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AG Experimentelle kardiale Elektrophysiologie

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Laboratory for Experimental Cardiac Electrophysiology


              

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Laboratory for Experimental Cardiac Electrophysiology

 
                   External webpage: www.OdeningLab.org

The general goal of the Laboratory for Experimental Cardiac Electrophysiology is to advance the mechanistic understanding of the pathogenesis of cardiac arrhythmias. Using different transgenic rabbit models of human inherited arrhythmogenic diseases such as long-QT and short-QT syndrome, our laboratory aims at elucidating molecular mechanisms of arrhythmogenesis. The main focus is on investigating the pro- or anti-arrhythmic effects of intrinsic and extrinsic factors - such as hormones or drugs - to deepen our understanding of how the arrhythmogenic phenotype can be modulated.

We have recently generated transgenic long-QT syndrome type 1 and type 2 rabbits over-expressing dominant-negative loss-of-function pore mutants of the human repolarizing K+ channels KvLQT1 (LQT1) or HERG (LQT2) in a cooperative project with Brown University (CVRC, Providence, RI, USA) and Penn State University (Hershey, PA, USA). These LQT1 and LQT2 rabbits are the first genetic models for long-QT syndrome in larger mammals and are the first animal models to mimic the human LQTS phenotype with QT prolongation, steeper QT/RR ratio in females, spontaneous pVTs, and SCD - with a particularly high incidence of SCD in the post-partum period. We are using these transgenic rabbit models to investigate how extrinsic and intrinsic factors modulate the arrhythmogenic phenotype and how these findings can help us in treating LQTS patients.

Pro- and anti-arrhythmic hormone effects in LQT2

Women with inherited long-QT syndrome type 2 (LQT2) are at higher risk for polymorphic ventricular tachycardia and sudden cardiac death than men and exhibit a particularly high arrhythmia incidence during the postpartum period. We have elucidated that sex hormones modulate the arrhythmogenic risk in transgenic LQT2 rabbits: estradiol exerts a pro-arrhythmic effect and progesterone and testosterone exert an anti-arrhythmic, protective effect in LQT2 syndrome in vivo. These differential effects are due to changes in the dispersion of repolarization, the susceptibility to pro-arrhythmic sympathetic stimuli and the regional expression of ion channels and Ca²+ cycling proteins.

Currently, we are investigating the mechanisms underlying these hormone-induced changes in the susceptibility to sympathetic stimuli and the mechanisms responsible arrhythmogenic effects of the postpartum hormones oxytocin and prolactin.

This work is in collaboration with the Prof. Gideon Koren and Prof. Bum-Rak Choi both at Brown University, Providence, USA, Prof. Xuwen Peng at Penn State University, Hershey, USA, and Prof. Lutz Hein at
Pharmacology Department, University Freiburg. It is funded by the German Research Foundation (DFG), the German Cardiac Society (DGK), the American Heart Association (AHA), the Prof. Just Foundation (Heilmeyer Stipendium), and the Margarete von Wrangell Program by the MWK Baden Württemberg and the European Social Fund.

Mechanisms of arrhythmogenesis in transgenic short-QT syndrome rabbits

We are currently in the process of generating transgenic short-QT syndrome (SQTS) rabbit models with gain-of-function mutations in repolarizing cardiac K+ channels as next transgenic animal model of arrhythmogenic diseases. SQTS is a recently identified inherited arrhythmogenic disease in which a pathological shortening of cardiac repolarization confers an arrhythmogenic phenotype. Patients are not only prone to polymorphic ventricular tachycardia and sudden cardiac death but also develop atrial fibrillation – the most common arrhythmia in humans. We will use this transgenic model to investigate the mechanisms of arrhythmogenesis in this relatively new disease entity and aim at elucidating pro-arrhythmic triggers in SQTS.

This work is in collaboration with Dr. Genevieve Jolivet at the INRA, Jouy-en-Josas, France, and Prof. Axel zur Hausen Dept. of Pathology, Maastricht, NL. It is funded by the German Research Foundation (DFG) and the Margarete von Wrangell Program by the MWK Baden Württemberg and the European Social Fund.

Electromechanical dysfunction in LQTS – image-based bio-physical modeling

We aim at elucidating how the impaired cardiac repolarization in LQTS affects mechanical function using phase contrast magnetic resonance imaging methods to determine regional differences in myocardial contraction and relaxation velocities in transgenic LQTS rabbits and human LQTS patients. Combining these data on mechanical function with monophasic action potential data on regional electrical function and data on regional differences in ion channel expression, we aim at generating an electromechanical in silico model of the LQTS heart.

This work is in collaboration with Dr. Daniela Foell, Cardiac MRI, Dept. of Cardiology, Heart Center University Hospital Freiburg, Dr. Bernd Jung, Department of Diagnostic, University Hospital Freiburg, Interventional and Pediatric Cardiology, University Hospital of Bern, Prof. Brigitte Stiller, Pediatric Cardiology, Heart Center University of Freiburg, Prof. Maxime Sermesant at the INRIA, Sophia-Antipolis, France, and King's College, London, UK, Gunnar Seemann, Karlsruhe Institute of Technology, and Prof. Peter Kohl, Imperial College London, UK.

Drug-effects on electromechanical dysfunction and arrhythmogenesis in LQTS

Drug-induced QT prolongations and polymorphic VTs are major and potentially fatal adverse drug-effects of a variety of different drug classes (such as anti-depressant, anti-psychotic, or antibiotic drugs) and have already caused the withdrawal of several widely used drugs from the market. However, not only the “classical” IKr blocking agents but also IKs blocking drugs can exert pro-arrhythmic effects in subjects with a reduced repolarization reserve. We aim at establishing whether the transgenic LQT1 and LQT2 rabbits could serve as an in vivo model to assess QT-prolonging and -shortening properties of drugs and to differentiate their arrhythmogenic risk. Therefore, we investigate drug effects on cardiac repolarization, electromechanical function, and arrhythmogenesis in transgenic LQTS rabbits.

This work is in collaboration with Dr. Daniela Foell, Cardiac MRI, Dept. of Cardiology, Freiburg, PD Dr. Bernd Jung, Department of Diagnostic, Freiburg, Interventional and Pediatric Radiology, University Hospital of Bern, Prof. Dr. Maxime Sermesant at INRIA, Sophia-Antipolis, France, and King's College, London, UK, and Prof. Morten Grunnet, Danish Arrhythmia Research Center, University of Copenhagen, Denmark.