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(Circulation. 2000;102:1216.)
© 2000 American Heart Association, Inc.

Editorial

It’s Time for a Change to a Troponin Standard

Allan S. Jaffe, MD; Jan Ravkilde, MD, DMSc; Robert Roberts, MD; Ulf Naslund, MD, PhD; Fred S. Apple, PhD; Marcello Galvani, MD; Hugo Katus, MD, PhD

From the Mayo Clinic, Rochester, Minn (A.S.J.); Aalborg University Hospital, Aalborg, Denmark (J.R.); Baylor College of Medicine, Houston, Tex (R.R.); Norrland University Hospital, Umea, Sweden (U.N.); Hennepin County Medical Center and the University of Minnesota, Minneapolis (F.S.A.); Ospedale G.B. Morgagni and Fondazione Cardiologica Sacco, Forlì, Italy (M.G.); and Universitat zu Lubeck, Lubeck, Germany (H.K.).

Correspondence Allan S. Jaffe, MD, 16th Floor, Mayo Building, 200 First Street SW, Rochester, MN 55905. E-mail Jaffe.Allan{at}mayo.edu

Key Words: Editorials • troponin • myocardial infarction • coronary disease

Recently, the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) convened a conference to discuss refinements in the diagnosis of acute myocardial infarction. The panel on biochemistry considered issues related to the use of marker proteins. We were guided predominantly by the science of the area. We were also cognizant of the impact that changes in the standards would have on epidemiology, clinical trials, education of physicians, and patient care. Our recommendations will be incorporated, with the recommendations of the other panels, into a position paper for the ESC and the ACC. However, the members of the biochemistry group decided to express the opinions we felt were important in this area independently. Our thinking does not represent the position of the ESC, the ACC, or of the conjoint task force.

Many modifications of the original World Health Organization criteria for acute myocardial infarction¹ have been accepted and incorporated into the ESC/ACC criteria; some deletions have also occurred. Until recently, most markers were detected using enzymatic activity; detection of the protein concentration now is preferred. Thus, it is more appropriate to refer to molecules released into the circulation as a consequence of cardiac injury as biochemical diagnostic markers or biomarkers. In this editorial, we emphasize issues related to the biochemical diagnosis of acute myocardial infarction. New and improved plasma biomarkers (troponins) with better sensitivity and specificity will be emphasized in preference to markers such as total creatine kinase (CK), CK-MB, lactate dehydrogenase, and aspartate aminotransferase. Rapid assays for the early detection of infarction that may be helpful will be delineated, and the use of the troponin markers to aid in the risk stratification of patients with acute coronary syndromes will be recommended.

Specific Recommendations

Biomarker Increases
Detectable increases in the biomarkers of cardiac injury are indicative of injury to the myocardium, but elevations are not synonymous with an ischemic mechanism of injury. Therefore, increases do not now and did not in the past mandate a diagnosis of myocardial infarction.^{2 3}

Cardiac Troponins Are Preferred Markers
Cardiac troponins (I or T) are the preferred markers for the diagnosis of myocardial injury.^{4 5 6} The improved tissue specificity of the troponins compared with CK-MB and other conventional markers is well established. Initially, because of assay difficulties, some questioned the specificity of cardiac troponin T (cTnT), especially in patients with renal failure.⁷ However, immunohistochemical and molecular studies on the skeletal muscle from such patients has established that the isoforms of cTnT that are re-expressed in response to injury are not detected with the second and third generation assays for cTnT.^{8 9} Thus, increased plasma levels of cTnI or cTnT are highly specific for release from the myocardium.

This advantage has been established in clinical studies. It is now clear that when conjoint skeletal muscle and cardiac injury is present, the improved specificity of the troponins reduces the number of false-positive results while maintaining high sensitivity.^{6 10 11 12}

This improved specificity is coupled with improved sensitivity.^{4 5 6 13} This fact, along with the prolonged time window^{14 15} during which troponin markers are elevated, allow for the detection of a larger number of patients at risk for subsequent adverse cardiac events.^{16 17 18 19} For these reasons, troponins should be the preferred marker for diagnostic use. Laboratories should move as rapidly as feasible to implement cTnI or cTnT as the new standard.

For clinical laboratories that cannot move as rapidly as others to implement this new standard, CK-MB values should be used.²⁰ CK-MB has less tissue specificity than the troponins^{8 11} ; however, the data documenting its specificity for irreversible injury is more robust.²¹ Most clinicians and laboratorians prefer to use mass assays.

