The laboratory methods for the determination of cardiac troponins (cTnI, cTnT) used nowadays are extremely diverse, which has a significant impact on our understanding of the biology and diagnostic value of cTnI and cTnT as biomarkers. The main classification of methods for the determination of cTnI and cTnT is based on the sensitivity of the immunoassay. Low- and moderately sensitive detection methods are known to be relatively low sensitive, which leads to a relatively late confirmation of cardiomyocyte death. Due to new highly sensitive methods used for the determination of cTnI and cTnT, designated as highly or ultrasensitive immunoassays (hs-TnT and hsTnT), we received new, revised data about the biology of cardiac troponin molecules. In particular, it became clear that they can be considered products of normal myocardium metabolism since hs-TnT and hs-TnT are detected in almost all healthy patients. It also turned out that hs-TnT and hs-TnT are differ by gender (in men, troponin concentration in the blood is higher than in women), age (in elderly patients, the levels of troponins are higher than in young ones) and circadian cycles (morning concentrations of troponins are higher than in the evening). A huge variety of methods for determining cTnI and cTnT, differing in their diagnostic capabilities, creates the need for tests in order to perform an unbiased assessment of analytical characteristics of each method. This review focuses on the most pressing issues related to the discussion of the biological characteristics of cardiac troponins and the analytical characteristics of troponin immunoassays from a historical and contemporary point of view.
Keywords: Troponin T; troponin I; analytical properties; 99th percentile; acute myocardial infarction
cTnI ve cTnT'nin biyolojik belirteçler olarak biyolojisini ve tanı değerini anlamamızda önemli bir etkiye sahip olan günümüzde kullanılan kardiyak troponinlerin (cTnI, cTnT) tayini için kullanılan laboratuvar yöntemleri son derece çeşitlidir. cTn1 ve cTnT'nin tayini için kullanılan yöntemlerin ana sınıflandırması immunoassayin duyarlılığına dayanır. Düşük ve orta derecede duyarlı tespit yöntemlerinin görece düşük duyarlılığa sahip olduğu bilinmektedir, ki bu da kardiyomyosit ölümünün görece geç doğrulanmasına yol açar. cTnI ve cTnT'nin belirlenmesi için kullanılan, yüksek veya aşırı duyarlı immünolojik testler (hs-TnT ve hs-TnT) olarak adlandırılan yeni yüksek duyarlı yöntemler nedeniyle, kardiyak troponin moleküllerinin biyolojisi hakkında yeni, gözden geçirilmiş veriler aldık. Özellikle, hs-TnT ve hsTnT hemen hemen tüm sağlıklı hastalarda tespit edildiğinden, normal miyokard metabolizmasının ürünleri olarak kabul edilebilecekleri ortaya çıktı. Ayrıca hs-TnT ve hs-TnT'nin cinsiyete (erkeklerde kandaki troponin konsantrasyonu kadınlardan daha yüksek), yaşa (yaşlı hastalarda troponin seviyeleri gençlerden daha yüksek) ve sirkadiyen döngüler (sabah troponin konsantrasyonları akşamdan daha yüksektir) ile farklılık gösterdiği ortaya çıktı. cTnI ve cTnT'yi belirlemek için kullanılan, teşhis yeteneklerinde farklılık gösteren çok çeşitli yöntemler her yöntemin analitik özelliklerinin tarafsız bir değerlendirmesini yapmak için ihtiyaç yaratır. Bu derleme, kardiyak troponinlerin biyolojik özelliklerinin ve troponin immünolojik tahlillerinin analitik özelliklerinin tartışılmasıyla ilgili en acil konulara tarihsel ve çağdaş bir bakış açısıyla odaklanmaktadır.
