Key result
CHIP mutations were highly prevalent in patients with coronary artery disease (46.9% in the MISSION cohort and 14.2% in the STARNET cohort), with CHIP-mutated leukocytes directly invading human atherosclerotic plaques.
Why the study?
The prevalence and functional relevance of CHIP in CAD were unclear, and CHIP-affected cells had not been detected in human atherosclerotic plaques.
Observational (n=1,481)
Yes
This study provides direct evidence that CHIP-mutated leukocytes invade human atherosclerotic plaques and exhibit distinct, mutation-specific pro-atherosclerotic signaling profiles.
Answers are grounded in this paper and cite their sources.
CHIP-mutated cells in plaques may implicate CHIP in CAD progression; leaves open causal contribution and need for targeted trials.
Background Leukocyte progenitors derived from clonal hematopoiesis of undetermined potential (CHIP) are associated with increased cardiovascular events. However, the prevalence and functional relevance of CHIP in coronary artery disease (CAD) are unclear, and cells affected by CHIP have not been detected in human atherosclerotic plaques. Methods CHIP mutations in blood and tissues were identified by targeted deep-DNA-sequencing (DNAseq: coverage >3,000) and whole-genome-sequencing (WGS: coverage >35). CHIP-mutated leukocytes were visualized in human atherosclerotic plaques by mutaFISH TM . Functional relevance of CHIP mutations was studied by RNAseq. Results DNAseq of whole blood from 540 deceased CAD patients of the Munich cardIovaScular StudIes biObaNk (MISSION) identified 253 (46.9%) CHIP mutation carriers (mean age 78.3 years). DNAseq on myocardium, atherosclerotic coronary and carotid arteries detected identical CHIP mutations in 18 out of 25 mutation carriers in tissue DNA. MutaFISH TM visualized individual macrophages carrying DNMT3A CHIP mutations in human atherosclerotic plaques. Studying monocyte-derived macrophages from Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET; n=941) by WGS revealed CHIP mutations in 14.2% (mean age 67.1 years). RNAseq of these macrophages revealed that expression patterns in CHIP mutation carriers differed substantially from those of non-carriers. Moreover, patterns were different depending on the underlying mutations, e.g. those carrying TET2 mutations predominantly displayed upregulated inflammatory signaling whereas ASXL1 mutations showed stronger effects on metabolic pathways. Conclusions Deep-DNA-sequencing reveals a high prevalence of CHIP mutations in whole blood of CAD patients. CHIP-affected leukocytes invade plaques in human coronary arteries. RNAseq data obtained from macrophages of CHIP-affected patients suggest that pro-atherosclerotic signaling differs depending on the underlying mutations. Further studies are necessary to understand whether specific pathways affected by CHIP mutations may be targeted for personalized treatment.
No takes yet. Share an insight, caveat, or question.
Scheidt et al. (2023) conducted an observational in Coronary artery disease (n=1,481). Clonal Hematopoiesis of Indeterminate Potential (CHIP) mutations vs. Non-carriers was evaluated on Prevalence of CHIP mutations in whole blood. CHIP mutations were highly prevalent in patients with coronary artery disease (46.9% in the MISSION cohort and 14.2% in the STARNET cohort), with CHIP-mutated leukocytes directly invading human atherosclerotic plaques.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: