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The structural modifications proposed and investigated included cleavage of the first two residues and oxidation, which were suggested to result from free radical damage, exposure to free iron and copper, or disruption of ion pumps. It was hypothesized that ischemia causes the N-terminal end of the albumin protein to undergo structural modifications, hence that IMA corresponded to N-terminally modified albumin. Based on the general assumption that Co 2+ would preferentially bind to an N-terminal site, ,, efforts to elucidate the molecular causes of reduced cobalt binding concentrated on this site. high readings in the absence of ischemia.Īfter its first description, the molecular identity of IMA remained elusive. However, a severe shortcoming is the high incidence of false positives, i.e. low IMA readings correspond well to the absence of myocardial ischemia.

The ACB test has an excellent negative predictive value, i.e. The reduced cobalt-binding capacity of IMA leaves more unbound Co 2+ to complex with DTT, resulting in higher absorbance readings. The resulting ill-defined brown DTT-Co 2+ product is measured by absorption spectrophotometry at 470 nm and compared to a serum-cobalt blank without DTT present. Dithiothreitol (DTT), a metal chelator that forms a coloured complex with Co 2+, is then added. In the commercially available ACB test, cobalt(II) chloride (approximately 1.5 mol equivalents per albumin molecule) is added to a serum sample, to allow albumin-cobalt binding. IMA is solely characterised by its reduced cobalt-binding affinity, which can be measured indirectly by the Food and Drug Administration-approved albumin cobalt-binding (ACB) assay. So-called “ischemia-modified albumin” (IMA) is found to be significantly elevated in ischemic patients, ,, ,, and serves as a biomarker for early detection of myocardial ischemia before the onset of irreversible cardiac injury. One of these biomarkers is based on albumin, the most abundant protein in blood plasma. While a plethora of cardiac biomarkers have been described for detecting the development of other acute coronary syndromes (ACS), , there are still few well-defined biochemical markers for identification of myocardial ischemia in advance, or in the absence of myocardial necrosis. Diagnosis of myocardial ischemia typically includes exercise-electrocardiography stress tests, coronary angiography, and imaging stress-echo tests. The main cause of this can be the partial or complete blockage of a coronary artery, and a critical depletion of myocardial oxygen leads to cell death, or infarction. Myocardial ischemia occurs due to restricted blood supply to the muscular tissue of the heart (myocardium) resulting in insufficient oxygen supply. This is supported by biophysical studies and the co-association of a range of pathological conditions with positive ACB assays and high plasma FFA levels. Thus, this review advances the hypothesis that high IMA levels in myocardial ischemia and many other conditions originate from high plasma FFA levels hampering the binding of Co 2+ to sites A and/or B.

This insight paved the way for a new consistent molecular basis of the ACB assay: albumin is also the main plasma carrier for free fatty acids (FFAs), and binding of a fatty acid to the high-affinity site FA2 results in conformational changes in albumin which prevent metal binding at site A and partially at site B. More recent work suggested that Co 2+ ions as used in the ACB assay bind preferentially to site B, then to site A, and finally to the NTS. Previous efforts to clarify the identity of IMA and the causes for its reduced cobalt-binding capacity were focused on the NTS site, but the degree of N-terminal modification could not be correlated to the presence of ischemia. Albumin binds most metal ions and harbours four primary metal binding sites: site A, site B, the N-terminal site (NTS), and the free thiol at Cys34. Elucidating the molecular mechanism underlying the identity of IMA and the ACB assay hinges on understanding metal-binding properties of albumin. “Ischemia-modified albumin” (IMA), a form of albumin displaying reduced cobalt-binding affinity, is significantly elevated in ischemic patients, and the albumin cobalt-binding (ACB) assay can measure its level indirectly.

Myocardial ischemia is difficult to diagnose effectively with still few well-defined biochemical markers for identification in advance, or in the absence of myocardial necrosis.

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