Untargeted Plasma Metabolomics Reveals Molecular Subtypes Associated with Reintervention Risk in Peripheral Artery Disease after Revascularization

Abstract Peripheral artery disease (PAD) shows substantial outcome heterogeneity after revascularization that is incompletely explained by conventional severity indicators. We performed untargeted plasma LC–MS metabolomics in 175 PAD patients undergoing revascularization and applied variability-based feature selection, unsupervised clustering, pathway and chemical-class analyses, survival modeling, and metabolite prioritization. Three metabolically defined molecular subtypes were identified: redox protective (n = 93), metabolic burden (n = 72), and renal dysfunction (n = 10). Compared to the redox-protective subtype, the metabolic-burden subtype showed higher risks of composite adverse outcomes, reintervention, and major adverse cardiovascular events, accompanied by acylcarnitine accumulation, fatty-acyl enrichment, and COX-prostaglandin-related inflammatory signaling. Secondary clustering of high-risk patients identified a subgroup with increased reintervention risk, despite no corresponding increase in Rutherford classification or ankle-brachial index severity, characterized by sphingomyelin, diglyceride, and thromboxane/leukotriene-related lipid mediator signatures. A five-metabolite score was associated with reintervention risk and showed numerically higher apparent discrimination than the original and expanded clinical models. These findings establish an untargeted metabolomics framework for molecular subtyping of PAD after revascularization and nominate metabolic phenotypes for future validation.