Abstract
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.
| Original language | English |
|---|---|
| Journal | European Heart Journal |
| Volume | 44 |
| Issue number | 47 |
| Pages (from-to) | 4935-4949 |
| Number of pages | 15 |
| ISSN | 0195-668X |
| DOIs | |
| Publication status | Published - 14.12.2023 |
Funding
P.S.W. reports grants and personal fees from Boehringer Ingelheim, grants from Philips Medical Systems, grants and personal fees from sanofi-aventis, grants and personal fees from Bayer Vital, grants from Daiichi Sankyo Europe, personal fees from AstraZeneca, personal fees and non-financial support from DiaSorin, non-financial support from I. E. M., and grants from Evonik. J.H.P. received support for lecturing from Bayer Health Care, Boehringer Ingelheim, and Daiichi-Sankyo outside the topic of the present study. P.S.W. is principal investigator of the DIASyM research core of the MSCoreSys consortium (BMBF 161L0217A). H.H. and K.S.-F. are codirectors of CellTrend. G.R. is an advisor of CellTrend and earned honoraria for her advice between 2011 and 2015. The other authors declare no competing interests. This work was supported by the government of Rhineland-Palatinate (‘Stiftung Rheinland Pfalz für Innovation’, contract no. AZ 961-386261/733), the research programmes ‘Wissen schafft Zukunft’ and ‘Schwerpunkt Vaskuläre Prävention’ of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and Philips Medical Systems including an unrestricted grant for the GHS as well as through the grants from the Initiative Health Economy Rhineland-Palatinate by the Ministry of Health and the Ministry of Economics, Rhineland-Palatinate, Germany (AZ.623-1) and the Federal Ministry of Education and Research, Germany (BMBF, 01EO1003). P.S.W., and T.M. are principal investigators of the DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany, and J.E. of the Partner Site Hamburg/Kiel/Lübeck, Lübeck. P.S.W. is principal investigator of the future cluster curATime (BMBF 03ZU1202AA, 03ZU1202CD, 03ZU1202DB, 03ZU1202JC, 03ZU1202KB, 03ZU1202LB, 03ZU1202MB, and 03ZU1202OA). (BMBF 161L0217A). F.S.M. is supported by a rotation grant of the foundation Heart of Mainz. Z.A. and J.E. were supported by the German Federal Ministry of Education and Research (BMBF) in the context of the German Centre for Cardiovascular Research (FKZ81Z0700108, FKZ81X2700133) and by Fondation Leducq (18CVD02, PlaqOmics). J.Y.H., H.G., L.J., and G.R. were supported by the Cluster of Excellence ‘Precision Medicine in Chronic Inflammation (PMI)’ of the Universities Kiel and Luebeck funded by the German Research Foundation (DFG, EXC 2167), by the DFG project RI 1056/11-3, as well as by the BMBF project Mesinflame (01EC1901A). The authors dedicate this work to the late Prof. Jeanette Erdmann, who is remembered as a warm-hearted mentor and outstanding researcher and whose unique dedication and professionalism greatly shaped an entire field of research. We are indebted to the participants and staff of the Gutenberg Health Study, without whom this work would not be possible. We gratefully acknowledge the technical support provided by Annett Liebers, Petra Bruse, and Gabriele Marschner, as well as expert scientifc advice by Prof. Philip Wenzel. F.S.M. thanks the Foundation Heart of Mainz for funding and support.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
- Centers: Cardiological Center Luebeck (UHZL)
DFG Research Classification Scheme
- 2.21-05 Immunology
- 2.22-12 Cardiology, Angiology
