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

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 JustDylan 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^*

^*Corresponding author for this work

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	566
Journal	Journal of translational medicine
Volume	21
Issue number	1
Early online date	24 Aug 2023
DOIs	https://doi.org/10.1186/s12967-023-04420-z
Publication status	E-pub ahead of print - 24 Aug 2023

Keywords

Atrial fibrillation
Acyl-carnitine
Translational medicine
Metabolites
Engineered heart tissue

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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., ... Zeller, T. (2023). An arrhythmogenic metabolite in atrial fibrillation. Journal of translational medicine, 21(1), Article 566 . Advance online publication. https://doi.org/10.1186/s12967-023-04420-z

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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 = "Atrial fibrillation, Acyl-carnitine, Translational medicine, Metabolites, Engineered heart tissue",

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",

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doi = "10.1186/s12967-023-04420-z",

language = "English",

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journal = "Journal of translational medicine",

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Krause, J, Nickel, A, Madsen, A, Aitken-Buck, HM, Stoter, AMS, 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, RB, Karakas, M, Iacoviello, L, Salomaa, V, Linneberg, A, Tunstall-Pedoe, H, Kuulasmaa, K, Kirchhof, P, Blankenberg, S, Christ, T, Eschenhagen, T, Lamberts, RR, Maack, C, Stenzig, J & Zeller, T 2023, 'An arrhythmogenic metabolite in atrial fibrillation', Journal of translational medicine, vol. 21, no. 1, 566 . https://doi.org/10.1186/s12967-023-04420-z

TY - JOUR

T1 - An arrhythmogenic metabolite in atrial fibrillation

AU - Krause, Julia

AU - Nickel, Alexander

AU - Madsen, Alexandra

AU - Aitken-Buck, Hamish M.

AU - Stoter, A. M. Stella

AU - Schrapers, Jessica

AU - Ojeda, Francisco

AU - Geiger, Kira

AU - Kern, Melanie

AU - Kohlhaas, Michael

AU - Bertero, Edoardo

AU - Hofmockel, Patrick

AU - Hübner, Florian

AU - Assum, Ines

AU - Heinig, Matthias

AU - Müller, Christian

AU - Hansen, Arne

AU - Krause, Tobias

AU - Park, Deung-Dae

AU - Just, Steffen

AU - Aïssi, Dylan

AU - Börnigen, Daniela

AU - Lindner, Diana

AU - Friedrich, Nele

AU - Alhussini, Khaled

AU - Bening, Constanze

AU - Schnabel, Renate B.

AU - Karakas, Mahir

AU - Iacoviello, Licia

AU - Salomaa, Veikko

AU - Linneberg, Allan

AU - Tunstall-Pedoe, Hugh

AU - Kuulasmaa, Kari

AU - Kirchhof, Paulus

AU - Blankenberg, Stefan

AU - Christ, Torsten

AU - Eschenhagen, Thomas

AU - Lamberts, Regis R.

AU - Maack, Christoph

AU - Stenzig, Justus

AU - Zeller, Tanja

PY - 2023/8/24

Y1 - 2023/8/24

N2 - 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.

AB - 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.

KW - Atrial fibrillation

KW - Acyl-carnitine

KW - Translational medicine

KW - Metabolites

KW - Engineered heart tissue

U2 - 10.1186/s12967-023-04420-z

DO - 10.1186/s12967-023-04420-z

M3 - Article

SN - 1479-5876

VL - 21

JO - Journal of translational medicine

JF - Journal of translational medicine

IS - 1

M1 - 566

ER -

An arrhythmogenic metabolite in atrial fibrillation

Abstract

Keywords

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