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.
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.
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'.
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.
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.
Percutaneous coronary intervention
Heart failure (acute & chronic)
Critical illness (e.g., sepsis)
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.
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Saenger AK. Pick a Number, Any Number...Chose Your Troponin Cutoff Wisely. The Journal of Applied Laboratory Medicine.2019;3(5):753–5 Link
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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