(IP089) Proteomics and metabolomics associated with development of severe outcomes in patients with prevalent extracoronary vascular diseases

Objectives: Despite current treatment strategies for atherosclerosis focusing on lifestyle modification and cholesterol reduction, extracoronary vascular diseases affects >200 million patients worldwide and often remain indolent before progressing to severe disease with morbid complications. The aims of this cohort study were to (1) characterize biomarkers associated with development of severe outcomes and (2) compare pathways driving disease progression in different vascular beds in individuals with existing extracoronary vascular disease.

Methods: We used proteomic and metabolomic data from 939 individuals in the UK Biobank with prevalent extracoronary vascular disease at baseline, defined as peripheral artery disease (PAD), carotid artery stenosis (CAS), renal artery stenosis (RAS), or acute mesenteric ischemia. Cases were defined as individuals who subsequently developed severe outcomes corresponding to their original diagnosis including major adverse limb events (MALE; developed after PAD), stroke (after CAS), hemodialysis (after RAS), and death (after acute mesenteric ischemia). The first aim utilized Cox proportional hazards regression models to estimate the associations of 1,463 proteins and 249 metabolites with adjustment for age at enrollment, age at prevalent disease diagnosis, sex, cigarette smoking, systolic blood pressure, and statin prescriptions. The second aim utilized Gene Ontology and hypergeometric enrichment tools to identify enriched pathways.

Results: Among 939 individuals with existing extracoronary vascular disease, 144 individuals developed associated complications (Table 1). There were 19 proteins and 4 metabolites significantly associated (P < 0.001) with severe outcomes (Figure 1). Significant proteins were enriched for processes involving toll-like receptor 6 signaling pathways (fold-enrichment=100, P=9.23×10-4) and chemokine-mediating signaling pathways (fold-enrichment=100, P=2.77×10-3). ATP-dependent Clp protease adapter protein (CLPS) was associated with decreased risk, while insulin-like growth factor 2 receptor (IGF2R) was associated with increased risk. Significant metabolites were enriched for VLDL-related particles. Both cholesterol and free cholesterol content in VLDL particles were associated with lower risk, while saturated fatty acids and triglyceride content in VLDL particles were associated with increased risk of severe outcomes. The progression of PAD to MALE was uniquely associated with increased levels of biomarkers recently implicated in vascular dysfunction, including interleukin 17 receptor A (IL17RA; HR=2.24, P=9.83×10-4), tumor necrosis factor ligand superfamily member 13 (TNFSF13; HR=5.32, P=7.79×10-4), and decreased levels of linoleic acid (HR=0.68, P=5.64×10-4).

Conclusions: Severe outcomes were associated with VLDL-related metabolites and proteins involved in fibrosis, atherosclerosis, and inflammation. This cohort study provides evidence of the complex role of biomarkers in extracoronary vascular disease pathogenesis and highlights specific proteins and metabolites as potential targets to improve therapeutic strategies.