Biomarker in Peripheral Arterial Disease

Abstract & Commentary

By Andrew Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San FranciscoDr. Boyle reports no financial relationships relevant to this field of study.

Source: Wilson AM, et al. Beta2-microglobulin as a biomarker in peripheral arterial disease: Proteomic profiling and clinical studies. Circulation. 2007;116:1396-1403.

Peripheral arterial disease (PAD) is an exceedingly common manifestation of atherosclerosis. Its presence heralds an increased risk for death from coronary artery disease (CAD) and stroke, yet it continues to go unrecognized in a large proportion of patients. To improve our ability to non-invasively detect PAD, Wilson and colleagues developed a simple screening test. In an elegant series of three studies, they have discovered the presence of elevated levels of beta-2 microglobulin in the serum of patients with PAD, and then validated this as a predictive marker of the disease.

In their "discovery study," subjects with (n = 45) and without PAD (n = 43) were recruited, and peripheral serum was analyzed with proteomic profiling. This technique allows quantification of large numbers of serum proteins at one time (1619 proteins in this case). They found several proteins that were statistically significantly elevated in PAD patients, and went on to identify one of them as beta-2 microglobulin. Beta-2 microglobulin levels correlated with claudication time and correlated inversely with ankle-brachial index (ABI). Next, they performed a "confirmation" study, comparing serum levels of beta-2 microglobulin in a different group of subjects known to have PAD (n = 20) vs those without PAD (n = 20). Importantly, these patients were age- and gender-matched. Serum microglobulin levels were higher in those with PAD and independently predicted low ABI.

Having screened a large number of serum proteins as potential biomarkers in their discovery study and identified and confirmed beta-2 microglobulin as an independent marker of PAD in patients with known disease, Wilson et al went on to validate this as a predictor of PAD in their "validation" study. They recruited patients referred for coronary angiography (n = 237) and correlated beta-2 microglobulin levels with ABI. These patients represent a high-risk cohort for atherosclerosis. They found that beta-2 microglobulin levels were higher in patients with PAD, regardless of the presence or absence or CAD. The odds ration for CAD in patients with elevated beta-2 microglobulin was 7.2. In addition, the combination of high sensitivity C-reactive protein (hsCRP) and beta-2 microglobulin correlated with PAD diagnosis independent of other risk factors.

Wilson et al conclude that beta-2 microglobulin is elevated in PAD, that its level correlates with disease severity, and that further studies should be performed to confirm its clinical utility.

Commentary

Wilson et al have used the novel technique of proteomic profiling of PAD patients' blood to identify a possible biomarker of PAD. This marker, beta-2 microglobulin, is clearly elevated in association with the presence of PAD, and the levels correlate positively with claudication time and negatively with ABI. Importantly, this correlation exists even in the presence of atherosclerosis in another vascular bed, the coronary arteries. However, their data does not necessarily translate into a clinically relevant biomarker yet. Although they have taken an important first step in identifying a possible biomarker for PAD, significant concerns still exist about its applicability before we can advocate widespread clinical uptake.

Firstly, what happens in other disease states with elevated beta-2 microglobulin, such as lymphoma or multiple myeloma? Does this correlation still hold true, or should these patients be excluded. Secondly, some patients with significant PAD have normal ABI, and these would have been included in the normal group in these studies, thereby confounding the results. Thirdly, they have demonstrated that high beta-2 microglobulin is associated with PAD, but how accurate will a single reading be in determining the presence or absence of PAD in a single patient? Finally, would more aggressive treatment of these individuals, above that required by their existing risk factor profile, affect their long-term prognosis? These questions remain unanswered at this time, and are the subject of future studies. Accordingly, at this time, measurement of beta-2 microglobulin cannot be recommended for screening for PAD. Hopefully, a non-invasive screening test for PAD will one day identify patients who will benefit from more aggressive risk factor modification to prevent cardiovascular events.