An arrhythmogenic metabolite in atrial fibrillation

Julia Krause; Alexander Nickel; Alexandra Madsen; Hamish M Aitken-Buck; A M Stella Stoter; Jessica Schrapers; Francisco Ojeda; Kira Geiger; Melanie Kern; Michael Kohlhaas; Edoardo Bertero; Patrick Hofmockel; Florian Hübner; Ines Assum; Matthias Heinig; Christian Müller; Arne Hansen; Tobias Krause; Deung-Dae Park; Steffen Just; Dylan Aïssi; Daniela Börnigen; Diana Lindner; Nele Friedrich; Khaled Alhussini; Constanze Bening; Renate B Schnabel; Mahir Karakas; Licia Iacoviello; Veikko Salomaa; Allan Linneberg; Hugh Tunstall-Pedoe; Kari Kuulasmaa; Paulus Kirchhof; Stefan Blankenberg; Torsten Christ; Thomas Eschenhagen; Regis R Lamberts; Christoph Maack; Justus Stenzig; Tanja Zeller

doi:10.1186/s12967-023-04420-z

An arrhythmogenic metabolite in atrial fibrillation

J Transl Med. 2023 Aug 24;21(1):566. doi: 10.1186/s12967-023-04420-z.

Authors

Julia Krause^{1

2}, Alexander Nickel³, Alexandra Madsen^{2

4}, Hamish M Aitken-Buck⁵, A M Stella Stoter^{2

4}, Jessica Schrapers^{2

4}, Francisco Ojeda⁶, Kira Geiger³, Melanie Kern³, Michael Kohlhaas³, Edoardo Bertero³, Patrick Hofmockel³, Florian Hübner⁷, Ines Assum^{8

9}, Matthias Heinig^{8

9}, Christian Müller^{2

6}, Arne Hansen^{2

4}, Tobias Krause^{2

4}, Deung-Dae Park¹⁰, Steffen Just¹⁰, Dylan Aïssi⁶, Daniela Börnigen⁶, Diana Lindner^{2

6

11}, Nele Friedrich^{12

13}, Khaled Alhussini¹⁴, Constanze Bening¹⁴, Renate B Schnabel^{2

6}, Mahir Karakas^{2

15}, Licia Iacoviello^{16

17}, Veikko Salomaa¹⁸, Allan Linneberg^{19

20}, Hugh Tunstall-Pedoe²¹, Kari Kuulasmaa¹⁸, Paulus Kirchhof^{2

6

22}, Stefan Blankenberg^{2

6}, Torsten Christ^{2

4}, Thomas Eschenhagen^{2

4}, Regis R Lamberts⁵, Christoph Maack³, Justus Stenzig^#^{2

4}, Tanja Zeller^#^{23

24}

Affiliations

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 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.
¹² Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
¹³ DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany.
¹⁴ Department of Thoracic and Cardiovascular Surgery, University Clinic Würzburg, Würzburg, Germany.
¹⁵ Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁶ Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy.
¹⁷ Department of Medicine and Surgery, Research Center in Epidemiology and Preventive Medicine (EPIMED), University of Insubria, Varese, Italy.
¹⁸ Finnish Institute for Health and Welfare, Helsinki, Finland.
¹⁹ Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Capital Region of Denmark, Copenhagen, Denmark.
²⁰ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²¹ Cardiovascular Epidemiology Unit, Institute of Cardiovascular Research, University of Dundee, Dundee, UK.
²² Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.
²³ University Center of Cardiovascular Science, Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. t.zeller@uke.de.
²⁴ DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany. t.zeller@uke.de.

^# Contributed equally.

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.

Trial registration: ClinicalTrials.gov NCT02417311.

Keywords: Acyl-carnitine; Atrial fibrillation; Engineered heart tissue; Metabolites; Translational medicine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Atrial Fibrillation*
Heart Atria
Humans
Mitochondria
Muscle Contraction
Respiration

Associated data

ClinicalTrials.gov/NCT02417311