Elsevier

Clinica Chimica Acta

Volume 272, Issue 1, 6 April 1998, Pages 47-57
Clinica Chimica Acta

Troponin T: A sensitive and specific diagnostic and prognostic marker of myocardial damage

https://doi.org/10.1016/S0009-8981(97)00251-9Get rights and content

Abstract

Cardiac troponin T (cTnT) in serum is a highly sensitive and specific marker for myocardial damage. Quantitative immunoassays take 9 min. A rapid test (TropT, CardiacT) using plasma detects cTnT concentrations above 0.10 μg/l within 15 min. Both assays are specific for the cardiac isoform. In a study using the maximal values from serial sampling in 502 infarction-suspected patients, we found a diagnostic sensitivity for non-Q- and Q-wave infarctions of 100%, with a specificity of 99%. cTnT has been shown to be a powerful prognostic marker for risk stratification in acute coronary syndromes. In 30–40% of patients with unstable angina, cTnT≥0.10 μg/l detects minor myocardial damage (MMD) with poor prognosis. False positives may be found in certain skeletal muscle diseases, such as polymyositis and Duchenne's muscular dystrophy. Constantly increased values in renal failure may be due to uremic cardiomyositis. Even in uremia, a rapid increase of cTnT will indicate acute myocardial damage. We propose a diagnostic strategy based on timed, parallel determinations of myoglobin+cTnT.

Introduction

Troponin T (TnT), Mr 37 kDa [1], is part of the troponin–tropomyosin molecular switch of the thin filament of myofibrils in the sarcomere. The globular COOH-terminal domain mediates interactions with TnI and TnC, and the NH2-terminal tail binds to the tropomyosin strand [2]. TnT exists as three isotypes encoded by three genes, and a number of isoforms with different amino acid sequences in slow–fast twitch skeletal muscle and in cardiac muscle. For immunoassays, specific antibodies against the single cardiac isoform (cTnT) have been developed 1, 3. The cTnT concentration in normal human cardiomyocytes is around 12 mg per g of protein [4], with no significant difference between left and right ventricles. Of the cTnT, 6–8% is cytosolic, the remainder being filament-bound 4, 5. Following cell damage, cTnT concentrations in plasma shows a biphasic time pattern. Cytosolic cTnT is released first into the circulation, causing an initial peak in plasma 5, 6. Persisting ischemia leads to depolymerization of the thin filament [7]and a protracted release of filament-bound cTnT 5, 6, 8.

The biological half-life of cTnT has been found to be 2 h [6]. Following infarction, tailing-off of release gives apparent T1/2 values of the cytosolic peak at around 6–20 h [9]. This leads to either a second peak or a slowly decreasing plateau, with increased cTnT in plasma over days to weeks 5, 6, 8, 10, 11, 12, 13.

Current immunoassays of cTnT in plasma or serum are analytically specific for the cardiac isoform of TnT [3]. On a newly developed automated electroluminescence analyzer, the turnaround time is 9 min [14]. The latest version of a rapid bedside test for whole blood 15, 16, 17is specific for cTnT and detects concentrations above 0.10 μg/l within 15 min [18]. Preanalytical stability of cTnT in serum and plasma is at least 24 h at room temperature, ten days at 4–6°C and three and twelve months at −20°C and −70°C, respectively (W. Stein, personal communication). The reference range for healthy persons is 0–0.06 μg/l 3, 19and the discrimination limit for myocardial damage is 0.10 μg/l 3, 20, 21, 22, 23, 24, 25.

Estimates of early diagnostic sensitivities vary due to different materials from patients, AMI criteria and sampling intervals. For the entire group of myocardial damage and a discrimination limit of 0.10 μg/l, we estimate diagnostic sensitivities of around 50% 3–6 h after onset of symptoms (h.a.s), 100% around peak values 10–24 h.a.s. and up to two weeks in protracted time courses 5, 6, 8, 11, 13, 21, 24, 25, 26, 27. Median cTnT peaks are higher in Q-wave than in non-Q-wave infarctions 6, 13, 18. Obviously, in minor myocardial damage (MMD), cTnT increases later and decreases sooner than in larger definite infarctions. Most reports agree that myoglobin and creatine kinase (CK) MB isoforms are the earliest markers, albeit with lower diagnostic specificity than the troponins 24, 25, 26, 27. A single study has reported equal early sensitivities for all markers [28]. Using peak values from serial sampling in 502 consecutively admitted AMI-suspected patients in our critical care unit (CCU), we have found a diagnostic sensitivity of cTnT of 100% [13]. By classification into definite AMI versus NOT-AMI using CK MB mass as the diagnostic criterion, diagnostic specificity was 77%, and by classification into myocardial damage including MMD and subacute AMI detected by cTnT, the specificity was 99% [13].

