The association of accelerated epigenetic age with all-cause mortality in cardiac catheterization patients as mediated by vascular and cardiometabolic outcomes
Background
Epigenetic age is a DNA methylation-based biomarker of cellular and organ system aging. The difference between epigenetic age and chronological age, termed age acceleration (AA), is a strong predictor of lifespan and healthspan. The predictive capabilities of AA for all-cause mortality have been evaluated in the general population; however, its utility is less well evaluated in those with chronic conditions. Additionally, the pathophysiologic pathways whereby AA predicts mortality are unclear. We hypothesized that AA predicts mortality in individuals with underlying cardiovascular disease (CVD); and the association between AA and mortality is mediated, in part, by subclinical and clinical vascular measures.
Methods
We evaluated 562 participants in an urban, three-county area of central North Carolina from the CATHGEN cohort, all of whom received a cardiac catheterization procedure. We analyzed three AA biomarkers, Horvath epigenetic age acceleration (HAA), phenotypic age acceleration (PhenoAA), and Grim age acceleration (GrimAA), by Cox regression models to assess whether AAs were associated with all-cause mortality. We also evaluated if these associations were mediated by subclinical and clinical vascular outcomes, including left ventricular ejection fraction (LVEF), blood cholesterol concentrations, angiopoietin-2 (ANG2) protein concentration, peripheral artery disease (PAD), coronary artery disease (CAD), diabetes, and hypertension. The total effect, direct effect, indirect effect, and percentage mediated were estimated using pathway mediation test with a regression adjustment approach.
Results
Independent of other CVD risk factors, all three AA biomarkers were significantly associated with all-cause mortality. Accelerated epigenetic age was associated with greater hazard ratios for mortality, with PhenoAA and GrimAA more strongly associated than HAA. The association of mortality and PhenoAA was partially mediated by a marker of vascular function - ANG2 (19.8%, P=0.016) - and diabetes (8.2%, P=0.043). The GrimAA-mortality association was mediated by ANG2 (12.3%, P=0.014), and showed weaker evidence (by P-value) for mediation by left ventricular ejection fraction (5.3%, P=0.065).
Conclusions
In a population burdened with CVD and thus with different all-cause mortality risks than the general population, epigenetic age acceleration strongly predicted mortality. Mortality associations were differentially mediated by cardiometabolic factors, suggesting specific pathophysiologic pathways may link accelerated epigenetic aging with increased mortality risks.