High-Sensitivity C Reactive Protein Mediates Age-Related Vascular Dysfunction: The Rotterdam Study

Abstract

AIM: To investigate the role of chronic low-grade systemic inflammation-specifically high-sensitivity C-reactive protein (hsCRP)-in mediating the relationship between aging 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: We analyzed data from the Rotterdam Study, including 7,591 participants with longitudinal carotid intima-media thickness (cIMT) and 6,488 with cross-sectional pulse wave velocity (PWV) data. Mediation analysis assessed the roles of hsCRP, total cholesterol, and HDL 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. RESULTS: 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 aging and suggest that anti-inflammatory strategies may complement lipid-lowering approaches in reducing cardiovascular risk.