Blood Cell Mutations Linked to 27–52% Higher Heart Failure Risk in 417K Adults

Heart failure affects millions globally and its causes remain incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP)—where aging-related mutations in blood stem cells cause a single clone to expand and affect 10–20% of people over age 70—has emerged as a potential cardiovascular risk factor. This study is among the largest and most gene-specific investigations of CHIP and incident heart failure to date.

Researchers analyzed whole-exome sequencing data from 417,616 UK Biobank participants (mean age 56 years, 56% female) free of heart failure, hematologic malignancy, and key comorbidities at baseline, following them for a median of 11.1 years. CHIP was detected in 3.3% of participants, most commonly DNMT3A (63.5% of carriers), followed by TET2 (14.4%), ASXL1 (10.3%), DNA damage repair genes (4.3%), spliceosome genes (3.0%), and JAK2 (0.8%). The primary outcome was incident heart failure, identified via ICD-10 codes.

Overall CHIP was associated with a 27% higher risk of incident heart failure after multivariable adjustment. The non-DNMT3A composite showed a 52% increased risk (aHR 1.52), with striking individual gene-level associations: JAK2 CHIP conferred a 4-fold risk increase (aHR 4.01), spliceosome CHIP a 2.45-fold increase, ASXL1 a 1.51-fold increase, and TET2 a 1.34-fold increase. DNMT3A CHIP was only nominally significant overall (aHR 1.15), and only the R882 hotspot subtype reached significance (aHR 1.41). Higher variant allele frequency showed a linear relationship with heart failure risk for non-DNMT3A but not DNMT3A CHIP, and a sex interaction was observed for DNMT3A CHIP, with stronger risk in females.

Critically, mediation analyses using propensity-score-matched groups found that the four major CHIP-associated comorbidities—coronary artery disease, atrial fibrillation, type 2 diabetes, and chronic kidney disease—collectively explained only 28.2% of the non-DNMT3A CHIP–heart failure association. This implies that roughly 72% of the excess risk operates through independent, likely direct cardiac or inflammatory pathways, positioning CHIP as a potentially targetable upstream driver of heart failure rather than merely a comorbidity marker.

Sensitivity analyses including complete-case analysis, propensity score matching, Fine-Gray competing-risk models, and stricter heart failure definitions all yielded consistent results. These findings reinforce CHIP as an independent heart failure risk factor and suggest that therapeutic strategies targeting CHIP-associated inflammation or specific mutant clones could represent a novel prevention frontier.