Introduction:

Ischemia (literally, hold back blood) occurs when there is restricted blood flow to a tissue so that oxygen demands are not met. Cardiac ischemia results when an artery becomes narrowed or blocked or when cardiac oxygen demand is increased in the presence of a narrowed artery. In most cases, temporary blood shortage to the heart causes angina (chest pain, especially with exertion). If ischemia is severe and lasts too long, it can cause a heart attack (myocardial infarction). Myocardial infarct is the actual death of muscle or part of the muscle. Most cases of ischemia cause reduction of oxygen to the cells but do not cause cell death.

Albumin is modified in the presence of ischemia. This modification does not rely on cell death. Most of the previous cardiac markers do not become positive until cell death occurs. However, the test for Ischemia-Modified Albumin (IMA) becomes positive when ischemia occurs with or without cell death.
The American Heart Association estimates that three to four million Americans have episodes of cardiac ischemia per year. People who have had previous heart attacks or those who have diabetes are especially at risk for developing ischemia. Heart muscle disease caused by ischemia is among the more common causes of heart failure in the United States.

Initial diagnosis of acute coronary syndrome (ACS) is based almost entirely on history, risk factors and electrocardiogram (ECG). With the introduction of Ischemia-Modified Albumin testing, physicians now have an early predictor of oncoming cell damage.

History of ischemia-modified albumin:

1990: A practicing emergency room physician made the original discovery that albumin had decreased metal binding properties following exposure to ischemia (ischemia-modified albumin). A test called Albumin Cobalt Binding (ACB) was developed.
1992: Pilot clinical study showed IMA to be elevated in acute myocardial infarction (AMI) and unstable angina
1994: First patent on IMA core technology
1997: Ischemia Technologies was formed to commercialize IMA marker
1998: Pilot clinical study which showed that elevated IMA occurring during angioplasty was due to ischemia.
1999: ACB (Albumin Cobalt Binding) test to measure IMA was developed and put on clinical chemistry instruments.
2000: First multicentered clinical trial showed IMA improves diagnostic sensitivity of Troponin I.
2001: First test sales in Europe.
2003: Test approved by FDA for use in the United States.
2003: FDA approved Albumin Cobalt Binding (ACB) for diagnostic use in the United States by a company called Ischemia Technologies, Inc., which was formed strictly to work on this issue. The test is now called the IMA test instead of the ACB test.

Ischemia-Modified Albumin Chemistry:

Human serum albumin is a circulating protein with a metal binding site at the N-terminus. Although albumin is a fairly large complex protein, it is one of the most often measured compounds. Since physicians frequently look at the serum albumin to help assess what is going on in the patient, this has become a relatively straight forward test.

Free radicals seem to be produced during ischemia. These are strongly oxidative compounds which affect the N-terminal portion of albumin. Acetylation or depletion of one or more amino acids at the N-terminus results in a modified albumin protein that loses the ability to bind cobalt (or other metals). Cobalt happens to be used as the indicator in this assay.

In the test free cobalt atoms are incubated with the patient’s serum. When there is increased ischemia, the modified albumin is not able to bind with cobalt. The amount of free cobalt is measured and is increased above normal proportional to the amount of ischemia-modified albumin present.
IMA is produced continuously during an ischemic event and rises rapidly; it is not episodic. When a cell dies (necrosis) it releases compounds which are measured in cardiac marker tests such as troponin, myoglobin, CK-MB. This is something that happens more dynamically.

Cardiac angioplasty-balloon catheter studies helped demonstrate the dynamics of the production of ischemia modified albumin. In balloon catheter procedures the coronary arteries are temporarily occluded during a carefully controlled time period. It was found that ischemia-modified albumin rises so rapidly that it is present in the peripheral blood within 6-10 minutes after the episode. It occurs more rapidly than any other indicator. It also clears fairly rapidly, in about 6 hours from the blood.

Diagnostic Value of IMA:

Dr. Alan Wu (1) states, “Ideally the test would be used in the hospital emergency department on the millions of patients who present early with chest pain. These patients would probably have a negative troponin and other cardiac markers of cell death which don’t become positive until 4-6 hours after the episode. A negative IMA would place the patient at low risk for a cardiac ischemic event and consideration could be made to discharge the patient. A positive IMA would put the individual at much higher risk for cardiac ischemia and consideration could be made to more aggressively treat this individual. In either case, management decisions could be made sooner than having to wait 6 hours for a troponin rise or to reliably determine a negative troponin result.”

The advantages of IMA include:

• The IMA test becomes positive right after the ischemic episode occurs. A negative test indicates that an ischemic episode did not occur. The test returns to baseline within 6-12 hours after an ischemic event.
• When using traditional cardiac markers such as troponin, there is a substantial delay before the factor is expressed after cardiac damage, and many ischemic episodes do not lead to increased troponin levels.
• IMA detects the majority of patients (82%) with unstable angina or so called acute coronary syndrome (ACS). Troponin actually has a very poor record detecting ACS; it is only 14% sensitive.
• Negative values are especially useful; if there is a negative IMA, negative troponin, and a nondiagnostic ECG, the patient is 99% negative (predictive value) for acute coronary syndrome.
• IMA, troponin and electrocardiogram (ECG) comprise an excellent combination for non-invasive tests (except for the blood draw). When the physician is trying to decide whether to send the patient home or keep him in the hospital, the information from these tests is very useful.

The disadvantage of IMA is that it is non-specific for cardiac ischemia; other kinds of ischemia, especially gastrointestinal or cerebral, will cause a positive result. It is also elevated in other conditions such as cancer, acute infections, end stage renal disease, and liver cirrhosis. A positive result does not indicate where the ischemia has occurred. So this test, if positive, has to be used in conjunction with other tests. Therefore a negative result is fairly reliable and a positive result is not so valuable, due to the nonspecific nature of the marker (similar to myoglobin). In patients with low pre-test odds of disease, a negative test may allow reduction of workup and additional precautionary testing.

The workup of chest pain patients often depends upon the patient’s situation. If the patient is a 35 year old female who is seen because of a short duration of pain, is a nonsmoker, and has no other risk factors like hyperlipidemia and the IMA test is negative, the physician is more likely to conclude that this patient has non-cardiac pain and is sent home.

On the other hand, if the patient is a 65 year old male smoker, the physician is probably going to work him up anyway because his chest pain is more likely to be significant rather than elusive. So, as always, these tests are used in the context of the clinical setting. Again, a positive test is not so useful because there are other causes for positive IMA.