Several markers should no longer be used to evaluate cardiac disease. These include total CK, aspartate aminotransferase, total lactate dehydrogenase, and lactate dehydrogenase isoenzymes. These markers have poor specificity for the detection of cardiac injury because of their wide tissue distribution. Because total CK has served as the gold standard for so many years, some may wish to continue to measure it to allow for comparisons over time. This is a reasonable rationale for those conducting trials and epidemiologists. If used, a high threshold for abnormality (2-fold increase) should be utilized. We do not think that such values should be used for the definitive diagnosis of acute myocardial infarction in individual patients.

Increases in Marker Proteins of Cardiac Injury Likely Reflect Irreversible Rather Than Reversible Injury
This issue has been raised by the high frequency of mild-to-moderate increases in cTnI and cTnT observed clinically. This has lead some to question whether all such increases represent irreversible cardiac injury. This is a difficult issue. In a recent experimental study, increases in plasma CK were invariably associated with histological evidence of cardiac injury, as detected by electron microscopy in the experimentally-induced ischemic bed.²¹ Given the difficulty of detecting injured cardiac myocytes even in this model, it is likely that if one used markers and/or criteria with even greater sensitivity, it would have been impossible to find evidence of cardiac injury morphologically, but that does not mean it does not occur.

The troponins are smaller than CK-MB. However, the troponins, particularly cTnI, are released as complexes that are similar in weight to CK-MB.^{22 23} Thus, they are likely to be similar to CK-MB in terms of their egress out of cells. In addition, because most of the troponins (97% per cTnI and 95% for cTnT) are complexed to the contractile apparatus,^{16 23 24 25} it is likely that increases in proteins degraded from the contractile apparatus would have high specificity for irreversible injury, perhaps even higher than those released from the cytosol. Finally, the available clinical and experimental information suggests that troponin release represents irreversible injury. A relationship exists between the amount of a troponin released and the amount depleted from the myocardium,^{26 27 28} and intracardiac pacing studies using coronary sinus sampling have failed to find increases in response to ischemia (H. Katus, MD, PhD, unpublished observations). In experimental models of vital exhaustion in which troponin increases have been observed, they are associated with histological evidence of injury.²⁸ Unfortunately, only 2 case reports have been published in humans that pathologically confirm cardiac injury in association with subtle increases in troponin.^{29 30} Additional pathological studies are needed.

Although this issue is far from settled,³¹ if increases occur with both reversible and irreversible injury, this will likely be true for all biomarkers. Furthermore, there will likely be a continuum from reversible to irreversible release, and it may be impossible to determine which type a certain elevation represents. Because prognosis seems to be related to the presence of elevation, regardless of the mechanism of cellular injury, it may not be important for clinicians to distinguish between mechanisms of injury when formulating therapeutic plans for patients.

Standardize Assays
Various assays for marker proteins are available, and the diversity of such assays has led to substantial confusion. Much, but not all (eg, antibody standardization), of this confusion should be solved by standardization.

This issue has become topical in regard to cTnI measurements.^{6 32} A multiplicity of assays exist. They are composed of different antibody configurations recognizing different epitopes, some of which are more and some less stable; they have different coefficients of variability, and they demonstrate differences with calibration materials.^{32 33} The American Association of Clinical Chemistry has attempted to standardize assays for many years, and we strongly support these efforts. Only recently has some degree of standardization for CK-MB been induced by the sustained efforts of this group.³⁴ Similar efforts are ongoing for cTnI.

Assays should be standardized by manufacturers with appropriate and traceable calibration materials. Clinical studies in the peer-reviewed literature should provide the coefficients of variation, normal and abnormal reference ranges, analytic interferences, and the like. A high level of consistency across manufacturers’ lots is critical. Many believe that the competitive marketplace has led to a substantial misunderstanding of the accuracy and, therefore, the meanings of troponin increases, especially for cTnI. False-positive results and analytic difficulties should be published openly in a forum in which their tabulation can aid laboratorians and, subsequently, clinicians. The cardiology community is dedicated to assisting the laboratory community in making this a reality. However, the following concerns exist.

1. False-positive increases related to fibrin that can confound the assay for cTnI.³⁵ Thus, the use of heparinized plasma for this assay is preferred. This is not suggested by the manufacturer for cTnT (Roche).
   