Anahtar Kelimeler: Troponin T; troponin I; analitik özellikler; 99. yüzdelik dilim; akut miyokard infarktüsü
- Park KC, Gaze DC, Collinson PO, Marber MS. Cardiac troponins: from myocardial infarction to chronic disease. Cardiovasc Res. 2017; 113(14):1708-18. [Crossref] [PubMed] [PMC]
- Duplyakov DV, Chaulin AM. Mutations of heart troponines, associated with cardiomyopathies [Kardiologiya: novosti, mneniya, obuchenie]. Cardiology: News, Opinions, Training. 2019; 7(3):8-17. Russian. [Crossref]
- Pasquale F, Syrris P, Kaski JP, Mogensen J, McKenna WJ, Elliott P. Long-term outcomes in hypertrophic cardiomyopathy caused by mutations in the cardiac troponin T gene. Circ Cardiovasc Genet. 2012;5(1):10-7. [Crossref] [PubMed]
- Messner B, Baum H, Fischer P, Quasthoff S, Neumeier D. Expression of messenger RNA of the cardiac isoforms of troponin T and I in myopathic skeletal muscle. Am J Clin Pathol. 2000;114(4):544-9. Erratum in: Am J Clin Pathol 2000;114(6):986. [Crossref] [PubMed]
- Ricchiuti V, Apple FS. RNA expression of cardiac troponin T isoforms in diseased human skeletal muscle. Clin Chem. 1999;45(12): 2129-35. Erratum in: Clin Chem 2000;46(3): 437. [Crossref] [PubMed]
- Wens SC, Schaaf GJ, Michels M, Kruijshaar ME, van Gestel TJ, In 't Groen S, et al. Elevated plasma cardiac troponin T levels caused by skeletal muscle damage in pompe disease. Circ Cardiovasc Genet. 2016;9(1):6-13. [Crossref] [PubMed]
- Schmid J, Liesinger L, Birner-Gruenberger R, Stojakovic T, Scharnagl H, Dieplinger B, et al. Elevated cardiac troponin T in patients with skeletal myopathies. J Am Coll Cardiol. 2018;71(14):1540-9. [Crossref] [PubMed]
- Rusakov DY, Vologdina NN, Tulayeva ON. Развитие исчерченной сердечной мышечной ткани в стенках полых и легочных вен [The development of striated cardiac muscle tissue in the walls of the caval and pulmonary veins]. Journal of Anatomy and Histopathology. 2015;4(3):105. Russian. [Link]
- Dhoot GK, Gell PG, Perry SV. The localization of the different forms of troponin I in skeletal and cardiac muscle cells. Exp Cell Res. 1978;117(2):357-70. [Crossref] [PubMed]
- Filatov VL, Katrukha AG, Bulargina TV, Gusev NB. Troponin: structure, properties, and mechanism of functioning. Biochemistry (Mosc). 1999;64(9):969-85. [PubMed]
- Chaulin AM, Karslyan LS, Duplyakov DV. Некоронарогенные причины повышения тропонинов в клинической практике [Non- coronarogenic causes of increased cardiac troponins in clinical practice]. 2019;10(4):81-93. Russian. [Crossref]
- Chaulin AM, Duplyakov DV. MicroRNAs in atrial fibrillation: pathophysiological aspects and potential biomarkers. International Journal of Biomedicine. 2020;10(3):198-205. [Crossref]
- Chaulin AM, Abashina OE, Duplyakov DV. Pathophysiological mechanisms of cardiotoxicity in chemotherapeutic agents. Russian Open Medical Journal. 2020;9(3):1-9. [Crossref]
- Chaulin AM, Duplyakov DV. Arrhythmogenic effects of doxorubicin. Complex Issues of Cardiovascular Diseases. 2020;9(3):69-80. [Crossref]
- Chaulin AM. Elevation mechanisms and diagnostic consideration of cardiac troponins under conditions not associated with myocardial infarction. Part 1. Life (Basel). 2021;11(9): 914. [Crossref] [PubMed] [PMC]
- Wilhelm J, Hettwer S, Schuermann M, Bagger S, Gerhardt F, Mundt S, et al. Elevated troponin in septic patients in the emergency department: frequency, causes, and prognostic implications. Clin Res Cardiol. 2014;103(7): 561-7. [Crossref] [PubMed]
- Dubin RF, Li Y, He J, Jaar BG, Kallem R, Lash JP, et al; CRIC Study Investigators. Predictors of high sensitivity cardiac troponin T in chronic kidney disease patients: a cross-sectional study in the chronic renal insufficiency cohort (CRIC). BMC Nephrol. 2013;14:229. [Crossref] [PubMed] [PMC]
- Zümrütdal A, Bakinen O, Uçan H, Atalay HV, Bodur H. Relationship between uremic myopathy and false-positive cardiac troponin T test. Nephron. 2000;86(4):522-3. [Crossref] [PubMed]
- Chaulin AM. Diagnostic value of highly sensitive cardiac troponins and mechanisms of their increase in serum and urine in arterial hypertension. La Rivista Italiana della Medicina di Laboratorio. 2021;17(2):99-107. [Link]
