by Dr. Adele Visser

Introduction

Cardiac troponins have by and large replaced older cardiac assays like total creatine kinase (CK), creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) to assess for cardiac tissue injury. The heterotrimeric troponins, consisting of Troponin T (TnT), Troponin I (TnI) and Troponin C (TnC) complexes with the tropomyosin molecule, which through conformational change following calcium binding, brings about muscle contraction (figure 1). Each of the troponin T and I subtypes, are encoded for on 3 distinct genes in the form of slow skeletal, fast skeletal and cardiac muscle. It is the presence of a distinct cardiac subtype that allows for specific cardiac immunoassays, used in the evaluation of myocardial injury.

 

 

In addition to the distinctive subtypes, cardiac tissue is considered as postmitotic and therefore not able to re-differentiate. Therefore, detection of extruded protein in blood, is interpreted as a sign of necrosis or injury. The progression from qualitative and low-sensitivity assays to high sensitivity assays (hs-cTn) further cemented its use in the evaluation of patients with chest pain and general risk stratification.

The presence of c-TnT in foetal skeletal muscle¹ has historically raised the question of whether it can be expressed in adult skeletal muscle². This was demonstrated in patients with inherited and acquired skeletal myopathies³, ⁴, ⁵, in addition to exercise studies⁶, where hc-cTnT were demonstrated to be elevated but not hs-cTnI.

Comparing cTnI and cTnT

Comparison between the two markers is complicated by various issues. Firstly, from a pre-analytic viewpoint, both false positive and false negative results have been attributed to native antibody interference in both markers. Secondly, from an analytic stance, the hs-cTnT assay is only available from one manufacturer, Roche Diagnostics, due to patenting, whereas the hs-cTnI is offered by various manufacturers (Siemens, Abbott, Beckman Coulter amongst others). This complicates comparison with varying reference ranges and assay harmonization. Lastly, with reference to the post-analytical, subsequent use of these markers in combination with other risk factors, various population groups and for clinical indications also affect its predictive value.

i. Diagnosis of AMI

Both assays perform similarly in their ability to serve as predictive markers for acute coronary events based on the results obtained from the APACE study⁷, ⁸. The use of both assays in combination has been proposed to overcome some of the pre-, post- and analytical issues discussed with some success, however, this effect is only marginal and not always practically justifiable.

ii. General population

The use of hs-cTn assays have been of interest as a marker for cardiovascular risk stratification in the general population. Despite its promise, studies are lack running both assays head-to-head, making comparison difficult owing to cohort differences. Comparison of data from studies run separately, demonstrate a slightly higher hazard ratio for future CVD events⁹ as well as non-CVD death¹⁰ using hs-cTnT over hs-cTnI. Of note, hs-cTnI show a greater predictive correlation in combination with age, male sex, body mass index and systolic pressure, whereas hs-cTnT shows greater predictive correlation in combination with diabetes¹¹.

Conclusion

No clear data currently justify the specific use of either hs-cTnT versus hs-cTnI in either the diagnosis of an AMI or as part of risk stratification. It is likely that genetic variation with regards to expression of these subsets as found within specific populations may guide future guidelines as to preferred use, however this is still lacking at this point.

References

1. Anderson PA, Malouf NN, Oakeley AE, Pagani ED, Allen PD. Troponin T isoform expression in humans. A comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle. Circ Res 1991;69:1226-33.

2. Jaffe AS, Vasile VC, Milone M, Saenger AK, Olson KN, Apple FS. Diseased skeletal muscle: a noncardiac source of increased circulating concentrations of cardiac troponin T. J Am Coll Cardiol 2011;58:1819-24.

3. Schmid J, Liesinger L, Birner-Gruenberger R, et al. Elevated Cardiac Troponin T in Patients With Skeletal Myopathies. J Am Coll Cardiol 2018;71:1540-9.

4. Rittoo D, Jones A, Lecky B, Neithercut D. Elevation of cardiac troponin T, but not cardiac troponin I, in patients with neuromuscular diseases: implications for the diagnosis of myocardial infarction. J Am Coll Cardiol 2014;63:2411-20.

5. Wens SC, Schaaf GJ, Michels M, et al. Elevated Plasma Cardiac Troponin T Levels Caused by Skeletal Muscle Damage in Pompe Disease. Circ Cardiovasc Genet 2016;9:6-13.

6. Klinkenberg LJ, Luyten P, van der Linden N, et al. Cardiac Troponin T and I Release After a 30-km Run. Am J Cardiol 2016;118:281-7.

7. van der Linden N, Wildi K, Twerenbold R, et al. Combining High-Sensitivity Cardiac Troponin I and Cardiac Troponin T in the Early Diagnosis of Acute Myocardial Infarction. Circulation 2018;138:989-99.

8. Boeddinghaus J, Twerenbold R, Nestelberger T, et al. Clinical Validation of a Novel High-Sensitivity Cardiac Troponin I Assay for Early Diagnosis of Acute Myocardial Infarction. Clin Chem 2018;64:1347-60.

9. Willeit P, Welsh P, Evans JDW, et al. High-Sensitivity Cardiac Troponin Concentration and Risk of First-Ever Cardiovascular Outcomes in 154,052 Participants. J Am Coll Cardiol 2017;70:558-68.

10. Welsh P, Preiss D, Hayward C, et al. Cardiac Troponin T and Troponin I in the General Population. Circulation 2019;139:2754-64.

11. Welsh P, Preiss D, Shah ASV, et al. Comparison between High-Sensitivity Cardiac Troponin T and Cardiac Troponin I in a Large General Population Cohort. Clin Chem 2018;64:1607-16.

12. By Mohamed Elshennawy, M.D. – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=121404909