Abstract 4145859: Clonal Hematopoiesis of Indeterminate Potential Increases Mortality Risk in Coronary Artery Disease
Authors: Von Scheidt Moritz , Adkar Shaunak , Krefting Johannes , Hoermann Gregor , Meggendorfer Manja , Bauer Sabine , Pugach Irina , Friess Christian , Ma Angela , Hao Ke , Steigerwald Sophia , Kessler Thorsten , Mokry Michal , Bongiovanni Dario , Fleig Julia , Oldenbuettel Lilith , Chen Zhifen , Hecker Judith S. , Bassermann Florian , Maegdefessel Lars , Graw Matthias , Ruusalepp Arno , Hilgendorf Ingo , Leuschner Florian , Koenig Wolfgang , Cremer Sebastian , Leistner David , Dimmeler Stefanie , Zeiher Andreas , Braun Christian , Mitchell Shaneice , Jaiswal Siddhartha , Kovacic Jason , Mann Matthias , Kastrati Adnan , Haferlach Claudia , Haferlach Torsten , Leeper Nick , Björkegren Johan , Schunkert Heribert 
Published: November 2024

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.