Comparison of Fatty Acid Binding Protein 3 and Ankle Brachial Index for Predicting Peripheral Artery Disease Outcomes

Background: Peripheral artery disease (PAD) impacts more than 200 million individuals globally. Despite its prevalence, management remains suboptimal, partly due to the lack of reliable blood-based biomarkers. The ankle–brachial index (ABI), the current gold-standard test for PAD, is limited by inter-operator variability, misinterpretation, and reduced accuracy in patients with diabetes. Fatty acid binding protein 3 (FABP3) has emerged as a potential biomarker for PAD; however, its prognostic performance relative to ABI remains unclear. This study compared FABP3 and ABI for predicting PAD outcomes using statistical and machine learning approaches. Methods: A total of 1001 participants were prospectively recruited, including 644 patients with PAD and 357 without PAD. The primary outcome was 2-year major adverse limb event (MALE), defined as a composite of vascular intervention, major amputation, or acute limb ischemia. At enrollment, plasma FABP3 was quantified using a validated multiplex immunoassay. Kaplan–Meier analysis of MALE-free survival was performed across pre-specified FABP3 tertiles (high >3.55 ng/mL, moderate 1.55–3.55 ng/mL, and low [ 3.55 group. In contrast, ABI severity groups showed less pronounced separation, with 24-month MALE-free survival rates of 80.3% for mild ABI, 73.2% for moderate ABI, and 71.3% for severe ABI, without a statistically significant overall difference (p = 0.170). In adjusted Cox proportional hazards models, FABP3 demonstrated strong prognostic performance for 2-year MALE. A 1 SD increase in log-transformed FABP3 was independently associated with a higher risk of 2-year MALE (HR 1.90, 95% CI 1.60–2.25; p < 0.001), with minimal change after additional adjustment for ABI (HR 1.90, 95% CI 1.60–2.24; p < 0.001). Machine learning analyses similarly favored FABP3 over ABI, with the FABP3-based model achieving an AUC of 0.773 compared to 0.686 for the ABI-based model. Adding ABI to the FABP3 model did not improve discrimination. Conclusions: Circulating plasma levels of FABP3 are strongly associated with PAD outcomes. Specifically, FABP3 demonstrated a stronger and more robust association with 2-year MALE compared to ABI. This study validates the prognostic value of FABP3 for PAD outcomes in comparison to ABI.