Abstract 8972: Discovery and Temporal Validation of Proteomic Signatures for Incident Chronic Limb-Threatening Ischemia in the Atherosclerotic Risk in Communities (ARIC) Study

Abstract

Background: Chronic limb-threatening ischemia (CLTI), a severe form of peripheral artery disease (PAD) with rest pain, non-healing ulcers, or gangrene, is a devastating condition with high risks of limb loss and mortality. Emerging evidence indicates that CLTI reflects a distinct pathophysiologic state rather than simply progressed PAD. Yet, the ability to identify individuals at risk for future CLTI remains limited. High-throughput plasma proteomics offers an opportunity to identify CLTI-specific biological signatures, but evidence from large, longitudinal cohorts is lacking. Aim: To identify and temporally validate plasma proteomic markers associated with incident CLTI in community-dwelling adults from the ARIC study. Methods: We included participants free of PAD who had proteomic measures in the ARIC study: 10,878 (mean age 57 [SD 6] years, 23% Black, and 55% female) from visit 2 and 4,427 (mean age 76 [SD 5] years, 17% Black, 56% female) from visit 5. We investigated 4,955 plasma proteins quantified using the SOMAscan v4.0 platform at both visits. CLTI was ascertained using hospital discharge codes of PAD concurrent with rest pain, gangrene, tissue loss or amputation. We used Cox models adjusting for traditional cardiovascular risk factors. Proteins identified in the discovery cohort (visit 2 as baseline) were validated in the visit 5 baseline cohort. To avoid double counting the same CLTI cases in both discovery and validation, the discovery cohort was censored at visit 5. In the validation analysis, participants were followed through2022. The Benjamini-Hochberg procedure with a false discovery rate (FDR) threshold of 0.05 was used to correct for multiple testing. Results: Over a median follow-up of 20 and 10 years, there were 162 and 34 incident CLTI cases in the discovery and validation cohorts, respectively. We identified 245 proteins significantly associated with incident CLTI in the discovery cohort. Of these, 19 proteins were temporally validated in the visit 5 cohort, showing consistent directions of association despite differences in age and follow-up duration. Nearly all the validated proteins were positively associated with CLTI risk in both cohorts. Phospholipase A2, cardiac troponin T, and heat shock protein beta 6 showed the most significant associations, based on p-value ranking, in both the discovery and validation cohorts (Table). Only one protein, arylamine N-acetyltransferase-1 involved in folate catabolism, showed an inverse association in both cohorts. Conclusion: We identified 19 proteins associated with future CLTI, which may be helpful to identify individuals at risk of CLTI, better understand CLTI pathophysiology, and discover potential treatment targets for CLTI.