JACC CardioOncol. 2026 Oct 15:S2666-0873(26)00306-6. doi: 10.1016/j.jaccao.2026.08.007. Online ahead of print.
ABSTRACT
BACKGROUND: Clonal hematopoiesis (CH), characterized by clonal expansion of hematopoietic stem cells harboring preleukemic mutations, is an emerging cardiovascular disease risk factor. The American Heart Association's Life's Essential 8 (LE8) score is the contemporary standard for quantifying cardiovascular health. However, the interplay between this novel genetic risk factor and classical health metrics remains unknown.
OBJECTIVES: This study sought to examine the association between LE8 score and CH prevalence, and determine their joint effects on incident coronary artery disease (CAD).
METHODS: We analyzed 427,295 UK Biobank participants. Exposures included LE8 score and CH (evaluated as a composite and by common drivers: DNMT3A, TET2, ASXL1). Associations with CH prevalence and incident CAD over a median 13.6-year follow-up were evaluated using multivariable regression.
RESULTS: CH prevalence was 3.4%. A higher LE8 score was associated with significantly lower odds of CH and examined driver mutations, strongest for ASXL1 (OR: 0.79; 95% CI: 0.75-0.83; P < 0.001). CH significantly modified the protective effect of LE8 on CAD incidence on multiplicative and additive scales. A 1-SD increase in LE8 yielded an adjusted CAD HR of 0.74 (95% CI: 0.70-0.78) in CH carriers vs 0.68 (95% CI: 0.67-0.69) in noncarriers (Pinteraction = 0.005). Participants with ASXL1 CH subtype and low LE8 scores experienced the highest absolute CAD risk (18.7 vs 2.0 events/1,000 person-years in noncarriers with high LE8).
CONCLUSIONS: Optimal cardiovascular health is associated with a lower prevalence of CH. Although maintaining ideal cardiovascular health is associated with lower CAD risk in CH carriers, this protective benefit is attenuated compared with noncarriers.
PMID:42886106 | DOI:10.1016/j.jaccao.2026.08.007