2. Assay-dependent false-positive cTnI results due to heterophilic antibodies and cross-reacting human anti-mouse antibodies, which appear in the plasma of patients who make antibodies and perhaps in those who receive therapy with extrinsic antibodies.³⁶
   
3. Differential antibody recognition of degradation products due to degradation of the epitopes on the C-terminal of cTnI assays. This has recently been described for specific assays.^{33 37} Some degradation can also occur at the amino terminus, and the reaction points for many of the cleavage products are still being defined.³⁸ Thus, although it appears that central region epitope-based assays will be preferred, making specific assay recommendations at this time seems premature.
   

Given our recommendation that detectable levels are abnormal (a very liberal threshold), conservative analytic thresholds should be used to improve specificity in light of the fact that for most assays, the lower limit of detectability is associated with increased imprecision. In most clinical circumstances, the upper limit of the reference range is defined as 2SDs (97.5 percentile) from the mean value of a control population.⁶ We recommend for the preferred markers (cTnI and cTnT) and for CK-MB that the upper limit be defined as the 99th percentile. This is 3SDs above the mean for the normal range. This information should be available from peer-reviewed information published for each of these assays, along with an acceptable level (<10%) of analytical variability in precision at this level of detection.⁶ Serial determinations are suggested to help clarify troponin increases when values are near the reference limit.

These considerations should assist laboratorians in making decisions regarding which assays to use. At times, laboratories rely on the ability to add a newly developed test to large chemical analyzers already in use in the laboratory in the interest of cost-effectiveness. We do not oppose cost-effectiveness, but considerations related to the accuracy of the values must be paramount. Accordingly, troponin assays should not be adopted for clinical use until their operating characteristics and levels of precision have been substantiated in the peer-reviewed literature.

"Myocardial Infarction" Should Indicate Cardiac Damage
The term "myocardial infarction" should be used when evidence of cardiac damage exists, as detected by marker proteins in a clinical setting consistent with myocardial ischemia.

The clinician should determine if the increases in marker proteins have been induced by a mechanism that is ischemic in nature. If that is the case, then the term "acute myocardial infarction" is warranted. We considered other terms, such as cardiac injury or damage, but we think that a continuation of the term that has served us for years is warranted. The term infarction is warranted, in our estimation, when increases in marker proteins (>99th percentile of the reference range) are documented in patients with known coronary heart disease who have chest pain and ECG changes and in the setting of interventional procedures. It is likely that clinicians can determine when an ischemic milieu is present based on a history of coronary heart disease or the presence of risk factors, the clinical presentation, and the ECG. However, if it is unclear whether the ischemia is etiologic (eg, in patients with less typical symptoms, fewer risk factors, and/or equivocal ECG changes), additional information may be necessary to determine the mechanism of the biomarker increase. One should not make the diagnosis of infarction predicated solely on the presence of increased marker protein values.

Because measurements of cTnI and cTnT improve the sensitivity of detecting ischemic injury, we suggest that clinicians use terms such as minor or small to describe infarctions predicated on abnormal troponin values near the upper limit of the reference range.³⁹

Prognosis in Those With Ischemic Injury Is Related to Extent of Marker Increases
For patients with an ischemic mechanism of injury for cTnI and cTnT increases, prognosis is related in part to the extent of the increases.

Data supporting this contention have been reported for patients with clinical unstable angina and overt acute myocardial infarction.^{16 17 18 19} Therapy should be predicated on the extent of the increases, the type of infarction (ie, Q-wave or non–Q-wave), and the other clinical factors that lead to high or low risk. Isolated elevations in the absence of other criteria do not mandate a similarly aggressive approach.

Consider All Causes of Cardiac Injury
If the clinical circumstance suggests that an ischemic mechanism is unlikely, other causes for cardiac injury should be pursued.

A partial list might include subendocardial injury due to the increased wall stress occurring in patients with congestive heart failure⁴⁰ or hypertension with left ventricular hypertrophy or, alternatively, in response to tachycardia and hemodynamic compromise (eg, in patients with shock) or to right ventricular injury in patients with pulmonary embolism. Biomarker increases can occur secondary to direct trauma to the heart,^{2 3} as a result of myocardial toxins such as adriamycin or 5-fluorouracil,⁴¹ or in response to endogenous substances released in critically ill patients (eg, patients with septic shock).^{42 43} Mechanical injury (such as ablation),⁴⁴ implantable cardioverter defibrillator discharges,⁴⁵ and cardioversion⁴⁶ all induce cardiac injury. Furthermore, a variety of transitory abnormalities can cause minor degrees of myocardial injury that may be self-abating. For example, increases in biomarkers might occur with cardiotrophic viral infections, with only a small subset of patients progressing to overt myocarditis or heart failure. Recent investigations suggest that myocarditis is more frequent than previously suspected. It can be diagnosed when sensitive techniques such as immunohistochemistry are used to identify abnormal lymphocyte pools in combination with increases of troponin.⁴⁷ When a cause for a biomarker increase is detected, therapy should be predicated on this cause. If no cause can be ascertained, clinical follow-up may be all that is necessary.

