학술논문
An arrhythmogenic metabolite in atrial fibrillation
Document Type
Original Paper
Author
Krause, Julia; Nickel, Alexander; Madsen, Alexandra; Aitken-Buck, Hamish M.; Stoter, A. M. Stella; Schrapers, Jessica; Ojeda, Francisco; Geiger, Kira; Kern, Melanie; Kohlhaas, Michael; Bertero, Edoardo; Hofmockel, Patrick; Hübner, Florian; Assum, Ines; Heinig, Matthias; Müller, Christian; Hansen, Arne; Krause, Tobias; Park, Deung-Dae; Just, Steffen; Aïssi, Dylan; Börnigen, Daniela; Lindner, Diana; Friedrich, Nele; Alhussini, Khaled; Bening, Constanze; Schnabel, Renate B.; Karakas, Mahir; Iacoviello, Licia; Salomaa, Veikko; Linneberg, Allan; Tunstall-Pedoe, Hugh; Kuulasmaa, Kari; Kirchhof, Paulus; Blankenberg, Stefan; Christ, Torsten; Eschenhagen, Thomas; Lamberts, Regis R.; Maack, Christoph; Stenzig, Justus; Zeller, Tanja
Source
Journal of Translational Medicine. 21(1)
Subject
Language
English
ISSN
1479-5876
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.