A Review of the Pathophysiology and Potential Biomarkers for Peripheral Artery Disease
<p>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.</p> "> Figure 2
<p>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, <span class="html-italic">N</span>-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.</p> ">
Abstract
:1. Introduction
2. Epidemiology of PAD
3. Risk Factors for PAD
4. Current PAD Management Strategies
5. The Pathophysiological Response to Athero-Thombosis-Induced PAD
6. Potential Biomarkers for PAD
6.1. Circulating Markers Associated with the Presence of PAD
Circulating Biomarkers Assessed | Sample Size (N) | Sample Studied | Association with PAD Presence | Refs. |
---|---|---|---|---|
B2M & cystatin C | CAD & PAD (197); CAD (81) & healthy controls (262) | Plasma | A biomarker panel comprising B2M, cystatin C, hsCRP and glucose were associated with PAD. | [65] |
B2M, cystatin C, hsCRP & glucose | PAD (83) & controls (896) | Plasma | Levels of cystatin C and B2M but not hsCRP and glucose were significantly elevated in PAD patients. | [66] |
aPWV, AIx & B2M | PAD (66) & healthy controls (66) | Plasma | B2M, aPWV and AIx were significantly increased in patients with PAD; among patients with PAD elevated B2M levels were independently associated with higher aortic stiffness. | [67] |
hsCRP, fibrinogen & leukocyte count | The National Health and Nutrition Examination Survey 1999–2002 (4787 participants aged ≥ 40 years) | Blood | All 3 markers were independently associated with PAD. | [68] |
hsCRP | PAD (82) & healthy controls (41) | Plasma | Increased hsCRP levels in PAD patients. | [69] |
CD40 ligand, fibrinogen, Lp-PLA2 , osteoprotegerin, P-selectin, and TNF-R2, hsCRP, ICAM-1, IL-6, MCP-1 & MPO | Framingham Offspring Study participants (2800) | Plasma | IL-6 &TNF-R2 were associated with PAD independent of established risk factors. | [70] |
VEGF-A, TNF-α & IL-8 | PAD (130) & controls (36) | Serum | Lower VEGF-A and higher TNF-α & IL-8 in PAD patients. | [71] |
High molecular weight & total adiponectin | PAD (110) & healthy controls (230) | Plasma | Lower adiponectin in women with PAD. | [72] |
OxPL/ApoB & Lp-a | Men with PAD (143), women with PAD (144) & controls (432) | Plasma | Increased levels of OxPL/ApoB and Lp-a were associated with PAD. | [73] |
Lp-PLA2 activity | PAD (172) & healthy controls (787) | Plasma | Increased Lp-PLA2 activity in PAD patients. | [74] |
Lp-PLA2 level | PAD (145) & healthy controls (837) | Plasma | Lp-PLA2 levels were significantly associated with PAD. | [75] |
NOx &, sNOX2-dp | PAD (50) & healthy controls (50) | Serum | NOX2 up-regulation is associated with artery dysfunction in PAD. | [76] |
NO | PAD (82) & healthy controls (41) | Plasma | Increased NO levels & hsCRP levels in PAD patients. | [69] |
TBARS & ICAM-1 | PAD (31) & healthy controls (10) | Plasma | Increased in PAD. | [77] |
Rho-kinase activity | PAD (40), combined CAD/PAD (40) & healthy controls (40) | Circulating leukocytes | Increased in PAD. | [78] |
HCgp-39 | PAD (316) & healthy controls (39) | Plasma | Median levels of HCgp-39 were significantly higher in PAD patients. | [79] |
CD163 & TWEAK | PAD (155) & healthy controls (251) | Plasma | Decreased TWEAK level and higher sCD163 levels in PAD patients. | [80] |
PON-3 | PAD (118), CAD (72) & healthy controls (175) | Serum | Increased in PAD. | [81] |
IL-6, E-selectin, MMP-2, MMP-9 & TGF-β1 | PAD (80) & healthy controls (3076) | Plasma | Increased levels of IL-6, E-selectin, MMP-2 & MMP-9 and reduced levels of TGF-β1 in PAD patients. | [82] |
sRAGE | PAD (201) & healthy controls (201) | Plasma | Decreased levels of sRAGE in PAD patients. | [83] |
VEGF | PAD (293) & healthy controls (26) | Serum | Higher levels of VEGF in PAD patients. | [84] |
Ang2, sTie2, VEGF, sVEGFR-1 & PlGF | PAD (46) & healthy controls (23) | Plasma | Levels of VEGF and sTie2 were significantly increased in PAD patients. | [85] |
VEGF, PlGF & TSP-1 | PAD (184) & healthy controls (330) | Plasma | Elevated TSP-1 levels associated with PAD. | [86] |
VEGF-A, TNF-α & IL-8 | PAD (130) & controls (36) | Serum | PAD patients have lower circulating VEGF-A and higher levels of TNF-α and IL-8. | [71] |
EPCs, CD133, VEGFR-2, MDA-LDL & pentraxin-3 | PAD (48) & healthy controls (22) | Serum & Plasma | EPCs and pentraxin-3 were increased in PAD patients; Cardiovascular events in PAD patients were associated with reduced EPC and increased MDA-LDL. | [87] |
EPCs | PAD (45) & healthy controls (24) | Blood | The number and proliferative activity of circulating EPCs was significantly increased in PAD patients. | [88] |
6.1.1. Markers of Athero-Thrombosis and Inflammation
6.1.2. Markers of Oxidative Stress
6.1.3. Markers of Vascular Remodeling
6.1.4. Circulating Progenitor Cells
6.2. Markers Associated with the Severity and Outcome of PAD
Circulating Biomarkers Assessed | Sample Size (N) | Sample Studied | Association with PAD Severity | Refs. |
