AU - Behrends, Jan C.

AU - Doleschall, Zoltan

AU - Zur Hausen, Axel

AU - Bode, Christoph

AU - Jolivet, Genevieve

AU - Brunner, Michael

N1 - Funding Information: This work was supported by the German Research Foundation (DFG-BR2107/4-1 to K.E.O. and M.B.) and the ‘Margarete-von-Wrangell-Program’ by the Ministry of Science and Research Baden Wuerttemberg (to K.E.O.). Publisher Copyright: © 2019 Published on behalf of the European Society of Cardiology. All rights reserved.

PY - 2019/3/7

Y1 - 2019/3/7

N2 - Aims Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/I-Kr. 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 -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, 147.82ms vs. 166.4 +/- 3, PConclusion 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.

AB - Aims Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/I-Kr. 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 -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, 147.82ms vs. 166.4 +/- 3, PConclusion 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.

KW - Short-QT syndrome

KW - Animal models

KW - Cardiac repolarization

KW - Ion channels

KW - Electrical remodelling

KW - Arrhythmia

KW - SUDDEN-DEATH

KW - MUTATION

U2 - 10.1093/eurheartj/ehy761

DO - 10.1093/eurheartj/ehy761

M3 - Article

C2 - 30496390

SN - 0195-668X

VL - 40

SP - 842

EP - 853

JO - European Heart Journal

JF - European Heart Journal

IS - 10

ER -

Odening KE, Bodi I, Franke G, Rieke R, de Medeiros AR, Perez-Feliz S et al. 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. European Heart Journal. 2019 Mar 7;40(10):842-853. doi: 10.1093/eurheartj/ehy761