Biomarkers of peripheral arterial disease

Abstract

Atherosclerotic arterial occlusive disease affecting the lower extremities is also known as peripheral artery disease (PAD). This disorder affects 8 to 12 million individuals in the U.S. and is increasingly prevalent in Europe and Asia. Unfortunately, most patients are not diagnosed and are not optimally treated. A blood test for PAD, if sufficiently sensitive and specific, would be expected to improve recognition and treatment of these individuals. Even a biomarker panel of moderate sensitivity and specificity for PAD could refine risk stratification to select individuals for diagnostic vascular examination. Alternatively, biomarkers for PAD may be useful in determining prognosis, the risk for progression, or the response to therapy. Finally, the discovery of biomarkers associated with PAD may provide novel insights into the pathophysiology of PAD and new therapeutic avenues to pursue. Biomarkers may be derived from studies of the genome, transcriptome, proteome, or metabolome. The focus of this review is on proteomic biomarkers associated with PAD.

Figure 1

ROC analysis of conventional risk factors, the biomarker panel score, and a combination of conventional risk factors and the biomarker panel score.

Figure 2

Odds ratio of CAD+PAD status by AHA risk score and by biomarker panel score. There is a positive interaction between the two assessments of disease risk. Individuals were assigned an AHA risk score using the traditional cardiovascular risk factors as described (19). AHA risk scores of <5 (low), 5 to 10 (medium) and >10 (high) were associated with increasing risk of PAD (p=0.006 for men and p<0.001 for women using the score from the linear regression by ANOVA). The tertile cutoffs of the biomarker panel score were used to determine the risk level: low (<.991), medium (.991–1.033), and high (>1.033). n.s., not significant.

Figure 3

The optimal PAD blood test is likely to be comprised of a panel of biomarkers that circulate systemically, but which reflect the activity of local pathophysiological processes contributing to inflammation, oxidative stress, matrix remodeling, endothelial dysfunction, coagulation, metabolic perturbations and ischemia-reperfusion. Unique characteristics of the peripheral circulation may provide for specificity of the biomarkers that are released. In brackets are biomarkers that are elevated in PAD, but which are not specific. The identification of novel and specific biomarkers is underway. VEGF = vascular endothelial growth factor; Lp(a) = lipoprotein (a); B2M = beta 2 microglobulin; MMP9 = Matrix metalloproteinase 9; glu = glucose; sRAGE = soluble receptor for advanced glycosylation endproducts; sVCAM = soluble vascular cell adhesion molecule; TF = Tissue Factor; MCP-1 = Monocyte chemotactic protein 1; ADMA = asymmetric dimethylarginine; EPCs = endothelial progenitor cells; IL-6 = interleukin 6 (,,–89)