Vitamin D status as a moderator of inflammation-mediated associations between adiposity and major adverse cardiovascular events: a cohort-based moderated mediation analysis.

BACKGROUND AND AIM: This study aimed to quantify the mediation of the adiposity-cardiovascular risk association by chronic low-grade inflammation and to test whether vitamin D status modulates this mediation.

METHODS AND

RESULTS

This prospective cohort study included 1828 adults without prior cardiovascular disease, recruited in 2016 and followed for 54 months. Baseline measurements included body fat percentage (BF%), serum 25-hydroxyvitamin D (25OHD), and high-sensitivity C-reactive protein (hsCRP). The primary endpoint was incidence of major adverse cardiovascular events (MACE). Associations were assessed using adjusted Cox proportional hazards models. Mediation and moderated mediation analyses were conducted to evaluate the role of inflammation and the potential modifying effect of vitamin D status. Among participants, 233 (12.7%) developed MACE. High BF% (aHR = 1.82 [1.13-2.92]), hsCRP (aHR = 2.92 [2.24-3.79]), and severe 25OHD deficiency (aHR = 1.37 [1.03-1.81]) independently predicted MACE. Inflammation significantly mediated the adiposity-MACE association, with mediated proportion decreasing as 25OHD increased: 21.3% in deficiency (-1SD), 14.9% for average values, and 7.1% for high concentrations (+1SD). 25OHD specifically modulated the inflammation→MACE pathway (β = -0.143, p < 0.001) without influencing the effect of adiposity on inflammation. The direct effect of adiposity persisted at all 25OHD levels.

CONCLUSION

Inflammation partially mediates the association between adiposity and cardiovascular risk, and is significantly modulated by vitamin D status in a dose-response relationship. Correcting vitamin deficiency could be an adjunctive strategy in obese individuals. Randomized trials are needed to establish the causality of this relationship.