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 Fürniss; 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

Eur Heart J. 2019 Mar 7;40(10):842-853. doi: 10.1093/eurheartj/ehy761.

Authors

Katja E Odening^{1

2}, Ilona Bodi^{1

2}, Gerlind Franke^{1

2}, Raphaela Rieke^{1

2}, Anna Ryan de Medeiros^{1

2}, Stefanie Perez-Feliz^{1

2}, Hannah Fürniss^{2

3

4}, Lea Mettke^{1

2}, Konstantin Michaelides^{1

2}, Corinna N Lang^{1

2}, Johannes Steinfurt^{1

2}, Naga Deepa Pantulu^{1

5

6}, David Ziupa^{1

2}, Marius Menza^{2

7}, Manfred Zehender^{1

2}, Heiko Bugger^{1

2}, Remi Peyronnet^{2

3}, Jan C Behrends^{2

8}, Zoltan Doleschall⁹, Axel Zur Hausen^{5

6}, Christoph Bode^{1

2}, Genevieve Jolivet¹⁰, Michael Brunner^{1

2

11}

Affiliations

¹ Department of Cardiology and Angiology I, Heart Center University of Freiburg, Hugstetter Str. 55, Freiburg, Germany.
² Faculty of Medicine, University of Freiburg, Breisacher Str. 153, Freiburg, Germany.
³ Institute for Experimental Cardiovascular Medicine, Heart Center University of Freiburg, Elsässer Str. 2Q, Freiburg, Germany.
⁴ Department of Congenital Heart Disease and Pediatric Cardiology, Heart Center University of Freiburg, Mathildenstr. 1, Freiburg, Germany.
⁵ Department of Pathology, University Hospital Freiburg, Breisacher Str. 115A, Freiburg, Germany.
⁶ Department of Pathology, Maastricht University Medical Center, AZ Maastricht, Netherlands.
⁷ Department of Radiology and Medical Physics, Medical Center University of Freiburg, Killianstraße 5a, Freiburg, Germany.
⁸ Department of Physiology, University of Freiburg, Hermann-Herder Straße 7, Freiburg, Germany.
⁹ Department of Pathogenetics, National Institute of Oncology, 7-9 Ráth György str, H-1122 Budapest, Hungary.
¹⁰ INRA, UMR1198 Biologie du Développement et Reproduction, Allée de Vilvert, Jouy-en-Josas, France.
¹¹ Department of Cardiology and Medical Intensive Care, St. Josefskrankenhaus, Sautierstraße 1, Freiburg, Germany.

PMID: 30496390
DOI: 10.1093/eurheartj/ehy761

Abstract

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.

Keywords: Animal models; Arrhythmia; Cardiac repolarization; Electrical remodelling; Ion channels; Short-QT syndrome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials* / drug effects
Action Potentials* / genetics
Action Potentials* / physiology
Animals
Animals, Genetically Modified
Anti-Arrhythmia Agents / pharmacology
Arrhythmias, Cardiac* / genetics
Arrhythmias, Cardiac* / physiopathology
Disease Models, Animal
Electrocardiography
Female
Heart Atria / physiopathology*
Heart Conduction System / abnormalities*
Heart Conduction System / physiopathology
Heart Defects, Congenital* / genetics
Heart Defects, Congenital* / physiopathology
Heart Ventricles / physiopathology*
Humans
Male
Phenotype
Quinidine / pharmacology
Rabbits

Substances

Anti-Arrhythmia Agents
Quinidine

Supplementary concepts

Short QT Syndrome 1