Biomarkers Related to Local Reactions During Ischemia

Ischemia-Modified Albumin

Bar-Or et al. (27) made the original observation that the N-terminus of albumin is modified in the setting of myocardial ischemia. Normal albumin (a 66.7-kDa serum protein) binds cobalt (and other transitional metals) at the N-terminus. However, in the setting of ischemia, the affinity for transitional metals is reduced. When cobalt is added to a sample of serum containing ischemia-modified albumin (IMA), less of the cobalt is bound proportional to the amount of IMA present in the sample. Although the precise mechanisms for production of IMA during coronary ischemia are not known, the changes have been localized to modifications of the A-Asp-Ala-His-Lys sequence of human albumin and are proposed to be related to production of free radicals during ischemia and/or reperfusion, reduced oxygen tension, acidosis, and cellular alterations such as disruption of sodium and calcium pump function (28-30).

Initial studies suggest that the modification of albumin occurs rapidly after the onset of ischemia. Clinical studies of patients undergoing angioplasty show that levels of IMA rise rapidly after balloon inflation and return to normal by 12 h (28,30) (see Fig. 2). When evaluated in patients presenting to the ED with nontraumatic chest pain, IMA significantly improves the sensitivity of diagnostic testing for ACS using the ECG and troponin at presentation (Fig. 3). However, the specificity ofIMA testing has consistently been low (approx 30%) (27,31). On the basis of these data, IMA has been approved by the Food and Drug Administration for use in conjunction with the ECG and cardiac troponin for the exclusion of ACS in patients felt to be at low to intermediate risk for myocardial ischemia. A negative result paired with serial negative troponin and electrocardiographic data yields a very low posttest likelihood of disease. However, the low specificity ofthe analyte has the potential to result in numerous false positives, with more false positive than true positive

Time from Balloon Inflation (hrs) Duration (sec)

Fig. 2. Concentration of IMA after ischemia during percutaneous coronary angioplasty. (A) Temporal course. (Data from ref. 30.) (B) Adapted from ref. 27.

Time from Balloon Inflation (hrs) Duration (sec)

Fig. 2. Concentration of IMA after ischemia during percutaneous coronary angioplasty. (A) Temporal course. (Data from ref. 30.) (B) Adapted from ref. 27.

Troponi

Fig. 3. Sensitivity of IMA measured at presentation for ACS as determined by physician's diagnosis at discharge. (Data from ref. 31.)

Troponi

Fig. 3. Sensitivity of IMA measured at presentation for ACS as determined by physician's diagnosis at discharge. (Data from ref. 31.)

results when applied in populations with low prevalence of disease. Additional investigation will be valuable in clarifying the appropriate clinical role for IMA in diagnosis, risk stratification, and therapeutic decision making for patients with possible ACS.

Glutathione Peroxidase

Glutathione peroxidase 1 activity has been investigated as a potential marker ofischemia and atherosclerosis. Glutathione peroxidase 1 is a cellular antioxidant enzyme that protects against reactive oxygen species. Glutathione peroxidase 1 activity appears to be significantly decreased in patients presenting with AMI compared with a healthy population (32). In addition, in a study involving 643 patients (133 with unstable angina and 510 with stable angina), levels of glutathione peroxidase 1 were found to be inversely proportional to the future risk ofcardiovascular disease, in patients with both stable angina and unstable angina (33). When adjusted for age and sex, the marker exhibited an inverse relationship to future cardiovascular events (death or MI) over 4.7 yr of follow-up. Nevertheless, the application of glutathione peroxidase 1 for the diagnosis of ACS is yet to be established.

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