A review of the pathophysiology and potential biomarkers for peripheral artery disease

Abstract

Peripheral artery disease (PAD) is due to the blockage of the arteries supplying blood to the lower limbs usually secondary to atherosclerosis. The most severe clinical manifestation of PAD is critical limb ischemia (CLI), which is associated with a risk of limb loss and mortality due to cardiovascular events. Currently CLI is mainly treated by surgical or endovascular revascularization, with few other treatments in routine clinical practice. There are a number of problems with current PAD management strategies, such as the difficulty in selecting the appropriate treatments for individual patients. Many patients undergo repeated attempts at revascularization surgery, but ultimately require an amputation. There is great interest in developing new methods to identify patients who are unlikely to benefit from revascularization and to improve management of patients unsuitable for surgery. Circulating biomarkers that predict the progression of PAD and the response to therapies could assist in the management of patients. This review provides an overview of the pathophysiology of PAD and examines the association between circulating biomarkers and PAD presence, severity and prognosis. While some currently identified circulating markers show promise, further larger studies focused on the clinical value of the biomarkers over existing risk predictors are needed.

Keywords: angiogenesis; arteriogenesis; biomarkers; critical limb ischemia; peripheral artery disease.

Figure 1

Schematic representation of the response to ischemia in peripheral artery disease. Initially the ischemic limb tries to compensate and resolve the hypoxia by changing the hemodynamics and promoting microvascular adaptations by promoting angiogenesis and/or arteriogenesis. As the severity of the hypoxia increases, the microvascular adaptations are not able to compensate. All these changes lead to mitochondrial injury and free radical generation and subsequent muscle fibre damage, myofibre degeneration and fibrosis. These changes eventually result in decreased oxygen supply and increased metabolic demands leading to conditions such as rest pain, chronic non-healing wounds and gangrene, subsequently threatening the limb function and viability. Blue arrows show the direction of blood flow in the artery and white arrows shows the increase in severity of disease. Abbreviations: ECs, endothelial cells; HIF-1α, Hypoxia inducible factor-1α; NO, Nitric oxide; PAD, Peripheral artery disease; VEGF, Vascular endothelial growth factor WBCs, white blood cells.

Figure 2

Circulating biomarkers in peripheral artery disease. A schematic depiction of the stages at which circulating biomarkers could be informative in the peripheral artery disease (PAD) course. Since PAD is multifactorial it is likely that a single biomarker may not be sufficient to predict diagnosis or prognosis. Since PAD development and progression is due to the interaction of multiple factors, it is possible that the combination of a number of biomarkers may be preferable to a single maker. Abbreviations: ABI, Ankle brachial index; Ang-2, Angiopoetin-2; ApoA1, Apolipoprotein A1; B2M, β-2-microglobulin; EPC, Endothelial progenitor cell; HCgp, Human cartilage glycoprotein; Hcy, Homocysteine; hsCRP, high sensitivity C-reactive protein; IL, Interleukin; Lp-a, Lipoprotein-1; MMP, Matrix mettalloprotenase; MPO, Myeloperoxidase; NO, Nitric oxide; NOX, NADPH Oxidase; NT-pro-BNP, N-terminal pro-B-type natriuretic peptide; OxPL/ApoB, Oxidised phospholipids on ApoB100 containing lipoproteins; PAD, Peripheral artery disease; PAR, Protease activated receptor; PON, Paraoxonase; sICAM-1, soluble Intercellular adhesion molecule-1; sRAGE, soluble receptor for advanced glycation end product; sTie-2, soluble Tyrosine kinase with immunoglobulin-like and EGF-like domains 2; sVCAM-1, soluble Vascular cell adhesion molecule-1; TBARS, Thiobarbituric acid-reactive substrates; TGF, Transforming growth factor; TWEAK, Tumour necrosis factor like weak inducer of apoptosis; TSP, Thrombospondin; TIMP, Tissue inhibitor of matrix metalloproteinase; VEGF, Vascular endothelial growth factor.