The role of high sensitivity troponin outside the context of acute coronary syndromes

Abstract

Ischaemic heart disease remains the leading cause of mortality worldwide and, whilst there has been progress in reducing this, mainly due to smoking cessation, there are concerns that the obesity epidemic may negate this progress. Chest pain is a key presenting complaint for patients with ischaemic heart disease but it is also seen in a range of other conditions. Given that chest pain accounts for around 6% of emergency department presentations, healthcare systems need an efficient algorithm for managing these patients quickly. The use of biomarkers has become a central component in the diagnosis of myocardial infarction as defined by international guidelines. High sensitivity cardiac troponin (hs-cTn) is now considered the biomarker of choice and, as such, is widely used across a range of different healthcare systems.
Cardiac troponin (cTn) is a key component of the calcium-mediated contractile apparatus found within cardiac myocytes and is released upon injury to the myocardium. There are three isoforms of cTn, two of which have been found to be specific to the myocardium and, as such, these assays became embedded in routine practice. There was, however, one important limitation in their use; in order to reach adequate levels of sensitivity, a sample was needed at 10-12 hours after the onset of chest pain. This had significant resource implications for healthcare systems, and this became a driver for the development of high sensitivity cTn (hs-cTn) assays which now have
excellent performance within three hours of chest pain. Whilst this has proven highly beneficial to many aspects of clinical care, especially the ability to rule out a heart attack very early, the increased sensitivity of the assays, combined with increased usage, has resulted in concentrations above the manufacturer’s upper limit of normal (ULN) being frequently detected across a range of presentations not traditionally associated with acute myocardial infarction (AMI). The result has been uncertainty, and some inaccuracy, about the interpretation of these results in clinical practice. Excitingly, however, there are emerging data to suggest that the hs-cTn concentration, outside the context of myocardial infarction, may act as a biomarker of prognosis.
In view of this, the aim of my thesis was to assess whether there was an association between hs-cTn concentration and mortality outside the context of AMI in several patient populations. The first two chapters of this thesis follow on from the original CHARIOT study (which was performed by my predecessor, Dr Mark Mariathas). In the first chapter I demonstrate that elevated hs-cTnI concentrations are frequently seen on presentation to the emergency department and, whilst these are associated with the severity of illness, they are also independent predictors of short term mortality. In the second chapter, I demonstrate that hs-cTnI concentrations are independently associated with one year mortality (both cardiovascular and non-cardiovascular) across a complete, consecutive hospital cohort of 20,000 patients (inpatients, outpatients and those in the emergency department) regardless of whether there was a clinical indication for the test. Finally, in a population of patients in critical care I show that the hs-cTnI concentration is associated with illness severity but is also independently associated with critical care mortality. Furthermore, that hs-cTnI concentration on admission to critical care performs as well as previously validated prognostic scores in discriminating critical care mortality.
In summary, this thesis demonstrates that hs-cTnI concentration is associated with both short and medium term outcomes across a range of populations. Further research is now required to assess whether any medical intervention can alter the risk in those patients identified by hs-cTn as having adverse prognosis. The potential clinical value of the concept that hs-cTn is a general biomarker for prognosis is far reaching: it would represent a novel application for the assay outside the context of its use to rule out AMI.

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ORCID for Nicholas Curzen: orcid.org/0000-0001-9651-7829

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