medRxiv · Oct 25, 2025
Association between adverse childhood experiences and future cardiovascular disease risk in a population with Cardiovascular-Kidney-Metabolic syndrome stage 0-3: Depression symptom plays a mediating role
By Wang Y, Sun M, Gao J et al.
Abstract Background While adverse childhood experiences (ACEs) are established risk factors for cardiovascular disease (CVD), their association with CVD risk among individuals already at high risk due to Cardiovascular-Kidney-Metabolic (CKM) syndrome remains unclear. This study aimed to investigate this relationship and to evaluate the potential mediating role of depression symptoms. Methods This longitudinal study included 6,113 middle-aged and older adults with CKM syndrome (stages 0-3) from the China Health and Retirement Longitudinal Study (CHARLS). Cumulative ACE scores (total, intrafamilial, social) were derived from a life history survey. Incident CVD was determined during follow-up (2013-2018). Cox proportional hazards models assessed ACE-CVD associations, with restricted cubic splines evaluating dose-response relationships. Counterfactual-based mediation analysis quantified the contribution of depression symptoms (CES-D ≥10). Results During follow-up, 931 incident CVD cases occurred. A graded, positive association was observed between cumulative ACE exposure and CVD risk. In fully adjusted models, compared to the low ACE group (0-2), participants in medium (3-4) and high (≥5) ACE groups had significantly increased CVD risks (HR=1.22, 95% CI: 1.05-1.41; HR=1.29, 95% CI: 1.07-1.55, respectively). Each 1-point increase in the total ACE score was associated with a 7% elevated CVD risk (HR=1.07, 95% CI: 1.03-1.10). Intrafamilial ACEs demonstrated a stronger association (HR=1.08 per point, 95% CI: 1.04-1.13) than social ACEs. A nonlinear dose-response relationship was identified (P for nonlinearity <0.001). Depression symptoms significantly mediated 14.26% (95% CI: 4.56%-24.17%) of the total ACE-CVD association, with varying proportions observed for intrafamilial (15.92%) and social (32.47%) ACE subtypes. Conclusions Among Chinese adults with CKM syndrome stages 0-3, cumulative ACE exposure, particularly intrafamilial adversities, is independently associated with an increased risk of incident CVD in a dose-response manner. Depression symptoms partially mediate this association. Integrating ACE screening and addressing depression could enhance cardiovascular risk stratification and primary prevention in this high-risk population.