Clonal Hematopoiesis Linked to Heart Failure Risk

Clonal hematopoiesis of indeterminate potential (CHIP), particularly non-DNMT3A CHIP subtypes, is an independent risk factor for incident heart failure (HF) and may represent a novel therapeutic target. In a UK Biobank cohort of 417,616 adults (mean age, 56.1 years; 56.2% women) without prior HF or major comorbidities, 7,183 participants (1.7%) developed HF over a median follow-up of 11.1 years. Overall, CHIP was associated with higher HF risk (adjusted hazard ratio [aHR], 1.27), driven mainly by non-DNMT3A subtypes (aHR, 1.52), including TET2, ASXL1, JAK2, and spliceosome gene variants. DNMT3A CHIP — the most prevalent CHIP subtype —showed a weaker association (aHR, 1.15). Mediation analyses revealed that CHIP-associated comorbidities—coronary artery disease, atrial fibrillation, type 2 diabetes, and chronic kidney disease—collectively explained only 28.2% of the link between non-DNMT3A CHIP and HF, suggesting that CHIP contributes to HF through mechanisms beyond traditional cardiometabolic pathways. These findings support the heterogeneity of HF risk across CHIP genes, and underscore CHIP’s emerging role in cardiovascular disease pathogenesis and its potential as a preventive and therapeutic target in HF. Source: https://jamanetwork.com/