Acceleration of GrimAge2 Epigenetic Clock Associates with Atherogenic Inflammageing and Independently Predicts Acute Coronary Syndrome Incremental to SCORE2-OP and PREVENT

Aims Available atherosclerotic cardiovascular disease (ASCVD) risk calculators predict acute events suboptimally in the elderly. We aimed to determine if DNA methylation (epigenetic) age acceleration (EAA) was associated with atherogenic inflammageing and predictive of adverse outcomes incremental to SCORE2-OP and PREVENT. Methods Participants stratified by FRAIL scale (robust/pre-frail/frail) were randomly selected in approximately equal proportions from a parent cohort of 1,400 community-living older adults. Five epigenetic clocks were developed from MethylationEPIC-analysed blood DNA to calculate baseline EAA by regressing chronological age on epigenetic age. Proton-NMR was used to profile serum lipoproteins/lipids and GlycA. The primary outcome was a composite endpoint of incident all-cause mortality, cardiovascular hospitalisation (CVH), and ASCVD/ACS hospitalisation (AAH). Time-to-event analyses were performed. Results Among epigenetic clocks analysed in 535 individuals aged 60–99y, GrimAge2 EAA (Grim2AA) was most significantly associated with cardiometabolic comorbidities and atherogenic inflammageing. During follow-up of 4.6y, 30 were lost to follow-up while 42 experienced AAH. Cox regression determined that Grim2AA was predictive of CVH (p<0.05) and AAH (p<0.01) but not all-cause mortality. For every one-year increase in Grim2AA, the hazards of CVH and AAH were significantly increased by 6% and 11%, respectively. The predictive performance of AAH by SCORE2-OP and PREVENT was improved by Grim2AA: C-index 0.693 to 0.734 (p<0.05) and 0.682 to 0.725 (p<0.01), respectively. In Kaplan-Meier analysis, the probability of AAH was significantly higher in individuals with Grim2AA ≥0 (acceleration or none) than <0 (deceleration) (p<0.01). Conclusion Grim2AA may independently predict AAH incremental to SCORE2-OP and PREVENT in older adults.