The laboratory diagnosis of myocardial infarction.
The diagnosis of acute myocardial infarction poses no problem in a patient who presents with shock, diaphoresis, an ashen gray appearance, and crushing substernal chest pain radiating down the left arm. Anyone who has once witnessed this classical presentation will be able to make the diagnosis in the future.
But many patients with acute MI present with less than classical signs and symptoms: indigestion, persistent pain in the back or in the base of the neck, or an unexplained arrhythmia. How is the diagnosis of acute myocardial infarction then established?
In this subset, the first step toward establishing the diagnosis is a high index of suspicion. Signs and symptoms among patients with "possible' or "probable' acute MI are not enough; further investigations are necessary to rule in or rule out the diagnosis. The diagnosis for many of these can be established with an electrocardiogram or a series of ECGs obtained as the infarct evolves. And for decades this was the only modality available other than the history and physical.
About 20 years ago, enzyme panels were introduced to confirm or exclude acute MI among patients with atypical presentations whose ECGs were equivocal. Enzymatic confirmations consisting of CK, SGOT, and LDH were employed initially. Characteristic time-dependent elevations of these enzymes would confirm the diagnosis, and approximate date, of a presumed acute MI. But false-positive CK elevations resulting from intramuscular injections, and nonspecific elevations of SGOT and LDH, limited the usefulness of these panels. About seven years ago, this triad was replaced with an equally sensitive but much more specific panel consisting of total CK and LDH as well as isoenzymes of each.1, 2
So now the laboratory diagnosis of acute MI is a reality. Or is it? Among patients with possible or probable acute MI whose ECGs are equivocal, how well can the lab rule in or rule out the diagnosis? This questions among patients increasing frequency by clinicians and pathologists alike, for it is important to diagnose the smallest acute MI at its earliest stage, while avoiding the significant implications of a false-positive diagnosis. The analogy to the diagnosis of early pregnancy or early malignancy should be apparent.
Individuals erroneously classified as having sustained acute MIs (false positives) run up huge hospital bills, are denied life insurance, are "rated' on their health insurance coverage, and may be restricted in their occupational and recreational activities. Patients with acute MI who fail to be diagnosed on the basis of clinical presentation, ECGs, and lab tests (false negatives) are also ill-served. They are at high risk for sudden death in the immediate post-infarction period; if they survive, they are at high risk for reinfarction in the future.
Failure to establish the diagnosis also precludes medical therapy and life-style modification programs designed to ameliorate positive risk factors for future vascular catastrophes: diabetes, high blood pressure, obesity, smoking, and insufficient exercise.
All lab determinations are subject to false-positive and false-negative results, and isoenzyme tests used to diagnose acute MI are no exception. Isoenzymes of CK have been scrutinized in this regard, since circulating CK-MB is accepted by many physicians as sure proof of an acute MI and as justification for admission to the coronary care unit. But a single CK-MB test tells the clinician nothing!
If no MB activity is demonstrated, it may be because the infarct is of such recent onset that insufficient time has elapsed to detect its presence in the blood. Serial CK-MB determinations are required in this instance to establish a lab diagnosis of acute MI.
On the other hand, the coronary atrtery occlusion may have occurred several days previously, and CK-MB activity since peaked and disappeared. In this case, only the flipped LDH1 and and LDH2 fractions will establish a laboratory diagnosis.
Then there are the false positives. These relate principally to definition of terms and to methodology, although gross and random error obviously occur as well.
CK-MB activity is present in the serum of normal individuals, albeit in small concentrations. The critical question is where does one place the cutoff between normal and abnormal concentrations, knowing that overlap exists between normals and patients who have recently sustained acute MIs?
Two criteria are employed in this regard: the absolute concentration of CK-MB activity in enzyme units per liter of serum, and the percentage of CK activity expressed relative to the total CK activity. CK-MB activity that is less than 3 per cent of the total is not considered pathologic, while a concentration greater than 5 per cent certainly is. A 4 per cent cutoff designed for high-sensitivity, low-specificity must be balanced against a 5 per cent cutoff, which provides higher specificity but a corresponding loss of sensitivity.
Regardless of the percentage of CK activity represented by the MB fraction, the absolute concentration is also significant but does not necessarily reflect damage to mayocardial tissue--all striated muscle contains small amounts of MB activity. Therefore damage to any striated muscle will elevate CK-MB, although such elevations are not pathognomic of acute MI unless the percentage of MB activity is simultaneously increased.
How high must concentrations of MB activity be before they are considered pathologic? Concentrations greater than 20 IU per liter are definitely elevated. There is a gray zone in the range of about 12-20 units, and values less than 12 units are observed among normal individuals without either cardiac or voluntary muscle damage.
Methodology is critical to CK isoenzyme testing.3 Electrophoresis is the most popular and also is the reference method. But several "quick and dirty' assays have been advocated to assist in rapid diagnosis of acute MI, for electrophoresis is tedious and not available in most labs on a Stat basis.
In lieu of electrophoresis, these alternatives employ chromatography, immunoinhibition, radioimmunoassay, and immunochemistry to quantitate MB activity. Although these assays have fairly rapid turnaround times, none provides the correlation to the reference method demanded by clinicians. So the search goes on for the ultimate CK-MB procedure.
The latest entrant into the field is an immunochemical assay based upon some clever monoclonal antibody technology. The procedure employs two monoclonal antibodies, one specific for CK-M and the second specific for CK-B.
The first antibody is bound to a solid phase--sich as a plastic bead--which in turn is incubated with the serum to be tested. The solid phase binds both CK-MM and MB, isoenzymes sharing CK-M activity. The solid phase is then incubated with the second antibody, which is specific for CK-B. A "sandwich' is formed only with solid-phase bound molecules of CK-MB. The second antibody is conveniently coupled to an alkaline phosphatase marker (although other markers could be substituted), making detection of MB activity simple through use of traditional laboratory procedures.
It should be noted that not all CK-MB is biologically active. This immunochemical method will detect both active and inactive forms of the molecule. Thus the assay detects the mass of CK-MB present rather than its biologic activity. (The fact that an alkaline phosphatase marker is employed should not confuse one into believing that he is measuring biologic activity of an enzyme.)
Since an elevated CK-MB is not, per se, an indication of cardiac muscle damage, an elevation is meaningful only activity is concomitantly of MB activity is concomitantly increased. It remains to be seen whether a biologic assay or a mass assay that measures both active and inactive forms to total CK will provide thebest denominator in detecting when the concentration of CK-MB is elevated.
This new procedure has yet to undergo the scrutiny of clinical trials. But its high specificity and ability to quantitate the mass of circulating CK-MB at low concentrations suggest that it may represent a significant advance in laboratory diagnosis.
Time will tell.
1. Galen, R.S.; Reiffel, J.A.; Gambino, S.R. Diagnosis of acute myocardial infarction. Relative efficiency of serum enzyme and isoenzyme measurements. JAMA 232: 145-147, 1975.
2. Galen, R.S. The enzyme diagnosis of myocardial infarction. Human Pathol. 6: 141-155, 1975.
3. Seckinger, D.L.; Vazquez, D.A.; Rosenthal, P.K.; Mendizabal, R.C. Cardiac isoenzyme methodology and the diagnosis of acute myocardial infarction. Am. J. Clin, Pathol. 80: 164-169, 1983.
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|Author:||Soloway, Henry B.|
|Publication:||Medical Laboratory Observer|
|Date:||Jan 1, 1984|
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