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Cardiac troponin assays may be used as diagnostic ... or healed MI, cTn should be interpreted together .... (ng/mL) should be replaced by ng/L (pg/mL) as.
Laboratory Insights

Clinical Use and Measurement of Cardiac Troponin (cTn) Clementine YF Yap, MSc, DLM (ASCP), Soon Kieng Phua, BSc, Tar Choon Aw, FRCPE, FRCPA Department of Laboratory Medicine, Changi General Hospital, Singapore

Abstract Cardiac troponins are cardio-specific and are widely used for the early diagnosis and triage of patients with acute coronary syndromes in conjunction with clinical history, electrocardiographic changes and imaging. Troponin is also useful for the prediction of outcomes in acute coronary syndromes, renal failure, sepsis, and critically ill patients. New developments in assay technology, designated as high sensitivity troponins, permit detection of lower levels of troponin in most healthy individuals, earlier diagnosis of myocardial infarction, and prognosis of stable coronary disease in the community. Keywords: Acute coronary syndromes, Cardiac troponins, cTnI, cTnT

INTRODUCTION Myocardial injury releases enzymes (CK, CK-MB) and proteins (troponins) into the circulation. These substances have been used as biomarkers of cardiac damage. Cardiac troponins (cTn), cTnI and cTnT, are cardio-specific. They are rapidly released after injury1. The biomarker remains in circulation for several days (cTnI 7–10 days and cTnT 10–14 days) and can be rapidly assayed at relatively low cost. Currently cTnI and cTnT are considered the best biomarkers in diagnosing acute coronary syndromes (ACS) which include unstable angina (UA) and acute myocardial infarction (AMI)2. They are the preferred biomarker for the evaluation of AMI3-5. Troponin is especially useful in the patient with chest pain and a non-diagnostic electrocardiogram (ECG). In UA, cTn measurements may be used for risk stratification. Cardiac troponin elevations are especially significant as they predict a higher risk of cardiac events in the weeks and months following chest pain. cTnT and cTnI Troponin comprises three subunits — T, I, and C each with differing actions1. While TnT and TnI are thought to be cardio-specific, TnC is also present in skeletal muscle. Troponin T interacts with

tropomyosin. Troponin I promotes the binding of myocardial actin and myosin. Troponin C enhances calcium binding in the troponin complex to produce myocyte contraction. The clinical utility of either cTnI or cTnT for the evaluation of ACS patients is comparable. Hence, a clinical laboratory may choose to offer either one or the other cTn. However, the field is very dynamic1 as assay improvements have resulted in a new generation of high-sensitivity troponins (hs-cTn)6,7. These hscTn methods can detect the presence of cTn in the majority of healthy subjects and assay precision at the 99th percentile cut-point in a healthy reference population is below 10%. Some of the hs-cTn allow faster results (9 minutes versus 18 minutes for TnT) and with lower limits of detection (3ng/L versus 10 ng/L for hs-cTnT and 1.2ng/L for hs-cTnI). HscTn can detect the presence of troponin in most healthy individuals8–11. SPECIMEN Non-additive tubes should be used for collecting specimens as plasma results may be lower than serum results by as much as 30%12. Ethylenediamine-tetraacetic acid (EDTA) may influence the formation of the cTnI complex while heparin may bind cTn and mask specific epitopes4,5. Fibrin,

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from incompletely clotted blood, has been shown to interfere with cTn results and performing laboratories should re-centrifuge such specimens for re-analysis.

may benefit from treatment with platelet GP IIb/IIIa inhibitors13. Troponin levels can assist in identifying patients who would benefit from more aggressive evaluation and intensive anti-thrombotic therapy34.

INDICATIONS Cardiac troponin assays may be used as diagnostic and prognostic tools for the evaluation of chest pain and the management of ACS2,4,5,13,14.

Non-ACS Settings Troponin elevation has been associated with many non-ACS conditions35-37, including heart failure, acute pericarditis, pulmonary embolism, myocarditis, sepsis and critically ill patients, especially in the intensive care units38 and usually correlates with poorer clinical outcomes39.

