Krause 2023 J Transl Med
|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 DD, 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. https://doi.org/10.1186/s12967-023-04420-z|
» J Transl Med 21:566. PMID: 37620858 Open Access
Krause Julia, Nickel Alexander, Madsen Alexandra, Aitken-Buck Hamish M, Stoter AM Stella, Schrapers Jessica, Ojeda Francisco, Geiger Kira, Kern Melanie, Kohlhaas Michael, Bertero Edoardo, Hofmockel Patrick, Huebner Florian, Assum Ines, Heinig Matthias, Mueller Christian, Hansen Arne, Krause Tobias, Park Deung-Dae, Just Steffen, Aissi Dylan, Boernigen 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 (2023) J Transl Med
Abstract: 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.
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.
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: Acyl-carnitine, Atrial fibrillation, Engineered heart tissue, Metabolites, Translational medicine • Bioblast editor: Plangger M • O2k-Network Lab: DE Wuerzburg Maack C
Labels: MiParea: Respiration Pathology: Cardiovascular
Organism: Human Tissue;cell: Heart Preparation: Isolated mitochondria, Intact cells
Regulation: mt-Membrane potential Coupling state: LEAK, OXPHOS Pathway: F, N, NS HRR: Oxygraph-2k, O2k-Fluorometer