Abstract
OBJECTIVES: Carotid atherosclerosis (CAS) plaques are independent risk factors for stroke, and chronic vascular inflammation is involved in their pathogenesis. This study aims to explore the association between the systemic immune-inflammation index (SII) and CAS, analyze sex-specific differences in this association, and provide evidence for the early prevention and control of atherosclerosis. METHODS: This single-center cross-sectional study included adults who underwent health examinations and completed carotid ultrasound assessments at Xiangya Hospital of Central South University between January and December 2023, among whom those with CAS were classified as a CAS group, and those without CAS were classified as a normal control group. Demographic characteristics, anthropometric measurements, and laboratory data were collected. Participants were categorized into Quartile 1 to 4 based on SII . Four binary logistic regression models were constructed to progressively adjust for confounders and evaluate the association between SII and CAS, with further stratification by sex. Mediation analyses stratified by sex. Mediation analyses stratified by sex were performed using the Bootstrap method (5 000 resamplings), with white blood cell and monocyte counts as mediators. Sensitivity analyses were conducted to verify robustness. RESULTS: A total of 19 788 participants were included, of whom 7 567 (38.24%) had CAS. Compared with controls, individuals with CAS had significantly higher proportions of males, age, waist circumference, systolic and diastolic blood pressure, fasting glucose, and white blood cell count (all P<0.001), and significantly lower high-density lipoprotein cholesterol levels (P<0.001). Logistic regression revealed notable sex heterogeneity. After adjusting for age and sex (Model 2), higher SII (Quartile 4) was significantly associated with increased CAS risk [odds ratio (OR)=1.26, 95% confidence interval (CI) 1.14 to 1.39, P<0.01]. This association persisted after further adjustment for metabolic risk factors (Model 3; OR=1.18, 95% CI 1.07 to 1.31, P<0.01). However, after additional adjustment for inflammatory markers such as C-reactive protein, white blood cell, and monocyte counts (Model 4), the association was substantially attenuated and became non-significant in the overall population and in men (P>0.05). Notably, among women, SII remained significantly associated with CAS across all models in both Quartile 2 (OR=1.19, 95% CI 1.02 to 1.39) and Quartile 4 (OR=1.20, 95% CI 1.01 to 1.43) groups (all P<0.05). Mediation analysis showed that in the overall population, white blood cell count exerted a complete mediating effect (indirect effect β=0.03, 95% CI 0.01 to 0.05, P<0.01; accounting for 46.3% of the total effect), while monocyte count partially mediated the association (indirect effect β=0.01, 95% CI 0 to 0.02, P<0.01; accounting for 18.9% of the total effect). Among men, the mediating role of inflammatory cells was amplified, with white blood cell count serving as a complete mediator (indirect effect β=0.04, 95% CI 0.02 to 0.06, P<0.01; accounting for 74.3% of the total effect) and monocyte count as a significant partial mediator (indirect effect β=0.01, 95% CI 0 to 0.02, P<0.05; accounting for 24.2% of the total effect). Among women, the mediating effect of monocyte count (β=0, 95% CI 0 to 0, P>0.05), and white blood cell count (β=0.01, 95% CI 0 to 0.02, P>0.05) were not statistically significant. After adjusting for all confounding factors, the direct effect of SII on CAS remained statistically significant in all cases (all P<0.05). Sensitivity analyses confirmed the robustness of the findings. CONCLUSIONS: A significant sex-specific heterogeneity exists in the association between SII and CAS. High SII is an independent correlate of CAS in women, driven primarily by direct effects and not mediated by white blood cell or monocyte counts. In men, SII influences CAS predominantly through complete mediation by white blood cells and partial mediation by monocytes. These findings suggest the differentiated value of SII in CAS risk assessment across sexes and provide evidence to support sex-targeted screening and intervention strategies.