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Krause, J.* ; Nickel, A.* ; Madsen, A.* ; Aitken-Buck, H.M.* ; Stoter, A.M.S.* ; Schrapers, J.* ; Ojeda, F.* ; Geiger, K.* ; Kern, M.* ; Kohlhaas, M.* ; Bertero, E.* ; Hofmockel, P.* ; Hübner, F.* ; Assum, I. ; Heinig, M. ; Müller, C.* ; Hansen, A.* ; Krause, T.* ; Park, D.D.* ; Just, S.* ; Aïssi, D.* ; Börnigen, D.* ; Lindner, D.* ; Friedrich, N.* ; Alhussini, K.* ; Bening, C.* ; Schnabel, R.B.* ; Karakas, M.* ; Iacoviello, L.* ; Salomaa, V.* ; Linneberg, A.* ; Tunstall-Pedoe, H.* ; Kuulasmaa, K.* ; Kirchhof, P.* ; Blankenberg, S.* ; Christ, T.* ; Eschenhagen, T.* ; Lamberts, R.R.* ; Maack, C.* ; Stenzig, J.* ; Zeller, T.*

An arrhythmogenic metabolite in atrial fibrillation.

J. Transl. Med. 21:566 (2023)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Acyl-carnitine ; Atrial Fibrillation ; Engineered Heart Tissue ; Metabolites ; Translational Medicine; Long-chain Acylcarnitines; Fatty-acid Oxidation; Heart; Mitochondrial; Calcium; Cardiomyocytes; Myocardium; Tissue; Leak

ISSN (print) / ISBN 1479-5876

e-ISSN 1479-5876

Journal Journal of Translational Medicine

Quellenangaben Volume: 21, Issue: 1, Article Number: 566

Publisher BioMed Central

Publishing Place Campus, 4 Crinan St, London N1 9xw, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)

Grants German Research Foundation (DFG)
Federal Ministry of Education and Research (BMBF)
German Center for Cardiovascular Research (DZHK)
Project DEAL
BiomarCaRE/MORGAM (European Commission)
ERA-CVD PREMED-CAD (European Research Area Network on Cardiovascular Diseases Precision Medicine in Coronary Artery Disease)
DZHK
Finnish Foundation for Cardiovascular Research
Juho Vainio Foundation
Barth Syndrome Foundation
Heart Foundation of New Zealand
European Research Council
European Research Council (ERC) under the European Union
European Union
ERACoSysMed3