- Klinkenberg LJ, Wildi K, van der Linden N, Kouw IW, Niens M, Twerenbold R, et al. Diurnal rhythm of cardiac troponin: consequences for the diagnosis of acute myocardial infarction. Clin Chem. 2016;62(12):1602-11. [Crossref] [PubMed]
- Chaulin AM, Duplyakova PD, Duplyakov DV. Circadian rhythms of cardiac troponins: mechanisms and clinical significance. Russian Journal of Cardiology. 2020;25(S3):4061. [Crossref]
- Apple FS, Jaffe AS, Collinson P, Mockel M, Ordonez-Llanos J, Lindahl B, et al; International Federation of Clinical Chemistry (IFCC) Task Force on Clinical Applications of Cardiac Bio-Markers. IFCC educational materials on selected analytical and clinical applications of high sensitivity cardiac troponin assays. Clin Biochem. 2015;48(4-5):201-3. [Crossref] [PubMed]
- Shah AS, Griffiths M, Lee KK, McAllister DA, Hunter AL, Ferry AV, et al. High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study. BMJ. 2015;350:g7873. Erratum in: BMJ. 2015;350:h626. Erratum in: BMJ. 2016;354:i4840. [PubMed] [PMC]
- Trupp RJ, Albert G, Ziegler A. Sex-specific 99th percentiles derived from the AACC Universal Sample Bank for the Roche Gen 5 cTnT assay: Comorbidities and statistical methods influence derivation of reference limits. Clin Biochem. 2018;52:173. [Crossref] [PubMed]
- van der Linden N, Cornelis T, Klinkenberg LJ, Kimenai DM, Hilderink JM, Litjens EJ, et al. Strong diurnal rhythm of troponin T, but not troponin I, in a patient with renal dysfunction. Int J Cardiol. 2016;221:287-8. [Crossref] [PubMed]
- Chaulin AM, Duplyakov DV. On the potential effect of circadian rhythms of cardiac troponins on the diagnosis of acute myocardial infarction. Signa Vitae. 2021;17(3)79-84. [Link]
- Pervan P, Svagu?a T, Prkačin I, Savuk A, Bakos M, Perkov S. Urine high sensitive Troponin I measuring in patients with hypertension. Signa Vitae. 2017;13(Suppl 3):62-4. [Crossref]
- Chaulin AM, Karslyan LS, Bazyuk EV, Nurbaltaeva DA, Duplyakov DV. [Clinical and diagnostic value of cardiac markers in human biological fluids]. Kardiologiia. 2019;59(11):66-75. Russian. [Crossref] [PubMed]
- Mirzaii-Dizgah I, Riahi E. Salivary high-sensitivity cardiac troponin T levels in patients with acute myocardial infarction. Oral Dis. 2013;19(2):180-4. [Crossref] [PubMed]
- Chaulin AM, Duplyakova PD, Bikbaeva GR, Tukhbatova AA, Grigorieva EV, Duplyakov DV. Concentration of high-sensitivity cardiac troponin I in the oral fluid in patients with acute myocardial infarction: a pilot study. Russian Journal of Cardiology. 2020;25(12):3814. [Crossref]
- Chaulin A. Clinical and diagnostic value of highly sensitive cardiac troponins in arterial hypertension. Vasc Health Risk Manag. 2021;17:431-43. [Crossref] [PubMed] [PMC]
- Cummins B, Auckland ML, Cummins P. Cardiac-specific troponin-I radioimmunoassay in the diagnosis of acute myocardial infarction. Am Heart J. 1987;113(6):1333-44. [Crossref] [PubMed]
- Katus HA, Looser S, Hallermayer K, Remppis A, Scheffold T, Borgya A, et al. Development and in vitro characterization of a new immunoassay of cardiac troponin T. Clin Chem. 1992;38(3):386-93. [Crossref] [PubMed]
- Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined--a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36(3):959-69. Erratum in: J Am Coll Cardiol 2001;37(3) :973. [Crossref] [PubMed]
- Hermsen D, Apple F, Garcia-Beltràn L, Jaffe A, Karon B, Lewandrowski E, et al. Results from a multicenter evaluation of the 4th generation Elecsys Troponin T assay. Clin Lab. 2007;53(1-2):1-9. [PubMed]
- Reichlin T, Hochholzer W, Stelzig C, Laule K, Freidank H, Morgenthaler NG, et al. Incremental value of copeptin for rapid rule out of acute myocardial infarction. J Am Coll Cardiol. 2009;54(1):60-8. [Crossref] [PubMed]
- Mingels A, Jacobs L, Michielsen E, Swaanenburg J, Wodzig W, van Dieijen-Visser M. Reference population and marathon runner sera assessed by highly sensitive cardiac troponin T and commercial cardiac troponin T and I assays. Clin Chem. 2009;55(1):101-8. [Crossref] [PubMed]
- Chaulin AM, Duplyakov DV. Факторы окружающей среды и сердечно-сосудистые заболевания [Environmental factors and cardiovascular diseases]. Hygiene and Sanitation. 2021;100(3):223-8. Russian. [Crossref]
