Table 1: Summary of the Major Circulating Biomarkers in Lower Extremity Artery Disease Presented in This Review.
| Major Circulating Biomarkers Assessed | Pathophysiological Pathway/Mechanism | Type of Biomarker | Discriminative Performance |
|---|---|---|---|
| Inflammation | |||
| IL-6[17,21–31] | IL-1/IL-6/CRP pathway | Diagnostic, prognostic | IL-6, CRP, TNF-α and risk factors: AUC 1.00 for MALE and 0.91 for MACE[30] |
| CRP[17,21,32–48] | IL-1/IL-6/CRP pathway | Diagnostic, prognostic | Diagnosing LEAD: AUC 0.811[34] Predicting composite of amputation, revascularisation, all-cause death: AUC 0.57[40] CRP, IL-6, TNF-α and risk factors: AUC 1.00 for MALE and 0.91 for MACE[30] |
| TNF-α[21,23,24,27,30,49,50] | Adipokine and cytokine | Prognostic | TNF-α, IL-6, CRP and risk factors: AUC 1.00 for MALE and 0.91 for MACE[30] |
| GDF-15[58–61] | Member of the TGF-β superfamily; regulation of inflammatory processes | Prognostic | Predicts all-cause mortality in LEAD with 90.0%
sensitivity, 52.6% specificity[60] Predicts all-cause mortality together with TRAIL-R2: AUC 0.74[61] |
| Endothelial Activation and Dysfunction | |||
| VCAM-1, ICAM-1[17,21,23–26,28,53–56] | Mediate leucocyte endothelial adhesion and transmigration | Diagnostic, prognostic | Diagnosing LEAD (VCAM-1): AUC 0.76[53] |
| Oxidative Stress | |||
| ADMA[63,67–71] | Inhibitor of NO production | Diagnostic, prognostic | Predict cardiovascular death: AUC 0.649[70] |
| Coagulation | |||
| Fibrinogen[33,35,43,73,77–79,81–84] | IL-1/IL-6/CRP pathway | Diagnostic, prognostic | Diagnosing LEAD: AUC 0.870[34] |
| Cardiac | |||
| NT-proBNP [43,88–92] | Precursor to BNP secreted by cardiomyocytes during ventricular stretch | Diagnostic, prognostic | Predicting all-cause mortality in LEAD: AUC 0.74[91] |
| Lipid Metabolism | |||
| Lp(a)[95–97] | LDL-like particle bound to apoB100 | Diagnostic | Risk factors, OxPL/apoB100, Lp(a) diagnosing LEAD: AUC 0.759 in women and 0.736 in men[97] |
| Lp-PLA2[98–102] | Modifies oxidised LDL | Diagnostic | Diagnosing LEAD: AUC 0.807[100] |
| Auxiliary | |||
| Circulating miRNAs[123–125] | Non-coding single-stranded RNAs from EVs, regulate gene expression | Diagnostic | Diagnosing LEAD: AUC >0.93 for miR-15b, miR-16 and miR-363[123] |
ADMA = asymmetric dimethylarginine; apoB100 = apolipoprotein B100; AUC = area under the curve; BNP = B-type natriuretic peptide; CRP = C-reactive protein; EVs = extracellular vesicles; GDF-15 = growth differentiation factor-15; IL = interleukin; LEAD = lower extremity artery disease; Lp(a) = lipoprotein (a); Lp-PLA2 = lipoprotein-associated phospholipase A2; MACE = major adverse cardiovascular events; MALE = major adverse limb events; miRNA = microRNA; NO = nitric oxide; NT-proBNP = N-terminal pro B-type natriuretic peptide; OxPL = oxidised phospholipids; TGF-β = transforming growth factor-β; TNF-α = tumour necrosis factor-α; TRAIL-R2 = tumour necrosis factor-related apoptosis-inducing ligand receptor 2; VCAM-1 = vascular cell adhesion molecule-1.