Abstract 1144 Autoantibodies against the CXC-motif-chemokine receptor 3 predict development and progression of cardiovascular disease and mortality

Background: Chronic inflammation and autoimmunity contribute to the development and progression of cardiovascular (CV) disease. Recently, autoantibodies (aAb) against the CXC-motif-chemokine receptor 3 (CXCR3), a G-protein coupled receptor regulating chemokine signaling with a key role in atherosclerosis, have been identified. The role of anti-CXCR3-aAb for CV risk and disease is unclear.

Methods: Anti-CXCR3-aAb were quantified by a commercially available sandwich enzyme-linked immunosorbent assay (CellTrend, Luckenwalde, Germany) in 5,000 participants (availability: 97.1%) of the population-based Gutenberg Health Study. Individuals were phenotyped by echocardiography, vascular ultrasound, and targeted proteomics using proximity extension assay technology. Regression analyses were carried out to identify determinants of anti-CXCR3-aAb and relevance for clinical outcome (i.e., all-cause mortality, cardiac death, heart failure (HF), and major adverse cardiac events (MACE) comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, ApoE knockout mice were immunized against CXCR3 to validate the pathophysiological relevance of anti-CXCR3-aAb for atherosclerosis progression by quantifying aortic atherosclerotic lesions upon Oil-Red-O staining and consecutive computational image analysis.

Results: The analysis sample constituted N=4,195 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-aAb translated into higher intima-media-thickness, left ventricular mass, and NT-proBNP. Adjusted for age and sex, anti-CXCR3-Aab above the 75th percentile predicted all-cause death (Hazard ratio (HR) [95%-confidence interval] 1.25 [1.02, 1.52], p=0.029), driven by excess cardiac mortality (HR 2.51 [1.21, 5.22], p=0.014). A trend towards a higher risk for MACE (HR 1.42 [1.0; 2.0], p=0.05) along with increased risk of incident HF (HR per standard deviation increase of anti-CXCR3-aAb: 1.26 [1.02, 1.79], p=0.03) may contribute to this observation. Using a supervised machine learning approach, targeted proteomics identified a molecular signature of anti-CXCR3-aAb 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-aAb and exhibited a higher burden of atherosclerosis compared to non-immunized controls.

Conclusions: In community-dwelling individuals free of overt autoimmune disease, anti-CXCR3-aAb 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, these findings suggest that anti-CXCR3-aAb are both biomarkers and mediators of atherosclerosis.

Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w
Autoantibodies against the CXC-motif-chemokine receptor 3 predict development and progression of cardiovascular disease and mortality
F. Müller¹, M. Heidorn¹, J. Y. Humrich², Z. Aherrahrou³, L. Johanson², A. Schulz⁴, V. Ten Cate⁴, A. Pallares Robles⁴, T. Koeck⁴, S. Rapp⁴, T. Lange², H. Grasshoff², L. Brachaczek², F. Lübber², J. Erdmann³, H. Heidecke⁵, K. Schulze-Forster⁵, R. Dechend⁶, K. Lackner⁷, N. Pfeiffer⁸, J. Ghaemi Kerahrodi⁹, O. Tüscher¹⁰, A. Schwarting¹¹, K. Strauch¹², T. Münzel¹, J. Prochaska¹³, G. Riemekasten², P. S. Wild⁴
¹Kardiologie 1, Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; ²Klinik für Rheumatologie und klinische Immunologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck; ³Institut für Kardiogenetik, Universitätsklinikum Schleswig-Holstein, Lübeck; ⁴Präventive Kardiologie und Medizinische Prävention, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; ⁵CellTrend Gesellschaft mit beschränkter Haftung (GmbH), Luckenwalde; ⁶Klinik und Poliklinik für Kardiologie und Nephrologie, HELIOS Klinikum Berlin-Buch, Berlin; ⁷Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsmedizin Mainz, Mainz; ⁸Augenklinik und Poliklinik, Universitätsmedizin Mainz, Mainz; ⁹Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; ¹⁰Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin Mainz, Mainz; ¹¹I. Medizinische Klinik und Poliklinik, Rheumatologie und klinische Immunologie, Universitätsmedizin Mainz, Mainz; ¹²Institut für Medizinische Biometrie, Epidemiologie und Informatik (IMBEI), Universitätsmedizin Mainz, Mainz; ¹³Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz;
Background: Chronic inflammation and autoimmunity contribute to the development and progression of cardiovascular (CV) disease. Recently, autoantibodies (aAb) against the CXC-motif-chemokine receptor 3 (CXCR3), a G-protein coupled receptor regulating chemokine signaling with a key role in atherosclerosis, have been identified. The role of anti-CXCR3-aAb for CV risk and disease is unclear. Methods: Anti-CXCR3-aAb were quantified by a commercially available sandwich enzyme-linked immunosorbent assay (CellTrend, Luckenwalde, Germany) in 5,000 participants (availability: 97.1%) of the population-based Gutenberg Health Study. Individuals were phenotyped by echocardiography, vascular ultrasound, and targeted proteomics using proximity extension assay technology. Regression analyses were carried out to identify determinants of anti-CXCR3-aAb and relevance for clinical outcome (i.e., all-cause mortality, cardiac death, heart failure (HF), and major adverse cardiac events (MACE) comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, ApoE knockout mice were immunized against CXCR3 to validate the pathophysiological relevance of anti-CXCR3-aAb for atherosclerosis progression by quantifying aortic atherosclerotic lesions upon Oil-Red-O staining and consecutive computational image analysis. Results: The analysis sample constituted N=4,195 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-aAb translated into higher intima-media-thickness, left ventricular mass, and NT-proBNP. Adjusted for age and sex, anti-CXCR3-Aab above the 75th percentile predicted all-cause death (Hazard ratio (HR) [95%-confidence interval] 1.25 [1.02, 1.52], p=0.029), driven by excess cardiac mortality (HR 2.51 [1.21, 5.22], p=0.014). A trend towards a higher risk for MACE (HR 1.42 [1.0; 2.0], p=0.05) along with increased risk of incident HF (HR per standard deviation increase of anti-CXCR3-aAb: 1.26 [1.02, 1.79], p=0.03) may contribute to this observation. Using a supervised machine learning approach, targeted proteomics identified a molecular signature of anti-CXCR3-aAb 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-aAb and exhibited a higher burden of atherosclerosis compared to non-immunized controls. Conclusions: In community-dwelling individuals free of overt autoimmune disease, anti-CXCR3-aAb 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, these findings suggest that anti-CXCR3-aAb are both biomarkers and mediators of atherosclerosis.
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