Association of Epigenetic Age Acceleration with Early Stage Heart Failure: Sex-Specific Effects in the Project Baseline Health Study

BackgroundEpigenetic age acceleration (EAA), defined as blood DNA methylation-derived biological age exceeding chronological age, has emerged as a potential biomarker of cardiovascular health and disease. EAA has been associated with symptomatic heart failure (HF); however, its connection to early-stage HF remains unclear. Moreover, the association of EAA with cardiovascular disease may differ by sex. MethodsWe analyzed participants from the Project Baseline Health Study, a deeply-phenotyped longitudinal cohort. HF staging was performed using echocardiographic measures and clinical criteria, classifying participants into stage 0/B0 (no HF risk factors), stage A (HF risk factors only, without structural cardiac abnormalities), and stage B1 (structural changes without HF symptoms). EAA was calculated as the residual of Horvath methylation epigenetic age regressed on chronological age. We compared EAA across HF stages using ANOVA models adjusted for sex, and in secondary analyses, investigated associations between EAA and echocardiographic parameters as well as sex-specific differences. ResultsAmong 1,338 participants (mean age: 49.2{+/-}15.4 years; 53.5% female), 41.7% were stage 0/B0 (n=558), 39.4% were stage A (n=527), and 18.9% were stage B1 (n=253). EAA tended to differ across HF stages (p=0.07), with higher EAA in stage B1 participants compared to those in stage 0/B0 or A. Sex-stratified models suggested that this trend was more pronounced in males than females. Among individual echocardiographic parameters, greater left ventricular posterior wall thickness was associated with higher EAA (p=0.046). In analyses restricted to stage A and B1 participants, higher EAA in B1 approached significance only in males (p=0.051). ConclusionsThese findings suggest that elevated EAA may occur even in the early, asymptomatic stages of HF, potentially reflecting underlying biological aging processes associated with early cardiac structural abnormalities. The effects may be sex-specific, with males showing a stronger relationship between EAA and stage B1 HF. Although validation through larger, longitudinal studies is necessary, our results support EAA as a potential biomarker for early cardiovascular risk assessment and underscore the need of considering sex differences in early HF pathophysiology.