Metabolic biomarker discovery for risk of peripheral artery disease compared with coronary artery disease: Lipoprotein and metabolite profiling of 31 657 individuals from 5 prospective cohorts

Abstract

BACKGROUND: Peripheral artery disease (PAD) and coronary artery disease (CAD) represent atherosclerosis in different vascular beds. We used detailed metabolic biomarker profiling to identify common and discordant biomarkers and clarify pathophysiological differences for these vascular diseases. METHODS AND RESULTS: We used 5 prospective cohorts from Finnish population (FINRISK 1997, 2002, 2007, and 2012, and Health 2000; n=31 657; median follow-up time of 14 years) to estimate associations between >200 metabolic biomarkers and incident PAD and CAD. Metabolic biomarkers were measured with nuclear magnetic resonance, and disease events were obtained from nationwide hospital records. During the follow-up, 498 incident PAD and 2073 incident CAD events occurred. In age-and sex-adjusted Cox models, apolipoproteins and cholesterol measures were robustly associated with incident CAD (eg, hazard ratio [HR] per SD for higher apolipoprotein B/A-1 ratio, 1.30; 95% CI, 1.25–1.36), but not with incident PAD (HR per SD for higher apolipoprotein B/A-1 ratio, 1.04; 95% CI, 0.95–1.14; Pheterogeneity <0.001). In contrast, triglyceride levels in lowdensity lipoprotein and high-density lipoprotein were associated with both end points (Pheterogeneity >0.05). Lower proportion of polyunsaturated fatty acids relative to total fatty acids, and higher concentrations of monounsaturated fatty acids, glycolysisrelated metabolites, and inflammatory protein markers were strongly associated with incident PAD, and many of these associations were stronger for PAD than for CAD (Pheterogeneity <0.001). Most differences in metabolic profiles for PAD and CAD remained when adjusting for traditional risk factors. CONCLUSIONS: The metabolic biomarker profile for future PAD risk is distinct from that of CAD. This may represent pathophysiological differences.