Diagnostic Tool Cardiac troponins are the most diagnostically sensitive and specific biomarker of myocardial injury available, and an elevated value is the “gold standard”4 for acute myocardial infarction. Cardiac troponin may be detected as early as two to four hours after onset of symptoms and remain elevated for up to 8 to 12 hours13. Current guidelines define myocardial necrosis as an elevation of at least one troponin value above the 99th percentile of a “normal” reference population3,4,15. Troponin results should be evaluated together with ischaemic symptoms, ECG abnormalities, imaging evidence and pathological findings of an AMI for acute, evolving or recent MI. For the diagnosis of healing or healed MI, cTn should be interpreted together with the presence of new Q waves in serial ECGs and associated pathological findings4,13. The use of hs-cTn has resulted in more subjects diagnosed with ACS, especially non-ST-segment elevation myocardial infarction NSTEMI16–21. An undetectable hs-cTnT has been used to rule out ACS22. The addition of a dynamic change in high sensitivity TnT (hs-TnT) values by ≥20% within two hours after presentation of symptoms has been shown to further improve the diagnostic specificity albeit with reduced but still clinically significant diagnostic sensitivity23; an absolute kinetic change of 9.2ng/L hs-TnT has been proposed to rule in or rule out NSTEMI24. Risk Stratification and Prognostic Tool Cardiac troponin has also been used to predict the risk of future disease and cardiac events in ACS patients25-33; cTn above or at the top end of the reference range is indicative of a higher risk of death and new cardiac events. Therapeutic Guide Elevated cTn or positive delta hs-cTn values may be used as a therapeutic guide for patients with unstable angina and/or NSTEMI as these patients

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Troponins have been used as a prognostic indicator in patients with heart failure40-42 and stable coronary artery disease43-45. Some studies46,47 have suggested a role for hs-cTn as a predictor of cardiac risk in the general population, but others48 sound a note of caution for community screening. Renal Disease Cardiac troponins have a prognostic role in acute kidney injury49 and dialysis50. It has been estimated that the prevalence of cardiovascular disease in chronic kidney disease is up to 73% and is responsible for about half of all chronic renal failure related deaths35. ASSAY METHODS Cardiac troponins are mostly tested on automated immunoassay platforms employing spectrophotometry, fluorescence, chemiluminescence and electro-chemistry12. Currently, two cTnT measurements are offered by Roche Diagnostics while there are 21 cTnI assays51. Roche offers hsTnT (cut-off 15ng/L; minimum level of detection 3ng/L) outside USA on its automated immunoassay platforms. In USA, Roche provides TnT Gen 4 (cutoff 30ng/L; minimum level of detection 10ng/L), pending FDA approval for its hs-TnT, as well as TnI. It must be appreciated that all cTnI methods are not equal52 (even from the same vendor) due to the heterogeneity of the cTn molecule, as well as different measurement procedures using proprietary capture antibodies against epitopes on the cTn proteins5,12 in addition to mergers and acquisitions of vendor entities with different TnI offerings. For example, Siemens has five TnI assays on five different analysers with cut-points ranging from 40–200ng/L7. Despite the availability of a cTnI reference material (SRM 2921), developed by the American Association for Clinical Chemistry and the National Institute

