Sustained estimated VLDL-C exposure is associated with cardiometabolic multimorbidity and foam cell dysfunction: evidence from prospective cohorts and in vitro studies.

Very-low-density lipoprotein cholesterol (VLDL-C) may contribute to cardiometabolic multimorbidity (CMM), but prospective evidence on cumulative exposure and cellular evidence in established foam cells remain limited. We aimed to evaluate the association between cumulative estimated VLDL-C exposure and incident CMM and to explore VLDL-r elated changes in established foam cells. We analyzed 4,055 participants from the China Health and Retirement Longitudinal Study (CHARLS) and 1,012 from the English Longitudinal Study of Ageing (ELSA). Cumulative estimated VLDL-C was calculated from two lipid measurements, and K-means clustering identified two-time-point exposure patterns. Cox regression, restricted cubic spline (RCS), and ROC analyses were performed. In vitro, ox-LDL-induced foam cells were exposed to VLDL (50, 100, and 200 μg/mL), followed by assessment of cholesterol handling and mRNA expression of inflammatory and insulin signaling-related genes. In CHARLS, each 1 mmol/L increase in cumulative estimated VLDL-C was associated with higher CMM risk (HR = 1.210, P < 0.001), and Q4 showed increased risk versus Q1 (HR = 1.691, P < 0.001). Similar quartile-based associations were observed in ELSA (Q4 vs. Q1: HR = 3.806, P = 0.006). The relatively high VLDL-C exposure pattern was associated with CMM in CHARLS (HR = 1.40, P = 0.002), while the ELSA association was borderline significant (HR = 1.867, P = 0.079). RCS analyses indicated linear associations. In foam cells, VLDL exposure dose- and time-dependently reduced cholesterol efflux, decreased mRNA expression of ABCA1/ABCG1, increased mRNA expression of IL-1β, CRP, and MCP-1, and altered mRNA expression of PTP1B and SOCS3. Cumulative estimated VLDL-C was associated with increased CMM risk, but its standalone discriminatory ability was limited. In vitro findings suggest that sustained VLDL exposure may aggravate foam cell dysfunction through impaired cholesterol efflux, inflammatory gene expression, and insulin signaling-related transcriptional changes.