Residual lipid-related proteomic and metabolomic signatures associated with major adverse cardiovascular events after revascularization in peripheral artery disease

Abstract

Patients with peripheral artery disease (PAD) remain at high risk for major adverse cardiovascular events (MACE) after lower-extremity revascularization. In contemporary practice, widespread lipid-lowering therapy may reduce the discriminatory value of conventional lipid parameters and clinically defined hyperlipidemia (HLD), leaving residual lipid-related molecular risk insufficiently characterized. This study aimed to characterize residual lipid-related proteomic and metabolomic signatures in PAD and examine their association with MACE after revascularization. We enrolled a prospective cohort of 165 consecutive patients with PAD who underwent lower-extremity endovascular revascularization. Untargeted plasma metabolomic and proteomic profiling was performed. Lipid and lipid-like metabolite coexpression modules were identified using weighted gene coexpression network analysis, and molecular subtypes were defined using nonnegative matrix factorization clustering. Differential metabolites and proteins between subtypes were identified, and a compact multi-omics molecular score was constructed using LASSO regression. Associations with MACE were evaluated using Kaplan-Meier analysis, time-dependent receiver operating characteristic analysis, and multivariable Cox regression. We identified a lipid-related coexpression module associated with HLD but independent of statin use, with enrichment in sphingolipid metabolism, bile acid biosynthesis, and steroid hormone biosynthesis. Molecular clustering stratified patients into two subtypes (C1, n = 64; C2, n = 101) with distinct lipid metabolomic and proteomic profiles. The C1 subtype had significantly poorer MACE-free survival (log-rank P = 0.001). A compact multi-omics score comprising QDPR and four putatively annotated metabolites (deoxycholylphenylalanine, succinylcarnitine, glutarylcarnitine, and acetolein) discriminated between subtypes and was independently associated with MACE (hazard ratio = 1.25, P = 0.032), with a 5-fold cross-validated 15-month AUC of 0.871. Integrated proteomic and metabolomic profiling revealed residual lipid-related molecular signatures beyond conventional lipid parameters in patients with PAD undergoing lower-extremity revascularization. These signatures were associated with subsequent MACE, supporting further validation of molecular biomarkers for postoperative cardiovascular risk stratification in PAD.