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of Standards and Technology, the issue of cTnI standardisation has not been resolved due to its instability5. The International Federation of Clinical Chemistry (IFCC) has formed a Working Group for Standardization of Troponin I (WG-TNI) but much work remains to be done53-55. Both cTnT and cTnI have comparable diagnostic and prognostic efficacy for the management of ACS and AMI in clinical practice but the ultimate outcomes depend on the respective assays and their deployment. Troponin T isoforms may be expressed in skeletal myopathy and they crossreact with the recombinant monoclonal antibodies used in cTnT assays; cTnI is unaffected5,56. Central laboratories should work towards producing cTn results within one hour from specimen collection as specified by current guidelines13,15 and possibly less than 30 minutes as patient outcomes are affected by door-balloon times exceeding 60 minutes. Otherwise, central laboratories risk being supplanted by improved point-of-care devices57. Recent guidelines have defined that the optimal precision or co-efficient of variation (CV) at the 99th percentile upper reference limit (URL) for cTn assays should be ≤10%3–5. Based on this technical specification, high-sensitivity cTn (hs-cTn) assays prove superior to conventional assays in discerning low level cTn elevations25,26,28,32,43,58-60. CK-MB Mass is an acceptable alternative only when cardiac troponins are not available4. It may be used to aid in the diagnosis of myocardial re-infarction when symptoms recur between two days and two weeks after the index MI or after interventional cardiac procedures61. Assays for cTn are specific to cardiac injury and contain more molecules per gram myocardial tissue than CK-MB by a factor of four to eight fold62. ASSAY LIMITATIONS Assay challenges include achieving satisfactory functional sensitivity at cut-off concentrations to meet the technical requirement of CV≤10% at the 99th percentile URL4,13. Additionally, the laboratory has to contend with interferences from haemolysis, anticoagulants, fibrin, rheumatoid factors, heterophile and auto-antibodies12,13. Dialogue between the requesting physician and the laboratory would clarify some of these issues. Regardless of the cTn assay, results trending or delta changes should be based on the same assay.

Clinicians should be aware of the inherent biological nature of cardiac troponins that may affect assay values or cloud clinical judgement. Assay interferents may include tube additives and specimen conditions such as hemolysis and icterus. Cardiac TnT is a slightly larger molecule than cTnI and would remain positive after AMI longer due to its half-life of less than six hours versus less than two hours for cTnI. Cardiac TnT is also found more frequently in patients with chronic renal failure than cTnI due to non-ischaemic myocardial damage (see above). REFERENCE VALUES Reference values vary with different assay methods and reference populations. As such cTn assays should be verified by each respective laboratory. The distribution of cTn values in the circulation is highly skewed to the right. To circumvent the distortionary effects of such high-end outliers, a sample size of 500 has been suggested6,7,64. While reference subjects should preferably be cardiohealthy as evidenced by normal natriuretic peptide levels, ECG or imaging (echocardiography, CT scan, or MRI), these caveats impose additional resource constraints for most laboratories. In our laboratory, we use the Roche hs-TnT with a 99th percentile URL of 15ng/L and a lower limit of detection of 5ng/L. High sensitivity cardiac troponin assays have improved the lower limits of detection tremendously. Prototype assays in development have a claimed level of detection of below 1ng/L7.The current cTn units in ug/L (ng/mL) should be replaced by ng/L (pg/mL) as a patient safety measure to prevent misreading or transcription errors when dealing with multiple decimals1,7. Men have higher cTnT than women in all the TnT reference range studies9,19,63-65. For TnI, gender differences have also been reported by some7,63,66,67, but not by others64,68. In an evaluation of a prototype hs-TnI assay (Abbott Laboratories) we found significant gender differences. The overall 99th percentile URL was 25.6ng/L, males 32.7ng/L and women 17.9ng/L. In a few studies65,70, age effects have been noted. We found notable differences in the URL for men below 50 (25.6ng/L) and those above 50 (38.5ng/L). The use of age- and sexmatched reference intervals has been previously suggested69,71. The impact of using gender- and sex-specific reference limits is unclear and remains

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to be studied further. CONCLUSION Cardiac troponin is useful for the early diagnosis of AMI and has improved the triage of patients with chest pain. Troponin results should be used in conjunction with clinical history, ECG changes and imaging. Troponin measurements are also useful for the prediction of clinical outcomes for various syndromes of acute myocardial ischemia, renal failure, sepsis and critical illness. It is likely that the hs-cTn assays will supersede the current cTn methods as institutions gain more familiarity with them, a trend that has already begun with hs-TnT in several centres locally and internationally.

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