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The Trouble with Troponin: Tales from Beyond the 99th Centile

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Measurement of plasma troponin concentration with high sensitivity cardiac troponin (hs-cTn) assays plays a central role in the assessment of patients with chest pain syndrome. The development of these assays has facilitated reliable early exclusion of ACS as the cause of symptoms in this group. However, a lack of understanding of the significance or otherwise of elevated troponin levels measured on these assays, may misdirect patient investigation and management.

What is 'troponin'?

As illustrated above, troponin (Tn) is a complex of three proteins (troponin C, troponin T and troponin I). This complex functions in the regulation of contraction of skeletal and cardiac muscle. Certain isoforms of troponin T and troponin I are specific to cardiac myocytes. These cardiac troponins (cTn) are released in increased amounts into the systemic circulation when cardiac myocytes are damaged. For this reason, elevated cTn levels in the systemic circulation are a useful marker of myocardial ischemia and infarction. Troponin C does not have an isoform specific to cardiac muscle and is, therefore, not of use in assessing the presence of myocardial damage.

Isoform: a protein that has the same function as another protein but which is encoded by a different gene and may have small differences in its sequence.

What is a 'high sensitivity' cardiac troponin (hs-cTn) assay?

High sensitivity cardiac troponin (hs-cTn) assays by definition are 1) capable of measuring the minute level of a specific cardiac troponin isoform (TnT or TnI) present in the plasma of normal individuals and 2) demonstrate a high degree of reproducibility in results close to a clinically important ‘cutoff’  level ('the 99th percentile', see below). At the present time the assays are carried out in the laboratory rather than 'at the bedside'.

How do we interpret the result of a hs-cTn assay?

Measured by these high sensitivity assays, troponin levels in a normal adult population  follow a distribution similar to that illustrated above. By convention, a ‘positive’ troponin result is said to be present if the plasma concentration lies within or above the top 1% of concentrations detected in a 'normal' reference population. As we will see the nature of the reference population is critical but remains controversial.

Using the 99th percentile as a cutoff level to determine appropriate investigation does not imply that, at any moment in time, 1% of the normal population are having an AMI!  We are simply choosing a cutoff troponin concentration below which ACS is reliably excluded as the cause of a chest pain syndrome presentation. When negative, the result of a hs-cTn assay is reported as 'less than' the cutoff value for the particular assay used (< X ng/l), the absolute value is not reported. Absolute values above the cutoff are reported.  While a troponin concentration below the cutoff level at 3 hours post symptom onset reliably excludes ACS as a cause of those symptoms, the significance of a value above the cutoff needs careful consideration in clinical context.

What conditions other than Myocardial Infarction elevate cTn?

It is important to realise that many heart conditions, unrelated to coronary artery thrombosis, may be associated with elevated cTn levels in the peripheral blood. The interpretation of an elevated troponin level detected by a  hs-cTn assay is critically dependent on the clinical context and on the pattern of change in troponin concentration over time. Being aware of this can allow us avoid error.

Causes of Elevated Plasma hs-cTn distinct from Myocardial Infarction

Cardiac Disease

Cardioversion

Cardiac surgery

Percutaneous coronary intervention

Heart failure (acute & chronic)

Tachyarrhythmia/bradyarrhythmia

Myo/endo/peri-carditis

Cardiac trauma

Extra-cardiac Disease

Pulmonary embolism

Renal failure

Cardiotoxic drugs

Pulmonary hypertension

Critical illness (e.g., sepsis)

Intracranial pathology

The trouble with troponin

The cutoff concentrations for the high sensitivity troponin assays currently licensed for clinical use were established in studies of 'reference' populations. However, the relevance of these 'reference' populations, which included adults as young as 18 years of age, to the overall population presenting to an ER/ED is highly questionable. Mariathas et al, have recently shown that in the case of one widely used hs-cTn assay, the true 99th percentile for an unselected population (with cases of AMI excluded) presenting to ER/ED, was five fold higher than the value quoted for the assay.

As illustrated in the table above, there are many possible causes of an elevated plasma troponin concentration unrelated to coronary artery thrombosis. We will present cases which illustrate the importance of the overall clinical context when interpreting a plasma troponin concentration above the quoted cutoff value.

Required Reading

Mariathas M et al. True 99th centile of high sensitivity cardiac troponin for hospital patients: prospective, observational cohort study. BMJ 2019;364:l729 Link

Vinay S et al. How to Interpret Elevated Cardiac Troponin Levels. Circulation. 2011;124:2350–4 Link

Brush JE et al. A Brief Review of Troponin Testing for Clinicians. 2017: J Am Coll Cardiol 2016;68:2365-75 Link

Twerenbold R et al. Update on high-sensitivity cardiac troponin in patients with suspected myocardial infarction. European Heart Journal Supplements. 2018;G2-10 Link

Neumann JT et al. Application of High-Sensitivity Troponin in Suspected Myocardial Infarction. NEJM 2019; 380:2529-40 Link

Saenger AK. Pick a Number, Any Number...Chose Your Troponin Cutoff Wisely. The Journal of Applied Laboratory Medicine.2019;3(5):753–5 Link

Jaffe AS and Ordonez-Llanos J. High-sensitivity Cardiac Troponin: From Theory to Clinical Practice. Rev Esp Cardiol. 2013;66(9):687–91 Link

Abbreviations: hs-cTn high sensitivity cardiac troponin assay, cTn cardiac troponin, ACS acute coronary syndrome, AMI acute myocardial infarction, ER emergency room, ED emergency department

Keywords: troponin, acute coronary syndrome, cutoff, 99th percentile, cardiac troponin, high sensitivity cardiac troponin assay

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