Ischemia-Modified Albumin Improves the Usefulness of Standard Cardiac Biomarkers for the Diagnosis of Myocardial Ischemia in the Emergency Department Setting

Saif Anwaruddin, MD; James L. Januzzi Jr, MD; Aaron L. Baggish, MD; Lee Lewandrowski, PhD, MPH; Kent B. Lewandrowski, MD

Disclosures

Am J Clin Pathol. 2005;123(1):140-145. 

In This Article

Discussion

The use of biomarkers for the identification of suspected acute coronary syndromes depends on the presence of myonecrosis as a surrogate indicator for myocardial ischemia. However, many patients have myocardial ischemia in the absence of myonecrosis, and markers such as myoglobin, CK-MB, and the troponins, although mainstays for the diagnosis of acute cardiac myonecrosis, thus are limited for the confident exclusion of coronary ischemia. Furthermore, the release of these markers is time-dependent; an initially negative result does not exclude the presence of MI. Therefore, a rapidly detectable, highly sensitive marker for myocardial ischemia would be desirable to identify patients with only ischemia and those early in the course of an acute coronary syndrome without evidence of myocardial necrosis. For such a marker to be useful, it should be accompanied by a high negative predictive value.

It has been reported that in the setting of myocardial ischemia, there are modifications to the amino acids of the N-terminus of the human albumin molecule. These modifications alter the N-terminus in such a way that it can no longer bind transition metals, such as cobalt.[1] From this observation, an assay measuring the ability of albumin to bind cobalt was developed, which has been suggested to be useful for the detection of myocardial ischemia. In experimental models and in clinical studies, IMA has been shown to rise within minutes after the onset of ischemia, stay elevated for 6 to 12 hours, and return to normal within 24 hours.[3,4] Furthermore, IMA has been shown to predict with high sensitivity subsequent elevation in the troponins in the clinical setting.[5] An automated chemistry assay for the measurement of IMA is approved by the US Food and Drug Administration, is widely available, and has rapid turnaround times. Accordingly, we performed the present study to explore the feasibility and value of the Albumin Cobalt Binding Test for IMA when used together with standard markers of myocardial necrosis for the evaluation of patients with suspected acute coronary syndromes.

By using a diagnostic cut point of 90 U/mL, we found the assay for the measurement of IMA was sensitive for the diagnosis of myocardial ischemia at the time of clinical diagnosis and had a high negative predictive value. The results of IMA testing were additive to those of ECG and useful when used in conjunction with markers of myocardial necrosis. Consistent with the findings of previous studies, we found that standard biomarkers of cardiac myonecrosis had low sensitivity and negative predictive value for the confident diagnosis or exclusion of coronary ischemia at the time of initial evaluation in the ED.[6,7] It is interesting that we found myoglobin of value for the early detection of patients with coronary ischemia when other markers of myonecrosis were negative. In this setting, IMA was elevated universally, offering complementary information to the myoglobin result.

Furthermore, we found that the combination of the triple screen plus IMA resulted in superior sensitivity for the detection of an acute coronary syndrome, with a simultaneous increase in the negative predictive value to 92%, largely by detecting patients with coronary ischemia and negative myoglobin or TnI results. As such, measurement of IMA together with myoglobin and TnI not only seems to augment sensitivity and, thus, potentially miss fewer patients with coronary ischemia but also might be a particularly useful strategy to confidently rule out myocardial ischemia. A similar biomarker strategy now is used to exclude the diagnosis of pulmonary embolism with measurement of D dimer, which has been reported to have sensitivity and negative predictive values similar to those of IMA.[8,9]

An appropriate setting in which to consider the use of the multimarker combination of IMA plus markers of myonecrosis would be for the rapid evaluation of low- to intermediate-risk patients with chest discomfort. Chest pain centers have been reported to allow for the complete and cost-effective evaluation of patients with low to intermediate pretest probability of having an acute coronary syndrome.[10,11] The goal in such centers would be to rapidly and confidently diagnose or exclude MI, unstable angina, or exercise-induced ischemia among patients without prevalent high-risk features, such as changes on the ECG. The role of myoglobin in chest pain centers has been limited by its lack of specificity; however, together with myoglobin, the use of IMA might be useful for the patients admitted to the ED early (ie, within 1 hour of symptom onset), permitting ruling out of myocardial ischemia in an earlier manner.

We propose a strategy incorporating rapid biomarker analysis Figure 3 using the combination of highly sensitive markers rising soon after coronary ischemia begins (such as IMA plus myoglobin), together with a marker with a high degree of specificity,[11] such as a troponin. Our data suggest that measurement of IMA plus myoglobin, followed by TnI testing, is an ideal marker strategy, offering high sensitivity, specificity, and negative predictive value. A negative value would be helpful in excluding a diagnosis of myocardial ischemia early in the evaluation algorithm, while adding further clinician confidence in the myoglobin result if positive. Furthermore, a subsequent (correctly timed) troponin measurement would effectively confirm or exclude myonecrosis.

Suggested flow diagram incorporating ischemiamodified albumin (IMA) testing into the diagnostic algorithm for patients admitted to the emergency department (ED) with chest pain. For patients with intermediate- or high-risk conditions, inpatient observation with serial troponin (Tn) testing (reserving coronary care unit [CCU]-level care for the highest risk patients) would be indicated. For those with low-risk conditions, a "rapid rule out" protocol combining IMA, myoglobin (Myo), and troponin testing provides high sensitivity and specificity with a strong negative predictive value. ECG, electrocardiogram.

The limitations of this study include its small size and the heterogeneous nature of the patient population being examined. Furthermore, the prevalence of true ischemia in this patient subgroup was low, which affects the specificity of the markers studied. However, the goal was to study the use of IMA in a population of ED with concerning clinical manifestations.

We demonstrated that the addition of testing for a putative marker of myocardial ischemia, namely IMA, to standard markers of myocardial injury (in particular, myoglobin and TnI) is useful in a strategy for the evaluation of patients in the ED with suspected acute coronary ischemia. This is accomplished by allowing for improvement in the sensitivity of standard markers of myonecrosis, while retaining a strong negative predictive value. Larger studies of this promising marker are needed to further clarify its role in a definitive biochemical rule-out strategy.

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