Blood Sampling
It is critical to be sure that blood samples are obtained at least 6 to 9 hours after the onset of symptoms. When the onset of symptoms is clear, a sample on admission and 6 to 9 hours after onset is recommended. However, if the onset is unclear, a sampling frequency of once at admission and once 6 to 9 hours thereafter, with an optional measurement at 12 to 24 hours, is suggested. It is often wise to insist on an increase in >1 sample to make a diagnosis.

For patients in need of rapid diagnosis, the use of a rapidly appearing marker (CK-MB isoforms or myoglobin) and a marker that rises later (troponin or CK-MB) is advocated.^{6 48} This approach should be used when the results will lead to changes in therapy. The sampling frequency should be at admission, at 2 to 4 hours, and at 6 to 9 hours, with a 12 to 24 hour sample being optional.⁶ A similar protocol is advocated for patients undergoing interventional procedures. However, in this situation, the initial sample should be taken before the procedure.

Special Circumstances
Because increases of troponin can persist,^{14 15} the timing of myocardial events can be unclear (eg, if the troponin values are increased in the first sample on presentation or in situations where reinfarction is suspected). In these situations, CK-MB values may be useful in helping clarify whether the event is recent (within 48 hours).

For patients undergoing interventional procedures, increases in biomarkers will occur more frequently than corresponding increases in CK-MB⁴⁹ and these increases will be of greater magnitude because of the higher release ratio and enhanced washout associated with occlusion and reperfusion.^{50 51} Thus, these events are often indicative of very small amounts of myocardial injury compared with other clinical situations. The classification of these events should still be as myocardial injury of an ischemic cause and, thus, the designation of infarction is appropriate. We would advocate the use of terms such as "minor" or even "minimal" in these circumstances. Because risk is related to the extent of biomarker increase,⁵¹ the management of these patients depends on the clinical situation and on the degree of the increase. We suggest that periprocedure infarctions be considered separate entities and not be combined with other infarctions for epidemiology, clinical trial, or reimbursement purposes.

For cardiac surgical patients, no marker is capable of distinguishing injury due to acute infarction from the obligatory injury associated with the procedure itself.⁵² However, we acknowledge that higher values suggest that the amount of injury, irrespective of mechanism, is greater.

In conclusion, we hope that our advocacy of these controversial topics will evoke an active intellectual exchange concerning these critical issues. We are pleased that the ESC and ACC have developed a format for this type of constructive approach.

Summary of Recommendations

1. Detectable increases in biomarkers of cardiac injury are indicative of injury to the myocardium, but elevations are not synonymous with an ischemic mechanism of injury. Therefore, increases do not now and did not in the past mandate a diagnosis of myocardial infarction.
   
2. Cardiac troponins (I or T) are the preferred markers for the diagnosis of myocardial injury.
   
3. Increases in marker proteins of cardiac injury likely reflect irreversible rather than reversible injury. The diagnostic and prognostic value of elevations, however, exists irrespective of the mechanism of cellular injury.
   
4. Various assays for these marker proteins are available, and the diversity of such assays has led to substantial confusion, much of which should be solved by standardization.
   
5. The term myocardial infarction should be used when there is evidence of cardiac damage, as detected by marker proteins in a clinical setting consistent with myocardial ischemia.
   
6. For patients with an ischemic mechanism of injury for cTnI and cTnT increases, prognosis is related in part to the extent of increases.
   
7. If the clinical circumstance suggests that an ischemic mechanism is unlikely, other causes of the cardiac injury should be pursued.
   
8. It is critical to be sure that blood samples are obtained at least 6 to 9 hours after the onset of symptoms.
   
9. Patients who undergo interventional procedures and cardiac surgery have large numbers of elevations because of the procedures themselves. Classification of elevations, their significance, and the care of patients that results should be individualized to these groups.
   

Note Added in Proof
After acceptance of this manuscript, data were published demonstrating that heparin confounds some cardiac troponin I assays. Thus, serum is preferred for the measurement of both cardiac troponin I and T.⁵³

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

Allan Jaffe serves as a consultant to Dade Behring, which manufactures kits for measuring cardiac troponin I.

Guest editor for this article was Eugene Braunwald, MD, Brigham and Women’s Hospital, Boston, Mass.

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