Cardiac Troponin:
A Marker of Myocardial Injury for the Next Millennium

Introduction
Coronary artery diseases continue to be the most common cause of morbidity and mortality among adults in the US and throughout the western world. Coronary disease begins with atherosclerosis, the narrowing of coronary arteries by cholesterol-rich plaque. A tear in an unstable plaque exposes the lipid-filled contents of the plaque to circulating blood, resulting in the formation of a blood clot.¹ When the clot produces a partial block of the artery, the patient has unstable angina, characterized by the presence of chest pain at rest. A totally blocked artery leads to a heart attack (acute myocardial infarction, AMI). Severe AMI leads to cardiac arrhythmias and sudden cardiac death. In addition to chest pain, each of these situations also produces abnormalities in the electrocardiogram. Chest pain, abnormal electrocardiogram, and clinical laboratory data for cardiac markers are the essential criteria established by the World Health Organization for the diagnosis of AMI.

Biochemistry
Creatine kinase (CK)-MB isoenzyme is the most widely used marker today for the diagnosis of AMI. However, this test has a limited diagnostic window (i.e., time interval in hours wherein abnormal results are expected after a heart attack) and clinical specificity (i.e., the ability of the test to differentiate between cardiac diseases and other conditions). This has led scientists to search for more effective biochemical markers. The most promising of the new markers are the cardiac troponins, T (cTnT) and I (cTnI). Together with troponin C, these proteins make up a complex that regulates muscle contraction.² Figure 1 illustrates the location and role of the troponin complex within the thin filament of striated muscle. Although the major form of troponin is located within the contractile apparatus, a small fraction of cTnT and cTnI is found free in the cytoplasm. Specificity is the key to the success of tests for these proteins: cardiac troponins T and I are not found in any human tissues other than the heart. Therefore, with sensitive immunoassays, the detection of any increase in cardiac troponin in blood is indicative of cardiac injury or disease.

Clinical Applications
Initial studies of cardiac troponin were centered on the diagnosis of AMI. Clinical data showed that troponin was both an early marker of AMI, being released at about the same time as CK-MB (6 to 9 hours); and a late marker, remaining elevated for more than a week after the infarct. The early appearance of troponin in blood is thought to be caused by release from the unbound cytosolic pool, and the prolonged appearance, from damage to the structural elements.³ Thus, many have advocated that cardiac troponin can replace both CK and lactate dehydrogenase isoenzymes for the diagnosis of AMI.⁴ Patients with AMI can be acutely treated with drugs designed to dissolve coronary artery blood clots to minimize the extent of heart damage.

Figure 1. Cardiac troponin complex in striated muscle during relaxation and contraction. (Reproduced with permission from McCord RG, Clark AW. Ultrastructure of the striated muscle. In: Wu AHB, editor. Cardiac markers. Totowa, NJ: Humana Press, 1998:96.)

For an enlarged view, click on the image.

The high sensitivity of cardiac troponin assays has led to the discovery that such tests can be useful in patients with unstable angina, where the degree of cardiac injury is considerably less than what occurs after a patient suffers an AMI.

The presence of minor myocardial damage suggests that an unstable angina patient has reduced coronary blood flow, and signifies the initial stages of what ultimately could result in AMI. Outcome studies have shown that patients with unstable angina and abnormal cardiac troponin levels have a 5-fold higher risk for AMI and cardiac death within 4 to 6 weeks than do patients with normal troponin levels.^5,6 Thus, measurement of troponin in blood has a dual role: highly abnormal concentrations are indicative of AMI, while mildly abnormal concentrations suggest that a patient is at high short-term risk for a future cardiac event. New antithrombotic and antiplatelet drugs that reduce the risk of the disease progressing to a more serious stage are available for unstable angina patients. Measurement of cardiac troponin may be useful in the selection of these therapies.

Other applications of cardiac troponin measurement in blood are being developed. These include the monitoring of the success of intravenous thrombolytic therapy, diagnosis of perioperative AMI, and detection of minor myocardial damage in patients with congestive heart failure. Clinical studies are being conducted to investigate the potential of cardiac troponin determinations in these patients.