---|---|---|---|---|
hsCRP, albumin, α-2 macroglobulin, fibrinogen, IL-1β, IL-1 receptor antagonist, IL-6, IL-6 receptor, IL-10, IL-18, TNF-α, & TGF-β | InCHIANTI study; PAD (955) | Serum | Higher levels of IL-1 receptor antagonist, IL-6, fibrinogen and hsCRP in PAD patients. | [107] |
hsCRP, DD, TAT III & vWF | IC (132) & CLI (30) | Plasma | Higher levels of hsCRP, vWF, and TAT III in CLI compared to patients with IC. | [108] |
hsCRP, fibrinogen & SAA | PAD (91) | Plasma | hsCRP, fibrinogen, and SAA levels were significantly associated with CLI; elevated hsCRP correlated with adverse graft-related or cardiovascular events. | [109] |
hsCRP, DD, IL-6, VCAM-1, ICAM-1 & Hcy | Walking and Leg Circulation Study (WALCS); PAD (423) | Serum | Higher levels of inflammation markers and DD were associated with poorer lower extremity performance. | [110] |
hsCRP, DD, SAA & fibrinogen | PAD (337) | Serum | Elevated baseline levels of inflammatory markers and DD were associated with greater decline in the physical performance. | [111] |
hsCRP | PAD (225) | Plasma | A risk prediction model including hsCRP combined with traditional risk factors, renal function, and nutrition had excellent discriminatory ability in predicting all-cause mortality in patients with clinically advanced PAD undergoing bypass surgery. | [112] |
hsCRP | PAD (118) | Plasma | Increased pre-procedural hsCRP levels were associated with major adverse limb events and late cardiovascular events. | [113] |
hsCRP | Hemodialysis patients undergoing endovascular therapy for PAD (234) | Serum | Elevated pre-procedural hsCRP levels were associated with re-intervention or above ankle amputation and any-cause death after endovascular therapy. | [114] |
hsCRP | European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort; Healthy participants (18,450) | Serum | In the EPIC-Norfolk cohort, hsCRP was associated with nonfatal PAD events. | [115] |
hsCRP, LDL & HDL | Total PAD (100); IC (73) | Blood | Walking disability in PAD was associated with arterial endothelial dysfunction; Endothelial dysfunction was more significantly associated with walking disability in IC. | [116] |
ApoA-I, HDL, Hcy, folate & vitamin B12 | Elderly volunteers from rural Sicily (667) | Serum | Decreased ApoA-I and increased Hcy were predictors of ABI. | [91] |
VCAM-1, ICAM-1 & MCP-1 | PAD (112) | Serum | Increased sVCAM-1 and sICAM-1 were associated with PAD. | [117] |
ICAM-1, leptin, Apolipoprotein-CIII | PAD (148) | Serum | African American women with symptomatic PAD had an increased oxidative stress related markers compared with men. | [96] |
MPO | PAD (406) | Plasma | Plasma level was useful for risk stratification of PAD. | [118] |
TRAP-6-inducible P-selectin expression | PAD (108) | Blood | Low thrombin generation potential was associated with an 11.7-fold increased risk of future atherothrombotic events. | [119] |
Galectin-3 | CLI (55) | Serum | Increased levels of Galectin-3 in CLI. | [120] |
NT-pro-BNP | PCA (100), PAD (300) & healthy controls (300) | Serum | Patients with PCA had higher levels of NT pro-BNP than PAD and controls suggestive of an adverse hemodynamic milieu and increased risk for adverse cardiovascular outcomes. | [121] |
NT-pro-BNP | PAD (481) | Serum | Higher levels of NT-pro-BNP were independently associated with a lower ordinal walking category or functional capacity. | [122] |
Ang2, Tie2, VEGF, VEGFR-1 & PlGF | PAD (46) & healthy controls (23) | Plasma | Levels of VEGF and sTie2 were significantly increased in CLI. | [85] |
VEGF-A 165b | PAD (18) | Serum | Increased anti-angiogenic VEGF-165b and a corresponding reduction in levels of the pro-angiogenic VEGF-A165a. | [123] |
6.2.1. Markers of Inflammation
6.2.2. Markers of Oxidative Stress and Endothelial Damage
6.2.3. Markers of Vascular Remodeling
7. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Krishna, S.M.; Moxon, J.V.; Golledge, J. A Review of the Pathophysiology and Potential Biomarkers for Peripheral Artery Disease. Int. J. Mol. Sci. 2015, 16, 11294-11322. https://doi.org/10.3390/ijms160511294
Krishna SM, Moxon JV, Golledge J. A Review of the Pathophysiology and Potential Biomarkers for Peripheral Artery Disease. International Journal of Molecular Sciences. 2015; 16(5):11294-11322. https://doi.org/10.3390/ijms160511294
Chicago/Turabian StyleKrishna, Smriti Murali, Joseph V. Moxon, and Jonathan Golledge. 2015. "A Review of the Pathophysiology and Potential Biomarkers for Peripheral Artery Disease" International Journal of Molecular Sciences 16, no. 5: 11294-11322. https://doi.org/10.3390/ijms160511294
APA StyleKrishna, S. M., Moxon, J. V., & Golledge, J. (2015). A Review of the Pathophysiology and Potential Biomarkers for Peripheral Artery Disease. International Journal of Molecular Sciences, 16(5), 11294-11322. https://doi.org/10.3390/ijms160511294