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Clonal haematopoiesis of indeterminate potential and mortality in coronary artery disease
Moritz von Scheidt1,2, Shaunak S Adkar3, Johannes Krefting1,2
1Department of Cardiology, TUM Klinikum Deutsches Herzzentrum, Technical University Munich, Lazarettstr. 36, Munich D-80636, Germany.
Insights
Clonal haematopoiesis of indeterminate potential (CHIP) predicts mortality in coronary artery disease (CAD) patients. TET2 mutations in CHIP promote plaque inflammation and instability by altering macrophage function, linking epigenetic changes to adverse cardiovascular outcomes.
Area of Science:
- Cardiovascular Medicine
- Hematology
- Genetics
Background:
- Clonal haematopoiesis of indeterminate potential (CHIP) is linked to cardiovascular risk, but its role in coronary artery disease (CAD) needs clarification.
- Understanding the prognostic significance and mechanisms of CHIP in CAD is crucial for patient outcomes.
Purpose of the Study:
- To investigate the association between CHIP and all-cause mortality in patients with confirmed CAD.
- To explore the cellular and molecular mechanisms underlying CHIP's impact on CAD, with a focus on TET2 mutations.
Main Methods:
- Deep sequencing of 13 CHIP driver genes in 8612 CAD patients.
- Propensity-score matching of CHIP carriers (variant allele frequency ≥2%) with non-carriers for 3-year mortality assessment.
- Mechanistic studies using post-mortem plaque proteomics, RNA sequencing, and in vitro macrophage models.
Main Results:
- CHIP was associated with a 39% increased risk of 3-year mortality in matched CAD patients (HR 1.39).
- Specific mutations (TET2, ASXL1, DNMT3A, etc.) independently increased mortality risk.
- TET2 CHIP carriers exhibited more unstable plaques with increased inflammation and necrotic cores, driven by altered macrophage lipid metabolism and inflammatory pathways via LDLR upregulation.
Conclusions:
- CHIP serves as a significant predictor of mortality in coronary artery disease patients.
- TET2 mutations in CHIP drive a pro-atherogenic macrophage phenotype, increasing plaque instability and adverse cardiovascular events through epigenetic dysregulation of lipid metabolism and inflammation.
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.
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