An arrhythmogenic metabolite in atrial fibrillation

Krause et al. Journal of Translational Medicine https://doi.org/10.1186/s12967-023-04420-z Journal of Translational Medicine (2023) 21:566 Open Access RESEARCH An arrhythmogenic metabolite in atrial fibrillation Julia Krause1,2, Alexander Nickel3, Alexandra Madsen2,4, Hamish M. Aitken‑Buck5, A. M. Stella Stoter2,4, Jessica Schrapers2,4, Francisco Ojeda6, Kira Geiger3, Melanie Kern3, Michael Kohlhaas3, Edoardo Bertero3, Patrick Hofmockel3, Florian Hübner7, Ines Assum8,9, Matthias Heinig8,9, Christian Müller2,6, Arne Hansen2,4, Tobias Krause2,4, Deung‑Dae Park10, Steffen Just10, Dylan Aïssi6, Daniela Börnigen6, Diana Lindner2,6,22, Nele Friedrich11,12, Khaled Alhussini13, Constanze Bening13, Renate B. Schnabel2,6, Mahir Karakas2,14, Licia Iacoviello15,16, Veikko Salomaa17, Allan Linneberg18,19, Hugh Tunstall‑Pedoe20, Kari Kuulasmaa17, Paulus Kirchhof2,6,21, Stefan Blankenberg2,6, Torsten Christ2,4, Thomas Eschenhagen2,4, Regis R. Lamberts5, Christoph Maack3, Justus Stenzig2,4† and Tanja Zeller1,2*†    Abstract Background Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. † Justus Stenzig and Tanja Zeller contributed equally to this work. *Correspondence: Tanja Zeller 1 University Center of Cardiovascular Science, Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany 2 DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany 3 Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany 4 Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 5 Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand 6 Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany 7 Institute of Food Chemistry, University of Münster, Münster, Germany 8 Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany 9 Department of Informatics, Technical University Munich, Munich, Germany 10 Molecular Cardiology, Department of Internal Medicine II, University of Ulm, Ulm, Germany 11 Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany 12 DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany 13 Department of Thoracic and Cardiovascular Surgery, University Clinic Würzburg, Würzburg, Germany 14 Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 15 Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy 16 Department of Medicine and Surgery, Research Center in Epidemiology and Preventive Medicine (EPIMED), University of Insubria, Varese, Italy 17 Finnish Institute for Health and Welfare, Helsinki, Finland 18 Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Capital Region of Denmark, Copenhagen, Denmark 19 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 20 Cardiovascular Epidemiology Unit, Institute of Cardiovascular Research, University of Dundee, Dundee, UK 21 Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK 22 Present Address: Department of Cardiology and Angiology, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, Medical Center – University of Freiburg, University of Freiburg, 79106 Freiburg, Germany © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Krause et al. Journal of Translational Medicine (2023) 21:566 Page 2 of 16 Methods and results Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contrac‑ tions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. Conclusion Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF. Keywords Metabolites, Acyl-carnitine, Atrial fibrillation, Translational medicine, Engineered heart tissue Background Atrial fibrillation (AF) affects up to 2% of the general population and remains a severe public health burden due to complications even on optimal therapy [1, 2]. The pathology of AF is complex and still incompletely understood. In addition to structural, contractile, and electrical features [3–5], metabolic alterations contribute to the pathogenesis of AF [6, 7], and vice versa AF can induce cardio-metabolic changes [8]. The metabolism of long-chain fatty acids in the mitochondria represents the main energy source for cardiac work [9]. The uptake of long-chain fatty acids from the cytoplasm into mitochondria is achieved by forming long-chain acyl-carnitines (ACs) [10]. These metabolites are readily accessible for quantification in the circulation and are routinely analysed in new-born screenings to detect inherited metabolic disorders [11]. The origin of circulating ACs can be both cellular release and dietary uptake. Recently, studies showed an association between AC me (...truncated)