Clonal Hematopoiesis of Indeterminate Potential Linked to Increased Risk of Heart Failure: JAMA
USA: Researchers have found in a new cohort study that clonal hematopoiesis of indeterminate potential (CHIP), particularly non-DNMT3A CHIP, was linked to a higher incidence of heart failure (HF). Other CHIP-related comorbidities accounted for only a small part of this relationship, suggesting CHIP itself may be a direct HF risk factor and a possible therapeutic target.
The study, published in JAMA Cardiology by Spencer Flynn and colleagues from the Broad Institute of Harvard and MIT, examined whether specific CHIP gene subtypes were linked to new-onset heart failure and to what extent associated comorbidities influenced this connection.
CHIP refers to the age-associated expansion of blood cell clones that acquire preleukemic mutations. While previous studies have connected CHIP to various cardiometabolic disorders, its role in heart failure development—particularly for specific genetic variants—had remained uncertain.
To address this, researchers conducted a large-scale, prospective cohort analysis using data from 417,616 participants in the UK Biobank. None of the participants had heart failure, hematologic cancers, or major CHIP-associated conditions such as coronary artery disease (CAD), atrial fibrillation (AF), type 2 diabetes (T2D), or chronic kidney disease (CKD) at baseline. Whole-exome sequencing (WES) data were analyzed between April and October 2025, and participants were followed for a median duration of 11.1 years.
The primary goal was to determine whether CHIP, or specific CHIP driver genes, were associated with new cases of heart failure. Using Cox regression models adjusted for demographic and cardiovascular risk factors, the researchers assessed both overall CHIP presence and gene-specific variants, including DNMT3A, TET2, ASXL1, JAK2, spliceosome genes, and DNA damage repair genes.
The key findings were as follows:
- During the follow-up period, 7183 participants (1.7%) developed new-onset heart failure.
- The presence of clonal hematopoiesis of indeterminate potential (CHIP) was linked to a 27% higher risk of heart failure (adjusted hazard ratio [aHR] 1.27).
- The association was mainly driven by non-DNMT3A CHIP subtypes, which showed a 52% increased risk of heart failure (aHR 1.52).
- DNMT3A CHIP showed only a modest link with heart failure (aHR 1.15).
- Among the non-DNMT3A variants, the strongest associations were observed for TET2, ASXL1, JAK2, and spliceosome gene mutations.
- CHIP-related comorbidities such as coronary artery disease, atrial fibrillation, type 2 diabetes, and chronic kidney disease collectively accounted for only 28.2% of the association between non-DNMT3A CHIP and heart failure.
- The findings indicate that while CHIP may influence heart failure risk partly through these comorbidities, most of the effect appears to be independent of them.
The authors concluded that CHIP, especially non-DNMT3A subtypes, represents an independent risk factor for the development of heart failure. These insights highlight the potential of CHIP as both a biomarker and a therapeutic target for HF prevention and management.
They further emphasized the need for future research to uncover the gene-specific pathways through which CHIP drives cardiac dysfunction, which could eventually pave the way for targeted interventions aimed at mitigating heart failure risk in individuals with CHIP.
Reference:
Flynn S, Schuermans A, Uddin MM, et al. Clonal Hematopoiesis and Incident Heart Failure. JAMA Cardiol. Published online November 09, 2025. doi:10.1001/jamacardio.2025.4603
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