High-sensitivity C-reactive protein mediates age-related vascular dysfunction: the Rotterdam study

Abstract

Aims To investigate the role of chronic low-grade systemic inflammation-specifically high-sensitivity C-reactive protein (hsCRP)-in mediating the relationship between ageing and vascular dysfunction, and to assess its causal contribution relative to lipid metabolism. We also examined sex-specific mediation to evaluate differences in inflammatory pathways between men and women. Methods and results We analysed data from the Rotterdam Study, including 7591 participants with longitudinal carotid intima-media thickness (cIMT) and 6488 with cross-sectional pulse wave velocity (PWV) data. Mediation analysis assessed the roles of hsCRP, total cholesterol, and high-density lipoprotein in the age-vascular dysfunction association accompanied by sex-stratification. Two-sample Mendelian randomization (MR) was conducted to explore the potential causal effects of hsCRP on vascular outcomes. hsCRP significantly mediated the effect of age on cIMT (2.66%, P = 0.001) and PWV (2.56%, P = 4.95 × 10 −9), with mediation magnitudes comparable to those of lipid markers and stronger in men compared to women. MR analyses provided genetic support for a potential causal relationship between hsCRP and PWV, but not cIMT. Conclusion Systemic inflammation indexed by hsCRP appears to mediate and potentially contribute causally to age-related vascular stiffness , particularly in men. These findings support the role of inflammation in functional vascular ageing and suggest that anti-inflammatory strategies may complement lipid-lowering approaches in reducing cardiovascular risk.Lay summary As we age, our blood vessels tend to stiffen and thicken, increasing the risk of heart disease. This study explored how inflammation (high-sensitivity C-reactive protein) and cholesterol contribute to these vascular changes and whether their effects differ in men and women.