Autoantibodies against the chemokine receptor 3 predict cardiovascular risk.

Autor: Müller FS; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; DZHK (German Centre for Cardiovascular Research), partner site RhineMain, Langenbeckstr. 1, 55131 Mainz, Germany.; Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Aherrahrou Z; Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany., Grasshoff H; Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany., Heidorn MW; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; DZHK (German Centre for Cardiovascular Research), partner site RhineMain, Langenbeckstr. 1, 55131 Mainz, Germany.; Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Humrich JY; Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany., Johanson L; Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany., Aherrahrou R; Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany.; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland., Reinberger T; Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany., Schulz A; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany., Ten Cate V; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; DZHK (German Centre for Cardiovascular Research), partner site RhineMain, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz,Germany., Robles AP; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz,Germany., Koeck T; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; DZHK (German Centre for Cardiovascular Research), partner site RhineMain, Langenbeckstr. 1, 55131 Mainz, Germany., Rapp S; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; DZHK (German Centre for Cardiovascular Research), partner site RhineMain, Langenbeckstr. 1, 55131 Mainz, Germany., Lange T; Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany.; Center of Brain, Behavior, and Metabolism (CBBM), University of Lübeck, Lübeck, Germany., Brachaczek L; Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany., Luebber F; Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany.; Social Neuroscience Lab, Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany., Erdmann J; Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany., Heidecke H; CellTrend Gesellschaft mit beschränkter Haftung (GmbH), Luckenwalde, Germany., Schulze-Forster K; CellTrend Gesellschaft mit beschränkter Haftung (GmbH), Luckenwalde, Germany., Dechend R; CellTrend Gesellschaft mit beschränkter Haftung (GmbH), Luckenwalde, Germany.; Experimental and Clinical Research Center, a cooperation of Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany.; Department of Cardiology and Nephrology, HELIOS Klinikum Berlin Buch, Berlin, Germany., Lackner KJ; DZHK (German Centre for Cardiovascular Research), partner site RhineMain, Langenbeckstr. 1, 55131 Mainz, Germany.; Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Pfeiffer N; Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Ghaemi Kerahrodi J; Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany., Tüscher O; Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Institute for Molecular Biology (IMB), Working Group Neurocognitive Mechanisms of Mental Resilience, Ackermannweg 4, 55128 Mainz, Germany., Schwarting A; Department of Internal Medicine I, University Medical Center Mainz, Mainz, Germany., Strauch K; Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany., Münzel T; DZHK (German Centre for Cardiovascular Research), partner site RhineMain, Langenbeckstr. 1, 55131 Mainz, Germany.; Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz,Germany., Prochaska JH; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; DZHK (German Centre for Cardiovascular Research), partner site RhineMain, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz,Germany., Riemekasten G; Department of Rheumatology and Clinical Immunology, University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany.; Centre for Infection and Inflammation Lübeck (ZIEL), University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany., Wild PS; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.; DZHK (German Centre for Cardiovascular Research), partner site RhineMain, Langenbeckstr. 1, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz,Germany.; Institute for Molecular Biology (IMB), Mainz, Working Group Systems Medicine, Ackermannweg 4, 55128 Mainz, Germany.
Jazyk: angličtina
Zdroj: European heart journal [Eur Heart J] 2023 Dec 14; Vol. 44 (47), pp. 4935-4949.
DOI: 10.1093/eurheartj/ehad666
Abstrakt: Background and Aims: Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear.
Methods: Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation.
Results: The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model.
Conclusions: In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze: MEDLINE