Inflammation in liver fibrosis and atrial fibrillation: A prospective population-based proteomic study
Joost Boeckmans,
Maurice Michel,
Alexander Gieswinkel,
Oliver Tüscher,
Stavros V. Konstantinides,
Jochem König,
Thomas Münzel,
Karl J. Lackner,
Jasmin Ghaemi Kerahrodi,
Alexander K. Schuster,
Philipp S. Wild,
Peter R. Galle,
Jörn M. Schattenberg
Affiliations
Joost Boeckmans
Metabolic Liver Research Center, Department of Medicine, University Medical Center Mainz, Mainz, Germany; I. Department of Medicine, University Medical Center Mainz, Mainz, Germany; In Vitro Liver Disease Modelling Team, Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
Maurice Michel
Metabolic Liver Research Center, Department of Medicine, University Medical Center Mainz, Mainz, Germany; I. Department of Medicine, University Medical Center Mainz, Mainz, Germany; Department of Medicine II, Saarland University Medical Center, Homburg, Germany
Alexander Gieswinkel
Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
Oliver Tüscher
Clinic for Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Institute of Molecular Biology (IMB), Mainz, Germany; Leibniz Institute for Resilience Research, Mainz, Germany
Stavros V. Konstantinides
Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Germany; Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece
Jochem König
Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
Thomas Münzel
Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany
Karl J. Lackner
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
Jasmin Ghaemi Kerahrodi
Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Alexander K. Schuster
Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Philipp S. Wild
Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Institute of Molecular Biology (IMB), Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Germany; German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany
Peter R. Galle
I. Department of Medicine, University Medical Center Mainz, Mainz, Germany
Jörn M. Schattenberg
Metabolic Liver Research Center, Department of Medicine, University Medical Center Mainz, Mainz, Germany; I. Department of Medicine, University Medical Center Mainz, Mainz, Germany; Department of Medicine II, Saarland University Medical Center, Homburg, Germany; Corresponding author. Address: Department of Medicine II, Saarland University Medical Center, Kirrberger Str. 100, 66421 Homburg, Germany. Tel.: +4968411615027.
Background & Aims: Elevated liver stiffness has been associated with atrial fibrillation (AFib) in the general population. The mechanism underlying this association is unclear. Methods: Participants were recruited from the general population and prospectively enrolled with follow-up for 5 years. The fibrosis-4 (FIB-4) index was used as a surrogate marker for liver fibrosis. Proteomics analysis was performed using the 92-target Olink inflammation panel. Validation was performed using the NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet index (APRI), and repeat confirmation proteomics. Results: A sample of 11,509 participants with a mean age of 54.0 ± 11.1 years, 51.3% women, and a median FIB-4 index of 0.85 (0.65/1.12), was used. The FIB-4 index was predictive for prevalent (FIB-4 index adjusted odds ratio (aOR) per SD: 1.100 with 95% CI 1.011-1.196; p = 0.026), but not incident AFib (log[FIB-4 index]) adjusted hazard ratio: 1.125 with 95% CI 0.943-1.342, p = 0.19). Elastic net regularized regression identified CCL20, DNER, and CXCL10 for prevalent AFib, and AXIN1, CXCL10, and Flt3L for the log(FIB-4 index) (per SD) as most important in common regulated proteins. The relationship between the FIB-4 index, the identified proteins, and AFib was relevant and reproduced at the 5-year follow-up for CXCL10 after adjusting for confounders (log[FIB-4 index] per SD - CXCL10 [per SD] adjusted β 0.160 with 95% CI 0.127-0.194, p <0.0001; CXCL10 [per SD] - AFib aOR 1.455 with 95% CI 1.217-1.741, p <0.0001), reproduced using the NFS and APRI, and corresponding to increased serum levels. Conclusions: CXCL10 is linked to liver fibrosis, as determined by the FIB-4 index, and to prevalent AFib. Impact and implications:: How elevated liver stiffness relates to atrial fibrillation in the general population remains to be clarified. We hypothesized that systemic inflammation against a background of liver fibrosis produced from metabolic dysfunction-associated steatotic liver disease (MASLD), is involved in the pathophysiology of atrial fibrillation. Using large-scale targeted proteomics, we found that CXCL10 is related to both liver fibrosis, as defined by the fibrosis-4 index, and to atrial fibrillation. These results can aid evidence-based drug development for patients with atrial fibrillation and MASLD-related liver fibrosis.
