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Journal Article Accepted manuscript
, Ilona Bodi Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Institute of Experimental Cardiovascular Medicine, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Translational Cardiology, Department of Cardiology, Inselspital, Bern University Hospital, and Department of Physiology, University of Bern , Bern , Switzerland Search for other works by this author on: Oxford Academic Lea Mettke Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Institute of Experimental Cardiovascular Medicine, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Search for other works by this author on: Oxford Academic Konstantin Michaelides Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Institute of Experimental Cardiovascular Medicine, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Search for other works by this author on: Oxford Academic Tibor Hornyik Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Institute of Experimental Cardiovascular Medicine, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Translational Cardiology, Department of Cardiology, Inselspital, Bern University Hospital, and Department of Physiology, University of Bern , Bern , Switzerland Search for other works by this author on: Oxford Academic Stefan Meier Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University and Maastricht University Medical Center , Maastricht, NL Search for other works by this author on: Oxford Academic Saranda Nimani Translational Cardiology, Department of Cardiology, Inselspital, Bern University Hospital, and Department of Physiology, University of Bern , Bern , Switzerland Search for other works by this author on: Oxford Academic Stefanie Perez-Feliz Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Institute of Experimental Cardiovascular Medicine, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Search for other works by this author on: Oxford Academic Ibrahim el-Battrawy Department of Cardiology and Angiology, and Institute of Physiology, Ruhr University , Bochum , Germany Search for other works by this author on: Oxford Academic Heiko Bugger Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Department of Cardiology, University Heart Center Graz, Medical University of Graz , Graz , Austria Search for other works by this author on: Oxford Academic Manfred Zehender Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Search for other works by this author on: Oxford Academic
https://orcid.org/0009-0006-0900-4317 , Michael Brunner Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Department of Cardiology and Medical Intensive Care , St. Josefskrankenhaus, Freiburg , Germany Search for other works by this author on: Oxford Academic Jordi Heijman Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University and Maastricht University Medical Center , Maastricht, NL Gottfried Schatz Research Center, Division of Medical Physics and Biophysics, Medical University of Graz , Graz , Austria Search for other works by this author on: Oxford Academic Katja E Odening Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty , Freiburg , Germany Translational Cardiology, Department of Cardiology, Inselspital, Bern University Hospital, and Department of Physiology, University of Bern , Bern , Switzerland Address for correspondence: Prof. Dr. med. Katja Odening, Professor for Translational Cardiology, Department of Physiology, University Bern, Buehlplatz 5, CH-3012 Bern, +41/31 631 54 02, katja.odening@unibe.ch; Department of Cardiology, Inselspital University Hospital Bern, Freiburgstrasse 8, CH-3010 Bern, +41/31 632 3019, katja.odening@insel.ch Search for other works by this author on: Oxford Academic
Ilona Bodi, Lea Mettke, Konstantin Michaelides and Tibor Hornyik shared first-authorship
Author Notes
Cardiovascular Research, cvae149, https://doi.org/10.1093/cvr/cvae149
Published:
17 July 2024
Article history
Received:
17 September 2023
Revision received:
09 May 2024
Accepted:
23 May 2024
Published:
17 July 2024
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Ilona Bodi, Lea Mettke, Konstantin Michaelides, Tibor Hornyik, Stefan Meier, Saranda Nimani, Stefanie Perez-Feliz, Ibrahim el-Battrawy, Heiko Bugger, Manfred Zehender, Michael Brunner, Jordi Heijman, Katja E Odening, Beneficial normalization of cardiac repolarization by carnitine in transgenic SQT1 rabbit models, Cardiovascular Research, 2024;, cvae149, https://doi.org/10.1093/cvr/cvae149
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Abstract
Aims
Short-QT-syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in HERG underlying the rapid delayed-rectifier K+ current (IKr), leading to QT-shortening, ventricular arrhythmias, and sudden cardiac death. Data on efficient pharmaco-therapy for SQT1 are scarce. In patients with primary carnitine-deficiency, acquired-SQTS has been observed and rescued by carnitine-supplementation. Here, we assessed whether carnitine exerts direct beneficial (prolonging) effects on cardiac repolarization in genetic SQTS.
Methods and Results
Adult wild-type (WT) and transgenic SQT1 rabbits (HERG-N588K, gain of IKr) were used. In vivo ECGs, ex vivo monophasic action potentials (APs) in Langendorff-perfused hearts, and cellular ventricular APs and ion currents were assessed at baseline and during L-Carnitine/C16-Carnitine-perfusion. 2D computer simulations were performed to assess reentry-based VT-inducibility.
L-Carnitine/C16-Carnitine prolonged QT intervals in WT and SQT1, leading to QT-normalization in SQT1. Similarly, monophasic and cellular AP duration (APD) was prolonged by L-Carnitine/C16-Carnitine in WT and SQT1. As underlying mechanisms, we identified acute effects on the main repolarizing ion currents: IKr-steady, which is pathologically increased in SQT1, was reduced by L-Carnitine/C16-Carnitine and deactivation kinetics were accelerated. Moreover, L-Carnitine/C16-Carnitine decreased IKs-steady and IK1. In silico modelling identified IKr-changes as main factor for L-Carnitine/C16-Carnitine-induced APD-prolongation. 2D-simulations revealed increased sustained reentry-based arrhythmia formation in SQT1 compared to WT, which was decreased to the WT-level when adding carnitine-induced ion current changes.
Conclusion
L-Carnitine/C16-Carnitine prolong/normalize QT and whole heart/cellular APD in SQT1 rabbits. These beneficial effects are mediated by acute effects on IKr. L-Carnitine may serve as potential future QT-normalizing, anti-arrhythmic therapy in SQT1.
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Author notes
Ilona Bodi, Lea Mettke, Konstantin Michaelides and Tibor Hornyik shared first-authorship
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
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