Early reperfusion is indicated by a high ratio of cytosolic peak cTnT/30–35 h 5, 6, 11, 29, by an earlier occurring cTnT peak, e.g. 14 versus 27 h 10, 30, or by initial rates of increase e.g. within 90 min after start of thrombolytic treatment 30, 31, 32. However, small infarctions, perhaps like those that have been reduced by thrombolysis, will show low peaks and, accordingly, lower rates of increase [33]. Recent reports indicate that early myoglobin increase rates may perform better 30, 31, 34.

Despite its prolonged release, TnT is a reliable indicator of re-infarction. Following a minor AMI, cTnT will show a second, generally higher peak than the initial one 12, 13. Following a larger AMI, cTnT will show a new increase from the plateau phase.

Unstable angina pectoris (UAP) and non-Q-wave AMI have similar pathophysiology and similar clinical presentation on admission 20, 35, 36. The classification into either group is arbitrary and depends on the diagnostic criteria, mainly on which biochemical markers and discriminator values are used [20]. Recently, two major studies of UAP+non-Q-wave infarctions showed a linear and direct relationship between admission or peak cTnT values ≥0.10 μg/l within the initial 24 h after admission and the risk of subsequent cardiac events 20, 23. cTnT levels remained independently significantly predictive, even after adjustment for electrocardiographic category and CK MB mass levels 20, 23. Similar results were reported with troponin I (Stratus) ≥0.4 μg/l [37]. Likewise, increased levels of cTnT on admission indicated a higher risk in patients with definite infarction [38].

cTnT is a powerful prognostic marker for risk stratification in unstable angina patients with MMD. MMD has been defined by increased cTnT in 20–39% of UAP patients in whom myocardial infarction had been excluded by negative routine markers 11, 13, 22, 27, 38, 39, 40, 41, 42. CK MB mass may show significant changes below its discrimination limit for infarction 8, 13, 27, 40, and myoglobin might be increased [27]. In the MMD group, the risk of subsequent cardiac events over weeks to three years is similar to that of patients with definite infarctions 27, 38, 39, 40, 41.

Fig. 1A shows a typical MMD pattern in an elderly man admitted with severe unstable angina. cTnT increased twofold, with parallel changes in CK MB below its discriminator. Two months later (Fig. 1B), the patient developed a non-Q-wave infarction, confirmed by increases in both markers and by the rapid cTnT test.

cTnT has been found to be useful in detecting complications following percutaneous transluminal coronary angioplasty (PTCA) 43, 44, by-pass surgery 45, 46and heart transplantation [47]. In patients with skeletal muscle damage, data reported with the early versions of the immunoassay (<1995) should be interpreted with caution due to cross-reactivity with skeletal muscle TnT.

Section snippets

Diagnostic specificity of cTnT

The current immunoassay is analytically specific for the cardiac isoform [3]and should be a reliable indicator of myocardial damage in the presence of skeletal muscle injury.

However, cTnT may be increased in polymyositis and Duchenne's muscular dystrophy [48]. Based on immunohistochemistry, albeit using anti-cTnT antibodies other than those of the current immunoassay, it was suggested that the fetal gene for cTnT may be reexpressed in regenerative skeletal muscle processes [49]. These findings

Recommendation of a routine diagnostic strategy

As troponins are “slow” markers, it appears rational to combine them with an “early” marker such as myoglobin. This has been proposed in the most recent draft (July 1997) of a “Position Paper On the Use of Biochemical Markers in Acute Ischemic Heart Disease”, prepared by joint German, Austrian, and Swiss professional Societies of clinical chemistry and cardiology. We feel that such a diagnostic strategy should be based on acute, parallel determinations of both markers, sampling on admission

Conclusion

cTnT has proved to be a diagnostic and prognostic marker for myocardial damage with high diagnostic sensitivity and specificity. It is a powerful tool for risk-stratification and management of patients with unstable angina. A rational routine diagnostic strategy can be based on acute determinations of the combination of the early marker myoglobin+later marker troponin.

Acknowledgements

The authors thank Professor Dr. W. Stein for TnI determinations on hemodialysis patients.

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