Is ischemia modified albumin overestimated or underestimated?

Acute myocardial infarction (AMI) is one of the leading deadly diseases encountered in an emergency room, and early diagnosis of AMI is critically important in reducing the morbidity and mortality. Conventionally, AMI is diagnosed by combining results from electrocardiogram, imaging, and various biochemical biomarkers. Cardiac troponin is regarded as the preferred cardiac biomarker in early diagnosis of ischemic heart disease (IHD), despite commercial availability of reagents for other biomarkers (e.g., creatine kinase-MB/CK-MB, myoglobin). One potential caveat for cardiac troponin is that it takes 12 h for troponin to reach peak concentrations in serum/plasma after myocardial damage. This significantly lowers the diagnostic value of cardiac troponin in AMI.

Ischemia-modified albumin (IMA) has been proposed as a more sensitive and specific myocardial biomarker for cardiac ischemia because IMA is measurable in serum/plasma within minutes and peaks within 2–4 h. However, most current assays for IMA fail to differentiate IMA from human serum albumin because of their similar antigenicity and epitopes. Currently, only one assay approved by FDA is clinically available for serum IMA determination. The albumin cobalt binding (ACB) test is designed on the premise that IMA loses its ability to bind to divalent cobalt. However, the specificity of the ACB test for IMA has been widely criticized, for the following reasons.

1. The mechanism of IMA generation remains unexplained. It is generally regarded that IMA is derived from oxidative stress and concurrently produced superoxide-free oxygen radicals that occur during ischemic events, regardless of tissue specificity. The definitive mechanism(s) still need to be illuminated.
2. There is inaccuracy of IMA detection using the ACB assay. With the ACB assay, IMA is indirectly determined using a colorimetric reaction that quantitatively measures unbound divalent cobalt that remains in solution after cobalt-albumin binding has occurred. However, this methodology has an inherent weakness of being influenced by the variation of total albumin concentration¹. Therefore, the corrected IMA concentration (or IMA index) has been proposed to decrease the interference from variations in serum albumin in biological specimens. However, reference values of such an IMA index are required to be established in each laboratory.

A newly established X-ray fluorescence (XRF) assay can specifically detect IMA by subtracting unaltered albumin from the total albumin in a specimen, thus correcting IMA results for variations in total albumin concentration. Additionally, the procedure can be completed within 30min². X-ray fluorescence spectroscopy, a conventional analytical approach in industry and environmental monitoring, has been utilized to realize rapid determination times. The rapid response (within seconds) characteristic of XRF shortens the detection time of intact albumin, which facilitates the determination of IMA by subtracting the intact albumin from total albumin³. The improved methodology provides a platform to investigate factors inducing the formation of IMA, which would be helpful in elucidating the mechanism causing ischemia events and providing further therapeutic measures.

With the use of XRF, controversies about the specificity of IMA assays could be resolved, owing to the improved assay performance characteristics. However, the following aspects still need to be stressed:

1. The improvement of XRF analysis could be realized by using divalent nickel instead of divalent cobalt, because divalent nickel has stronger XRF signals and greater affinity for albumin than divalent cobalt⁴.
2. The relationship between ischemia and more specific determinations of IMA concentrations should be evaluated using large scale population-based studies.

Can the nearly-abandoned biomarker IMA be rejuvenated to become a promising cardiac biomarker?

1. Lippi, G.; Montagnana, M.; Salvagno, G. L; et al. Clin Chem Lab Med 2007, 45, 261-262.
2. Luo, Y.; Wang, C.; Jiang, T.; et al. Biosens Bioelectron 2014, 51, 136-42.
3. West, M.; Ellis, A. T.; Potts, P. J; et al. J Anal Atom Spectrom 2014, 29, 1516-1563.
4. Jiang, T.; Liu, X.; Qiu, X.; et al. Biosens Bioelectron 2015, 65, 437-8.