One major limitation of CK-MB use is that in MI, abnormal levels of the isoenzyme cannot be detected until 4 to 8 h after onset of symptoms, regardless of the assay used. This problem has been partially overcome with the development of rapid assays for CK-MB isoforms (subforms). The isoenzymes CK-MM, CK-MB, and CK-BB are dimeric molecules consisting of three different combinations of two monomers, M and B. On its release from damaged cells, the M-monomer found in tissue CK (Mt) is acted on by an enzyme present in serum, carboxypeptidase-N, which cleaves off the C-terminal lysine. This action results in its conversion into the M-monomer found in serum CK (Ms). Because lysine is a positively charged amino acid, its cleavage results in the M s-monomer being more negatively charged than Mt. Because the rate of this conversion is limited, newly released, unmodified tissue CK-M tMt dimers (referred to as CK-MM3) undergo sequential C-terminal cleavage of its two Mt-monomers to create CK-MtMs (CK-MM2) and, subsequently, CK-MsMs (CK-MM!). Although the clinical utility of CK-MM isoform measurement is limited by its lack of specificity, the same modification also occurs to the Mt-monomer of CK-MB (CK-MB2), resulting in the formation of CK-MB!. By measuring MB2 activity and the MB2/MB1 ratio, evidence of infarction can be detected before the total level of CK-MB exceeds the normal range. Using this method, one multicenter study has reported a sensitivity of 95.7 percent and specificity of 93.9 percent for AMI among 1110 patients within 1.2 h of ED presentation (6 h from symptom onset). 11
Myoglobin is a small (17,500-Da), heme-containing protein found in striated (skeletal) and cardiac muscle cells. When disrupted, these cells rapidly release myoglobin into the serum. Myoglobin serum levels increase rapidly after significant muscle damage and return to baseline values relatively quickly in the presence of normal kidney function. This property makes myoglobin potentially valuable as a serum marker for myocardial necrosis. After MI, serum myoglobin levels begin to rise within
3 h of onset of symptoms and are abnormally elevated in 80 to 100 percent of patients after 6 to 8 h, peak from 4 to 9 h after symptom onset ( Fig 4.5:2), and return to baseline within 24 h. Because of this rapid rise and fall, serum myoglobin is very sensitive as a marker of MI when determined early in the course of infarction. However, a false-negative result may occur if the test is performed after myoglobin has already been cleared from the serum. Also, because the myoglobin found in myocardium is indistinguishable from that found in skeletal muscle, it is a nonspecific marker. Aside from MI, all conditions that cause significant skeletal muscle injury must be considered as possible causes of an elevated myoglobin level. Fortunately, these conditions can usually be detected clinically in patients with symptoms related to infarction.
Evaluation of the myoglobin/carbonic anhydrase III ratio can enhance the specificity of myoglobin. The enzyme carbonic anhydrase III is released from skeletal muscle in a fixed ratio with myoglobin. Combined assays can therefore help determine whether myoglobin is of skeletal or cardiac origin. When these dual assays are used, the high early sensitivity of myoglobin is maintained and specificity is improved. However, these assays are not yet commercially available and the use of dual assays for risk stratification has not yet been evaluated.
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