Abstract 4145859: Clonal Hematopoiesis of Indeterminate Potential Increases Mortality Risk in Coronary Artery Disease

Background: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased incidence of common late-onset diseases including myocardial infarction. Research Question: Here we examined the impact of CHIP on mortality in patients with coronary artery disease (CAD) and further explored potential underlying mechanisms. Methods: CAD patients were examined for CHIP-defining mutations using deep DNA sequencing. Propensity score matching was used to compare CHIP CAD with non-CHIP CAD patients. Survival was analyzed using Kaplan-Meier curves and Cox proportional hazard models. Functional aspects were investigated at the protein and RNA level in cardiovascular relevant human postmortem tissue from the Munich cardIovaScular StudIes biObaNk (MISSION), in CAD patients from an independent cohort and in in-vitro macrophage models. Results: Within 7,933 CAD patients screened by deep-DNA-sequencing with a 13 gene panel, 2,002 carried at least one CHIP defining mutation with a variant allele frequency ≥2%. After 1:1 matching with non-CHIP carriers we revealed a significantly elevated 3-year mortality in the group of CHIP carriers [HR 1.48 (CI 95% 1.23-1.78); p<0.0001)] as well as in carriers of mutations in one out of seven individual genes – ASXL1 , DNMT3A , PPM1D , SF3B1 , SRSF2 , TET2 , and U2AF1 . In human coronary atherosclerotic plaque we visualized CHIP-mutations within leukocytes. Further, within coronary artery plaque of deceased TET2 mutation carriers (n=26 vs. n=13 controls) we identified by proteomic profiling an upregulation of inflammatory and metabolic pathways, including enhanced lipid metabolism. In an independent cohort of CAD patients undergoing coronary bypass surgery, RNA sequencing data from monocyte-derived macrophages revealed in TET2 CHIP carriers associations with CAD complexity. TET2 -mutated macrophages studied in-vitro revealed an increased uptake of low-density lipoprotein (LDL) and oxidized LDL-cholesterol besides a known upregulation of inflammatory pathways. Conclusion: In summary, this study emphasizes CHIP as a significant prognostic factor in CAD patients, associated with increased complexity of CAD and altered gene expression within human coronary artery plaques. Mechanistically, TET2 mutations modify the behavior of CHIP-affected macrophages, leading to heightened inflammation and increased uptake of LDL-cholesterol.

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Journal
Circulation
Published
2024-11-11
DOI
https://doi.org/10.1161/circ.150.suppl_1.4145859
Primary Topic
Biomarkers in Disease Mechanisms
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article
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article

Abstract 4145859: Clonal Hematopoiesis of Indeterminate Potential Increases Mortality Risk in Coronary Artery Disease

Torsten Haferlach, Ke Hao, David M. Leistner, Heribert Schunkert et al.
Circulation
Biomarkers in Disease Mechanisms
article

Abstract 4145859: Clonal Hematopoiesis of Indeterminate Potential Increases Mortality Risk in Coronary Artery Disease

Torsten Haferlach, Ke Hao, David M. Leistner, Heribert Schunkert, Johannes Krefting, Thorsten Kessler, Adnan Kastrati, Shaneice Mitchell, Claudia Haferlach, Stefanie Dimmeler, Gregor Hoermann, Wolfgang Köenig, Irina Pugach, Lars Mäegdefessel, Shaunak Adkar, Christian Joerg Braun, Angela Ma, Manja Meggendorfer, Nick J Leeper, Matthias Graw, Ingo Hilgendorf, Dario Bongiovanni, Florian C. Bassermann, Andreas M. Zeiher, Judith S. Hecker, Johan Björkegren, Florian Leuschner, Arno Ruusalepp, Siddhartha Jaiswal, Julia Fleig, Michal Mokrý, Sophia Steigerwald, Moritz von Scheidt, Sebastian Cremer, Sabine Bauer, Jason C. Kovacic, Lilith Oldenbuettel, Zhifen Chen, Matthias Mann, Christian Frieß
article en

Abstract

Background: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased incidence of common late-onset diseases including myocardial infarction. Research Question: Here we examined the impact of CHIP on mortality in patients with coronary artery disease (CAD) and further explored potential underlying mechanisms. Methods: CAD patients were examined for CHIP-defining mutations using deep DNA sequencing. Propensity score matching was used to compare CHIP CAD with non-CHIP CAD patients. Survival was analyzed using Kaplan-Meier curves and Cox proportional hazard models. Functional aspects were investigated at the protein and RNA level in cardiovascular relevant human postmortem tissue from the Munich cardIovaScular StudIes biObaNk (MISSION), in CAD patients from an independent cohort and in in-vitro macrophage models. Results: Within 7,933 CAD patients screened by deep-DNA-sequencing with a 13 gene panel, 2,002 carried at least one CHIP defining mutation with a variant allele frequency ≥2%. After 1:1 matching with non-CHIP carriers we revealed a significantly elevated 3-year mortality in the group of CHIP carriers [HR 1.48 (CI 95% 1.23-1.78); p<0.0001)] as well as in carriers of mutations in one out of seven individual genes – ASXL1 , DNMT3A , PPM1D , SF3B1 , SRSF2 , TET2 , and U2AF1 . In human coronary atherosclerotic plaque we visualized CHIP-mutations within leukocytes. Further, within coronary artery plaque of deceased TET2 mutation carriers (n=26 vs. n=13 controls) we identified by proteomic profiling an upregulation of inflammatory and metabolic pathways, including enhanced lipid metabolism. In an independent cohort of CAD patients undergoing coronary bypass surgery, RNA sequencing data from monocyte-derived macrophages revealed in TET2 CHIP carriers associations with CAD complexity. TET2 -mutated macrophages studied in-vitro revealed an increased uptake of low-density lipoprotein (LDL) and oxidized LDL-cholesterol besides a known upregulation of inflammatory pathways. Conclusion: In summary, this study emphasizes CHIP as a significant prognostic factor in CAD patients, associated with increased complexity of CAD and altered gene expression within human coronary artery plaques. Mechanistically, TET2 mutations modify the behavior of CHIP-affected macrophages, leading to heightened inflammation and increased uptake of LDL-cholesterol.

CirculationVol. 150(Suppl_1)
Goethe University Frankfurt (DE), Karolinska University Hospital (SE), University of Freiburg (DE), Palo Alto University (US), Heidelberg University (DE), University Hospital Augsburg (DE), Tartu University Hospital (EE), TUM Klinikum (DE), Karolinska Institutet (SE), Munich Leukemia Laboratory (Germany) (DE), Deutsches Herzzentrum der Charité (DE), University Hospital Frankfurt (DE), Saratoga Hospital (US), Deutsches Herzzentrum München (DE), Max Planck Institute of Biochemistry (DE), Technical University of Munich (DE), Ludwig-Maximilians-Universität München (DE), Icahn School of Medicine at Mount Sinai (US)
Good health and well-being
Openalex Percentile: Top 74%
Biomarkers in Disease Mechanisms
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