Cardiac troponin T vs. I
The debate continues concerning which assay--cardiac troponin T or I--is better. Table 1 lists some differences between the two markers. Due to patent restrictions, assays for cTnT are available from only one manufacturer. For cTnI, many commercial assays are available on a variety of automated immunoassay platforms. The lack of assay standardization among maufacturers of cTnI assays requires that clinicians interpret serial test results generated only with the same manufacturer's assay. Absolute cTnI values obtained with assays from different manufacturers can vary by a factor of 15; therefore, comparison of assay results across manufacturers for a given sample would not be meaningful. (A subcommittee of the American Association for Clinical Chemistry has been assembled to address this issue.) Following AMI, cTnT levels remain abnormal slightly longer than those of cTnI. Differences in the release of the troponin complex into blood are thought to be responsible for the discordance in the clearance rates.⁷

Table 1. Summary of differences between cardiac troponin T and I assays.

Specificity of cardiac troponin assays in patients with chronic renal failure has also been an issue with both cTnT and cTnI assays. The incidence of abnormal concentrations in this patient population is slightly higher for cTnT than for cTnI. However, recent data now suggest that both assays are in fact detecting true myocardial injury.⁸ Strategies for reducing the risk of cardiac complications in patients with abnormal cardiac troponin levels must be developed in the coming years if this test is to be used and properly interpreted in these patients.

Because assays for cTnT were commercially available a few years before cTnI, more peer-reviewed publications on the clinical utility of cTnT have appeared. However, recent studies have shown that the clinical performance of cTnI is very similar to that of cTnT with regard to diagnostic accuracy of AMI⁹ and risk stratification.¹⁰ Thus, the final decision as to which assay a particular laboratory will choose is likely to be made on the basis of the availability to the laboratory of immunoassay instrumentation, and not on the clinical performance of the assays alone. Immunoassay platforms that offer a wide variety of assays will have a decided advantage.

DPC has developed a cardiac troponin I assay on the IMMULITE^® automated immunoassay analyzer to add to its menu of available assays. This assay has a sensitivity for cTnI of 0.1 ng/mL and precision better than 9% across the assay's calibration range. The IMMULITE assay compares well with the Dade Stratus assay, with a linear regression line of y = 1.6x ­ 0.03 ng/mL, and a correlation coefficient (r) of 0.969.

References

1. Fuster V, Badimon L, Badimon JJ, Cheseboro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. Part 1. N Engl J Med 1992;326:242-50.

2. Katus HA, Scheffold T, Remppis A, Zehlein J. Proteins of the troponin complex. Lab Med 1992;23:311-7.

3. Katus HA, Remppis A, Scheffold T, Diederich KW, Kuebler W. Intracellular compartmentation of cardiac troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction. Am J Cardiol 1991;67:1360-7.

4. Wu AHB, Apple FS, Gibler WB, Jesse RL, Warshaw MM, Valdes R. Recommendations for use of cardiac markers in coronary artery diseases. National Academy of Clinical Biochemistry Standards of Laboratory Practice. Clin Chem. In press.

5. Ohman EM, Armstrong PW, Christenson RH, Granger CB, Katus HA, Hamm CW, et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. The GUSTO IIa Investigators. N Engl J Med 1996;335:1333-41.

6. Antman EM, Tanasijevic MJ, Thompson B, Schactman M, McCabe CH, Cannon CP, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342-9.

7. Wu AHB. A comparison of cardiac troponin T vs. cardiac troponin I in patients with acute coronary syndromes. Cor Art Dis. In press.

8. Ricchiuti V, Voss EM, Ney A, Odland M, Anderson PAW, Apple FS. Cardiac troponin T isoforms expressed in renal diseased skeletal muscle will not cause false-positive results by the second generation cardiac troponin T assay by Boehringer Mannheim. Clin Chem 1998;44:1919-24.

9. Olatidoye AG, Wu AHB, Feng YJ, Waters D. Prognostic role of troponin T versus I in unstable angina for cardiac events with meta-analysis comparing published studies. Am J Cardiol 1998;81:1405-10.

10. Wu AHB, Feng YJ, Moore R, Apple FS, McPherson PH, Buechler KF, Bodor G for American Association for Clinical Chemistry Subcommittee on cTnI Standardization. Characterization of cardiac troponin subunit release into serum following acute myocardial infarction, and comparison of assays for troponin T and I. Clin Chem 1998;44:1198-208.