A validated biomarker panel to identify peripheral artery disease

Abstract

Current guidelines recommend obtaining an ankle-brachial index (ABI) to screen for peripheral artery disease (PAD) in subjects at risk. Previous work demonstrated that a combination of β(2)-microglobulin, cystatin C, high-sensitivity C-reactive protein and glucose was associated with PAD. This study evaluated the ability of these biomarkers combined with clinical parameters to predict PAD in at-risk subjects. This study enrolled 1025 subjects from 99 primary care clinics who were smokers and/or diabetics ≥ 50 years or any individual ≥ 70 years. Consented subjects underwent a clinical assessment, fasting blood draw, and an ABI measurement with PAD defined as an ABI < 0.90 in either leg. The biomarkers and their interactions were evaluated using logistic regression and performance was evaluated at a cut point of the biomarker panel selected to maximize sensitivity while minimizing the false positive rate of the test. Of the 1025 subjects enrolled, 46 did not meet the ABI or other criteria for inclusion in the analysis. Among the evaluable subjects (n = 979), PAD was detected in 83 (8.5%). The model had a C-statistic of 0.73 (95% CI 0.67-0.79). There were 20 patients with PAD who were judged to be at low to moderate risk for cardiovascular events by clinical assessment; the model correctly identified 17 of these 20 patients. The model also performed well in subjects with no prior history of PAD. Thus, a biomarker panel may have a role for identifying PAD.

Society for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities: Management of asymptomatic disease and claudication

“…Elevated markers of inflammation, including high-sensitivity C-reactive protein, interleukin-6, fibrinogen, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, asymmetric dimethylarginine, b-2 macroglobulin, and cystatin C are novel risk factors whose clinical utility for predicting PAD onset or progression is not yet clear. [23][24][25][26][27][28][29][30][31][32]…”

Revisiting the Middle Molecule Hypothesis of Uremic Toxicity: A Systematic Review of Beta 2 Microglobulin Population Kinetics and Large Scale Modeling of Hemodialysis Trials In Silico

“…On the other hand, cross-sectional, observational studies utilizing single measurements of β 2 M yielded partially conflicting associations [ 24 ],[ 55 ]. More recently, associations have been reported between β 2 M and survival (all-cause and cardiovascular in NHANES [ 56 ] and ARIC [ 57 ]), cardiovascular events and calcification in CKD [ 25 ], early-onset atherosclerosis in ESRD [ 58 ], stroke [ 59 ], peripheral arterial disease [ 60 – 63 ], and mortality in patients undergoing coronary angiography. [ 64 ] Although observational, these associations have held against adjustments for known risk factors and the prevailing level of kidney function (as assessed with cystatin-C or eGFR) suggesting that β 2 M elevations may have pathologic significance above and beyond its association with glomerular filtration.…”

A Review of the Pathophysiology and Potential Biomarkers for Peripheral Artery Disease

“…It was previously reported that a combination of β-2-microglobulin (B2M), cystatin C, high-sensitivity C-reactive protein (hsCRP) and glucose was associated with PAD [65,66]. Plasma B2M levels and parameters of arterial stiffness such as aortic pulse wave velocity and augmentation index have been reported to be significantly increased in PAD patients [67].…”

“…Plasma B2M levels and parameters of arterial stiffness such as aortic pulse wave velocity and augmentation index have been reported to be significantly increased in PAD patients [67]. Some studies have shown that combining these circulating markers of inflammation and atherosclerosis with clinical parameters may improve the identification of PAD patients [65,66,71]. A previous nested case-control study reported an increased relative risk of PAD (2.8, 95% CI: 1.3–5.9) for subjects in the highest hsCRP quartile compared with the lowest quartile [89].…”