@article{725a9453a5ce43b2b81bf4ff527eacd8,
title = "An arrhythmogenic metabolite in atrial fibrillation",
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.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 contractions 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 = "Humans, Atrial Fibrillation, Heart Atria, Mitochondria, Muscle Contraction, Respiration, Metabolites, Engineered heart tissue, Atrial fibrillation, Translational medicine, Acyl-carnitine",
author = "Julia Krause and Alexander Nickel and Alexandra Madsen and Aitken-Buck, {Hamish M.} and Stoter, {A. M. Stella} and Jessica Schrapers and Francisco Ojeda and Kira Geiger and Melanie Kern and Michael Kohlhaas and Edoardo Bertero and Patrick Hofmockel and Florian H{\"u}bner and Ines Assum and Matthias Heinig and Christian M{\"u}ller and Arne Hansen and Tobias Krause and Deung-Dae Park and Steffen Just and Dylan A{\"i}ssi and Daniela B{\"o}rnigen and Diana Lindner and Nele Friedrich and Khaled Alhussini and Constanze Bening and Schnabel, {Renate B.} and Mahir Karakas and Licia Iacoviello and Veikko Salomaa and Allan Linneberg and Hugh Tunstall-Pedoe and Kari Kuulasmaa and Paulus Kirchhof and Stefan Blankenberg and Torsten Christ and Thomas Eschenhagen and Lamberts, {Regis R.} and Christoph Maack and Justus Stenzig and Tanja Zeller",
note = "Funding Information: Open access funding enabled and organized by project DEAL. This work was supported by grants from the German Research Foundation (DFG, STE 2596/4-1/ZE 1098/10-1), the Federal Ministry of Education and Research (BMBF) e:Med symAtrial (FKZ: 01ZX1408A,B,C), e:Med Confirm (FKZ:01ZX1708A,C,G), German Center for Cardiovascular Research (DZHK, FKZs: 81Z0710102, 81X2710174, and 80714/156/2-5-2), BiomarCaRE/MORGAM (European Commission Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2011-278913), ERA-CVD PREMED-CAD (European Research Area Network on Cardiovascular Diseases Precision Medicine in Coronary Artery Disease, FKZ.01KL1807). TZ was additionally supported by the DZHK (FKZ 81Z0710102, 2018–2025). VS was supported by the Finnish Foundation for Cardiovascular Research and by the Juho Vainio Foundation. CMa is supported by the German Research Foundation (DFG; Ma 2528/7-1; Ma 2528/8-1; SFB 894; TRR-219; SFB 1525, Projekt #453989101), Federal Ministry of Education and Research (BMBF, 01EO1504) and Barth Syndrome Foundation. Human trabeculae work was supported by The Heart Foundation of New Zealand (Grant no. 1766). AM was supported by the German Research Foundation (DFG, 386103693) and the European Research Council (IndivuHeart, NCT02417311). RBS has received funding from the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme under the grant agreement no. 648131, from the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme under the grant agreement no. 847770 (AFFECT-EU), DZHK (81Z1710103), Federal Ministry of Education and Research (BMBF, 01ZX1408A), and ERACoSysMed3 (031L0239). Funding Information: We would like to thank Tim Hartmann, Grit H{\"o}ppner, Birgit Klampe, Thomas Schulze, Sarah Schweingruber, Anja Sauer, Alice Schaaf, and Caroline R{\"o}themeier for expert technical assistance as well as B{\"a}rbel M. Ulmer for hiPSC line generation. Moreover, we would like to thank Kristin Hartmann from the Mouse Pathology Core facility at the UKE for histological staining, the UKE FACS core facility for support with flow cytometry, and the UKE Microscopy Imaging facility. Finally, we also want to thank all participants of the cohort studies. We acknowledge financial support from the Open Access Publication Fund of UKE - Universit{\"a}tsklinikum Hamburg-Eppendorf and DFG – German Research Foundation. Publisher Copyright: {\textcopyright} 2023, BioMed Central Ltd., part of Springer Nature.",
year = "2023",
month = aug,
day = "24",
doi = "10.1186/s12967-023-04420-z",
language = "English",
volume = "21",
journal = "Journal of Translational Medicine",
issn = "1479-5876",
publisher = "BioMed Central",
number = "1",
}