- Keller T, Zeller T, Ojeda F, Tzikas S, Lillpopp L, Sinning C, et al. Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction. JAMA. 2011;306(24): 2684-93. [Crossref] [PubMed]
- Adams JE 3rd, Bodor GS, Dávila-Román VG, Delmez JA, Apple FS, Ladenson JH, et al. Cardiac troponin I. A marker with high specificity for cardiac injury. Circulation. 1993;88(1): 101-6. [Crossref] [PubMed]
- Apple FS. Counterpoint: Standardization of cardiac troponin I assays will not occur in my lifetime. Clin Chem. 2012;58(1):169-71. [Crossref] [PubMed]
- International Federation of Clinical Chemistry and Laboratory Medicine. Task Force on Clinical Applications of Cardiac Bio-Markers. Analytical Characteristics of Commercial Cardiac Troponin I and T Assays Declared by the Manufacturer. (date acess 05.05.2021) Available from: [Link]
- Anand A, Shah ASV, Beshiri A, Jaffe AS, Mills NL. Global adoption of high-sensitivity cardiac troponins and the universal definition of myocardial infarction. Clin Chem. 2019;65(3):484-9. [Crossref] [PubMed]
- Chaulin AM. Phosphorylation and fragmentation of the cardiac troponin T: mechanisms, role in pathophysiology and laboratory diagnosis. International Journal of Biomedicine. 2021;11(3):250-9. [Crossref]
- Armbruster DA, Pry T. Limit of blank, limit of detection and limit of quantitation. Clin Biochem Rev. 2008;29 Suppl 1(Suppl 1):S49-52. [PubMed] [PMC]
- Apple FS. A new season for cardiac troponin assays: it's time to keep a scorecard. Clin Chem. 2009;55(7):1303-6. [Crossref] [PubMed]
- Collinson PO, Heung YM, Gaze D, Boa F, Senior R, Christenson R, et al. Influence of population selection on the 99th percentile reference value for cardiac troponin assays. Clin Chem. 2012;58(1):219-25. [Crossref] [PubMed]
- Eggers KM, Apple FS, Lind L, Lindahl B. The applied statistical approach highly influences the 99th percentile of cardiac troponin I. Clin Biochem. 2016;49(15):1109-12. [Crossref] [PubMed]
- Chaulin AM, Abashina OE, Duplyakov DV. Высокочувствительные сердечные тропонины (hs-Tn): методы определения и основные аналитические характеристики [High-sensitivity cardiac troponins: detection and central analytical characteristics]. Cardiovascular Therapy and Prevention. 2021;20(2):2590. Russian. [Crossref]
- Cervellin G, Mattiuzzi C, Bovo C, Lippi G. Diagnostic algorithms for acute coronary syndrome-is one better than another? Ann Transl Med. 2016;4(10):193. [Crossref] [PubMed] [PMC]
- Sörensen NA, Neumann JT, Ojeda F, Schwemer T, Renné T, Schnabel RB, et al. Challenging the 99th percentile: A lower troponin cutoff leads to low mortality of chest pain patients. Int J Cardiol. 2017;232:289-93. [Crossref] [PubMed]
- Lippi G, Bonfanti L, Dipalo M, Aloe R, Cervellin G. Clinical, organizational and economic analysis of high-sensitivity cardiac troponin testing in the emergency department. Ann Res Hosp. 2017;1(6):1-7. [Crossref]
- Ferencik M, Mayrhofer T, Lu MT, Woodard PK, Truong QA, Peacock WF, et al. High-sensitivity cardiac troponin i as a gatekeeper for coronary computed tomography angiography and stress testing in patients with acute chest pain. Clin Chem. 2017;63(11):1724-33. [Crossref] [PubMed] [PMC]
- Jaeger C, Wildi K, Twerenbold R, Reichlin T, Rubini Gimenez M, Neuhaus JD, et al. One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I. Am Heart J. 2016;171(1):92-102.e1-5. [Crossref] [PubMed]
- Garcia-Osuna A, Gaze D, Grau-Agramunt M, Morris T, Telha C, Bartolome A, et al. Ultrasensitive quantification of cardiac troponin I by a Single Molecule Counting method: analytical validation and biological features. Clin Chim Acta. 2018;486:224-231. [Crossref] [PubMed]
- Chaulin AM, Duplyakov DV. Высокочувствительные сердечные тропонины: циркадные ритмы [High-sensitivity cardiac troponins: circadian rhythms]. Cardiovascular Therapy and Prevention. 2021;20(1):2639. Russian. [Crossref]
- High-Sensitivity* Cardiac Troponin I and T Assay Analytical Characteristics Designated by Manufacturer IFCC Committee on Clinical Applications of Cardiac Bio-Markers (C-CB) v122019. Access date (05.05.2021) Available from: [Link]
.: Process List