Sex Moderates the Fibrinogen-mediated Pathways between Cardiometabolic Factors and Lower Ankle Brachial Index: A Moderated-mediation Analysis

Abstract This study aimed to evaluate whether fibrinogen (FGN) and intercellular adhesion molecule-1 (ICAM-1) mediate the associations between multiple risk factors and the ankle–brachial index (ABI), and to determine whether these associations and mediations differ by sex. We analyzed biomarker data from the Midlife in the United States (MIDUS 3, 2017–2022) study using bias-corrected bootstrapped moderated-mediation models. The analysis assessed the mediating roles of FGN and ICAM-1 in the relationship between seven predictors—body mass index (BMI), low-density lipoprotein (LDL), systolic blood pressure (SBP), age, HbA1c, smoking, and statin use—and ABI. Sex was specified as a moderator, and all continuous covariates were mean-centered. After excluding inapplicable cases, 708 participants were included, with a slight predominance of women (56.6%) and a mean age of 66.2 years (SD = 9.7). In men, FGN fully mediated the association between HbA1c and ABI (coefficient per +5% HbA1c = −0.02; 95% CI: −0.045 to −0.005), partially mediated the negative association between age and ABI (coefficient per +10 years = −0.004; 95% CI: −0.01 to −0.0001), and partially mediated the inverse association between BMI and ABI (coefficient per +10 kg/m2 = −0.01; 95% CI: −0.02 to −0.001), despite a positive total effect of BMI on ABI (coefficient per +10 kg/m2 = 0.05; 95% CI: 0.01 to 0.08). Additionally, FGN mediated (indirect-only mediation) the associations of LDL and smoking history with ABI (coefficient per +30 mg/dL LDL = −0.006; 95% CI: −0.011 to −0.001; coefficient for smoking history = 0.01; 95% CI: 0.001 to 0.02). Among women, only SBP predicted a lower ABI without evidence of mediation (coefficient per +10 mm Hg = −0.01; 95% CI: −0.02 to −0.002). Unexpectedly, higher LDL levels were associated with higher ABI (coefficient per +30 mg/dL = 0.03; 95% CI: 0.01 to 0.04). ICAM-1 showed no significant mediation in either sex. Statin use was not associated with ABI, FGN, or ICAM-1 levels. These findings underscore the importance of investigating sex-specific differences in the pathophysiology and management of peripheral arterial disease (PAD).