Abstract 14745: Stem Cell Factor Associated With Critical Limb Ischemia in Patients With Peripheral Artery Disease

Abstract

Introduction: Critical limb ischemia (CLI) and related amputation (AMP) are severe manifestations of peripheral artery disease (PAD). The pathobiology of CLI/AMP is multifactorial including chronic ischemia in the context of large vessel and microvascular disease. Novel biomarkers may identify potential pathways for new therapies to prevent and treat CLI. Hypothesis: Exploration of the proteome will yield insights into new proteins and hence pathways relevant in the pathogenesis and complications of PAD. Methods: A nested case-control study including 50 patients with CLI/AMP and 83 without was assembled from patients with PAD in the TRA2P-TIMI 50 trial for proteomic exploration using the Olink CVDII panel. Candidate markers were identified based on a false discovery rate (FDR) p-value <0.05 and then validated among 7,077 patients with PAD from TRA2P-TIMI 50 and FOURIER trials. Biomarkers were evaluated continuously & by quartile and analyses adjusted for age, sex, diabetes mellitus, and prior peripheral revascularization. Results/Data: A total of 12 protein biomarkers were significantly associated with CLI/AMP in the case-control sample at an FDR of 5% (Fig-Panel A). Three remained significantly associated with CLI/AMP in the validation step, the strongest of which was stem cell factor (SCF), a cytokine expressed by endothelial cells and involved in vasculogenesis. There was a significant inverse association between SCF and CLI/AMP (p-Bonferroni 0.00047). Examined by quartiles and adjusting for baseline differences (Panel B), a graded inverse association between SCF and CLI/AMP was observed (Q4 vs Q1 Adjusted OR 0.52, 95% CI: 0.34, 0.77; p=0.002). Conclusions: A proteomic approach to identifying novel biomarkers associated with CLI/AMP revealed a strong inverse risk relationship with SCF levels. These data suggest that SCF and its effects on vasculogenesis warrant further investigation as a pathway to prevent and treat CLI/AMP in patients with PAD.