Inverted U‐Shaped Association of Plasma Resolvin D2 With Atherosclerotic Cardiovascular Disease and the Mediation Effects of Serum Cholesterol: A Chinese Community‐Based Study

Abstract

Background Resolvin D2 (RvD2) has been reported to protect against the development of atherosclerosis in animal models. The objective of this study was to examine the prospective association between plasma RvD2 and the risk of atherosclerotic cardiovascular disease (ASCVD) at the population level. Methods and Results A cohort of 2633 community‐dwelling individuals aged 35–60 years was followed for 8 years in this study. Adjusted hazard ratios and 95% CIs for ASCVD outcomes according to baseline RvD2 levels were calculated using Cox proportional hazards models. Mediation analysis was used to test the indirect effect of serum cholesterol indicators on the association between RvD2 and ASCVD probability. In total, 284 new cases of ASCVD were identified during follow‐up. An inverted U‐shaped association between natural log (ln)‐transformed RvD2 and incident ASCVD was determined, and the threshold value for lnRvD2 was 3.87. Below the threshold, each unit increase in lnRvD2 was associated with a 2.05‐fold increased risk of ASCVD (95% CI, 1.13–3.74; P =0.019). Above the threshold, each unit increase in lnRvD2 was associated with a 36% reduced risk of ASCVD (95% CI, 0.51–0.80; P <0.001). In addition, the association between RvD2 and ASCVD probability was partially mediated by high‐density lipoprotein cholesterol (15.81%) when lnRvD2 <3.87, but by total cholesterol (30.23%) and low‐density lipoprotein cholesterol (30.13%) when lnRvD2 ≥3.87. Conclusions Both lower and higher RvD2 levels are associated with a reduced risk of ASCVD, forming an inverted U‐shaped relationship. Furthermore, this association is partially mediated by total cholesterol, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol.