TY - JOUR
T1 - Clonal haematopoiesis of indeterminate potential and mortality in coronary artery disease
AU - von Scheidt, Moritz
AU - Adkar, Shaunak S
AU - Krefting, Johannes
AU - Hoermann, Gregor
AU - Meggendorfer, Manja
AU - Bauer, Sabine
AU - Mitchell, Shaneice
AU - Pugach, Irina
AU - Friess, Christian
AU - Ma, Angela
AU - Hao, Ke
AU - Steigerwald, Sophia
AU - Wahle, Maria
AU - Kessler, Thorsten
AU - Schwab, Marius
AU - Voll, Felix
AU - Mokry, Michal
AU - Sofokleous, Charalampos
AU - Palm, Kaylin C A
AU - Bongiovanni, Dario
AU - Fleig, Julia
AU - Oldenbuettel, Lilith
AU - Chen, Zhifen
AU - Hecker, Judith S
AU - Bassermann, Florian
AU - Maegdefessel, Lars
AU - Graw, Matthias
AU - Ruusalepp, Arno
AU - Hilgendorf, Ingo
AU - Leuschner, Florian
AU - Sager, Hendrik B
AU - Heimlich, J Brett
AU - Koenig, Wolfgang
AU - Cremer, Sebastian
AU - Leistner, David M
AU - Abplanalp, Wesley T
AU - Dimmeler, Stefanie
AU - Zeiher, Andreas M
AU - van der Laan, Sander W
AU - Pasterkamp, Gerard
AU - Braun, Christian
AU - Jaiswal, Siddhartha
AU - Kovacic, Jason C
AU - Kern, Wolfgang
AU - Haferlach, Claudia
AU - Mann, Matthias
AU - Cassese, Salvatore
AU - Kastrati, Adnan
AU - Haferlach, Torsten
AU - Leeper, Nicholas J
AU - Björkegren, Johan L M
AU - Schunkert, Heribert
N1 - Publisher Copyright:
© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2026/1/21
Y1 - 2026/1/21
N2 - Background and Aims Clonal haematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular risk, but its prognostic relevance and mechanistic role in coronary artery disease (CAD) remains incompletely understood. This study investigated the association between CHIP and all-cause mortality in CAD and explored the cellular and molecular mechanisms, focusing on TET2 mutations. Methods Targeted deep sequencing of 13 CHIP driver genes in 8612 patients with angiographically confirmed CAD was performed. Clonal haematopoiesis of indeterminate potential carriers (variant allele frequency ≥2%) were propensity-score matched 1:1 to non-carriers. Mortality was assessed over 3 years. Mechanistic insights were derived from post-mortem high-sensitivity plaque proteomics (MISSION), RNA sequencing from carotid plaques (Athero-Express), monocyte-derived macrophage transcriptomes (STARNET), and CRISPR/Cas9-generated TET2 +/− macrophages in vitro. Results Clonal haematopoiesis of indeterminate potential was associated with increased 3-year mortality (hazard ratio 1.39, 95% confidence interval 1.16–1.65, P <.001) in 2389 matched pairs. Mutations in TET2, ASXL1, DNMT3A, JAK2, PPM1D, SF3B1, SRSF2, and U2AF1 individually conferred higher mortality risk. In human plaques, CHIP mutations were found in lesional macrophages. TET2 CHIP carriers showed increased necrotic core size, inflammation, and reduced plaque stability. Multi-omics profiling revealed up-regulation of lipid metabolism and inflammatory pathways. TET2 +/− macrophages exhibited increased LDLR expression and lipid uptake, linked to enhanced chromatin accessibility at the LDLR promoter. These findings were confirmed in carotid plaques, which showed increased LDLR and inflammasome-related gene expression in TET2 CHIP carriers. Conclusions Clonal haematopoiesis of indeterminate potential is a predictor of mortality in CAD patients. TET2 mutations promote a pro-atherogenic macrophage phenotype via LDLR up-regulation and inflammatory activation, linking epigenetic dysregulation to adverse outcomes in CAD.
AB - Background and Aims Clonal haematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular risk, but its prognostic relevance and mechanistic role in coronary artery disease (CAD) remains incompletely understood. This study investigated the association between CHIP and all-cause mortality in CAD and explored the cellular and molecular mechanisms, focusing on TET2 mutations. Methods Targeted deep sequencing of 13 CHIP driver genes in 8612 patients with angiographically confirmed CAD was performed. Clonal haematopoiesis of indeterminate potential carriers (variant allele frequency ≥2%) were propensity-score matched 1:1 to non-carriers. Mortality was assessed over 3 years. Mechanistic insights were derived from post-mortem high-sensitivity plaque proteomics (MISSION), RNA sequencing from carotid plaques (Athero-Express), monocyte-derived macrophage transcriptomes (STARNET), and CRISPR/Cas9-generated TET2 +/− macrophages in vitro. Results Clonal haematopoiesis of indeterminate potential was associated with increased 3-year mortality (hazard ratio 1.39, 95% confidence interval 1.16–1.65, P <.001) in 2389 matched pairs. Mutations in TET2, ASXL1, DNMT3A, JAK2, PPM1D, SF3B1, SRSF2, and U2AF1 individually conferred higher mortality risk. In human plaques, CHIP mutations were found in lesional macrophages. TET2 CHIP carriers showed increased necrotic core size, inflammation, and reduced plaque stability. Multi-omics profiling revealed up-regulation of lipid metabolism and inflammatory pathways. TET2 +/− macrophages exhibited increased LDLR expression and lipid uptake, linked to enhanced chromatin accessibility at the LDLR promoter. These findings were confirmed in carotid plaques, which showed increased LDLR and inflammasome-related gene expression in TET2 CHIP carriers. Conclusions Clonal haematopoiesis of indeterminate potential is a predictor of mortality in CAD patients. TET2 mutations promote a pro-atherogenic macrophage phenotype via LDLR up-regulation and inflammatory activation, linking epigenetic dysregulation to adverse outcomes in CAD.
KW - Aging
KW - Atherosclerotic cardiovascular disease
KW - Cardiovascular disease
KW - Clonal haematopoiesis of indeterminate potential
KW - Coronary artery disease
KW - Inflammation
KW - LDLR
KW - Macrophages
KW - Mortality
KW - TET2
UR - https://www.scopus.com/pages/publications/105028575242
U2 - 10.1093/eurheartj/ehaf602
DO - 10.1093/eurheartj/ehaf602
M3 - Article
C2 - 40900105
SN - 0195-668X
VL - 47
SP - 453
EP - 469
JO - European heart journal
JF - European heart journal
IS - 4
ER -