Fat distribution, inflammatory mechanisms, and cardiovascular disease risk: mediation analysis based on the Framingham risk score

Abstract Objective To examine the association between fat distribution and 10-year cardiovascular disease (CVD) risk, and to evaluate the mediating roles of inflammatory markers in this relationship. Methods Data were obtained from the 2017–2018 cycle of the National Health and Nutrition Examination Survey (NHANES), including 4,741 participants aged ≥ 30 years. Fat distribution was assessed using body mass index (BMI), waist circumference (WC), and regional fat percentages (upper limbs, lower limbs, trunk, and total body) measured via dual-energy X-ray absorptiometry (DXA). The Framingham Risk Score (FRS) was used to estimate 10-year cardiovascular disease (CVD) risk. Multivariable linear regression models were applied to evaluate the associations between fat distribution and FRS. In addition, mediation analysis was performed to assess the indirect effects of inflammatory markers—including C-reactive protein (CRP), white blood cell count (WBC), and neutrophil-to-lymphocyte ratio (NLR)—on the relationship between fat distribution and FRS. All analyses were stratified by sex. 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 Different fat distribution patterns exert varying influences on long-term cardiovascular risk, with total body fat percentage showing the strongest association with increased risk. Inflammatory responses may serve as key biological mediators linking fat distribution to cardiovascular disease (CVD), highlighting the importance of monitoring and managing inflammation to reduce CVD risk.