Abstract Body: Background: Peripheral artery disease (PAD) is a prevalent yet underrecognized vascular condition associated with significant morbidity and mortality. Traditional atherosclerotic risk factors such as smoking and diabetes increase the risk of PAD but do not fully explain its pathogenesis. Metabolomics offers a novel approach to identifying biochemical pathways, but studies focusing on PAD are sparse.
Aim: To identify metabolites independently associated with incident PAD and its severe form critical limb ischemia (CLI).
Methods: We included 4,032 participants (mean age 54 [SD 6] years, 62% Black, and 60% female) from the Atherosclerosis Risk in Communities (ARIC) study with serum metabolomic data at visit 1 (1987-89). We investigated 636 endogenous metabolites quantified by an untargeted gas and liquid chromatography–mass spectrometry approach. PAD and CLI were ascertained using discharge codes. We ran Cox proportional hazards models adjusting for sociodemographic, clinical, and lifestyle factors. Multiple testing was corrected using the Benjamin-Hochberg method.
Results: Over a mean follow-up of 24 years, there were 453 cases of PAD, including 132 CLI cases. We identified 12 metabolites independently associated with PAD and 10 with CLI, representing peptides, lipids, and carbohydrates. Of these, gamma-glutamylthreonine (HR of PAD per 1SD metabolite increment 0.84 [95% CI 0.76-0.92]), gamma-glutamyltyrosine (0.85 [0.78-0.93]), 1,5-anhydroglucitol (0.79 [0.72-0.87]) and glucose (1.25 [1.10-1.42]) were associated with both PAD and CLI (Table). Asparagylvaline, lysylleucine, 1-docosahexaenoylglycerol, 1-linoleoylglycerol and 1-linoleoylglycerophosphocholine (18:2n6) were uniquely associated with CLI.
Conclusion: We identified several metabolites independently associated with PAD and its severe form, CLI. Of these, gamma-glutamylthreonine, gamma-CEHC, asparagylvaline, lysylleucin and arginylproline have not been reported previously for any atherosclerotic diseases.