Fat Distribution, Inflammatory Mechanisms, and Cardiovascular Disease Risk: Mediation Analysis Based on the Framingham Risk Score

Abstract Objective: To investigate the impact of fat distribution characteristics on the 10-year risk of cardiovascular disease (CVD) and to analyze the potential mediating effects of various inflammatory markers in this relationship. Methods: Using data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018, 4,741 participants aged 30 years and older were included in the study. Body mass index (BMI), waist circumference (WC), and fat percentages measured at various sites (upper limbs, lower limbs, trunk, and total body) via dual-energy X-ray absorptiometry (DXA) were used as exposure variables. The Framingham Risk Score (FRS) was utilized as the CVD risk assessment indicator. Multivariable linear regression analysis was employed to explore the relationship between fat distribution and FRS. Additionally, a mediation analysis model was applied to examine the mediating effects of inflammatory markers (CRP, WBC, NLR, etc.) in the association between fat distribution and FRS, with separate analyses conducted by gender. Results:In men, the total fat percentage showed the strongest positive correlation with the Framingham Risk Score (FRS) (β = 0.08, 95% CI: 0.07–0.10), followed by the trunk fat percentage (β = 0.09, 95% CI: 0.08–0.11) and BMI (β = 0.07, 95% CI: 0.06–0.08). C-reactive protein (CRP) exhibited a significant mediating effect in the relationship between total fat and FRS (indirect effect = 0.019, 95% CI: 0.015–0.025), with a mediation proportion of 23.1%. In women, total fat percentage demonstrated a significant "U-shaped" nonlinear relationship with FRS (P_nonlinear = 0.046), with risk increasing sharply when body fat exceeded approximately 35%. In the fully adjusted model, the three major fat distribution indicators influencing FRS were total fat percentage (β = 0.11, 95% CI: 0.07–0.14), trunk fat percentage (β = 0.11, 95% CI: 0.07–0.14), and BMI (β = 0.09, 95% CI: 0.07–0.11). The mediating effect of CRP was the most significant (indirect effect = 0.041, 95% CI: 0.031–0.054), with a mediation proportion of 38.1%. Conclusion:Fat distribution types have a differential impact on future cardiovascular risk, with total fat percentage being particularly associated with a significant increase in CVD risk. Inflammatory responses may represent an important biological pathway through which fat distribution elevates CVD risk, suggesting that monitoring and controlling inflammatory markers is crucial for reducing cardiovascular risk.