Year: 2022
Type: article
Abstract: Few clinicians are aware of the complex story of how cardiac troponin (cTnI and cTnT) displaced creatine kinase (CK) MB as the standard biomarker for the detection of myocardial injury and myocardial infarction.1 The same is true for the global movement towards the introduction of high-sensitivity cardiac troponin (hs-cTn) assays into clinical practice.2–6 Just as the clinical laboratory and practice initially transitioned from total CK to CK MB in the 1980s, two decades later, there was a transition from CK MB to cTn testing for the diagnosis of acute myocardial infarction.1 The same thoughts were explored for both transitions regarding what the implications were for patient care: (i) the new biomarker measurement should be reproducible in multiple settings; (ii) it should be sensitive and specific; and (iii) it should add independent information about the risk of adverse outcomes and account for a large proportion of the risk associated with disease.2–6 Clinical use of CK MB began to lose favour upon the recognition that CK MB was expressed in diseased skeletal muscle (i.e. muscular dystrophy and end-stage renal disease) and in muscle from marathon runners due to the trauma of long-distance running from degradation and regeneration of muscle resulting in higher CK MB concentrations, that when released after injury, appeared as a false indication of myocardial injury (at an ∼5% false-positive rate).1 Following regulatory clearance of both cTnI and cTnT assays in 1995 and 1996, both the laboratory medicine and cardiology communities published expert opinions with recommendations introducing the replacement of CK MB with cTn assays; proposing the concept of the 99th percentile upper reference limit (URL) as the diagnostic threshold for myocardial infarction.3,4 The strength of cTn measurements was predicated on tissue specificity of cTnI and cTnT; however, it has since been demonstrated that the cTnT isoform is expressed, albeit rarely, in skeletal muscle of patients with neuromuscular diseases.3 As is often found with new biomarkers, the first generation of cTn assays lacked precision at the 99th percentile URL, a cause of clinical misclassification of patients with possible myocardial infarction. As such, the introduction of this test into practice received both compliments and criticisms. This led to improved cTn immunoassays, approved by regulators as early as 2007, with an imprecision value of <10% at sex-specific URLs and the ability to measure >50% of cTn concentrations in healthy persons. These novel assays were designated ‘high-sensitivity (hs)’.2–6 What was most misunderstood for the hs-cTnI assay compared with hs-cTnT was that there were no significant increases in the number of patients diagnosed with myocardial injury or myocardial infarction following their implementation into clinical practice.2 High-sensitivity cardiac troponin testing has become an extremely sensitive tool for the early rule-out of myocardial infarction at concentrations around the assays’ limit of detection, an accurate diagnostic tool for myocardial infarction, and a powerful risk assessment tool for stratifying patients at a continuum of risk for major adverse events (Figure 1).2–6 All laboratories should establish hs-cTn assays as their primary assay for patient care and research. High-sensitivity cardiac troponin assays do not appear to have any real challengers in 2022. As for the future, hs-cTn assays may be used more widely than in the assessment of patients with possible myocardial infarction, with clinical applications in multiple settings to predict future risk of adverse cardiovascular outcomes.3,6 High-sensitivity cardiac troponin for risk stratification and diagnosis. High-sensitivity cardiac troponin assay concentration cut-offs for the diagnosis of myocardial infarction and the assessment of risk to enable early rule-out and the early identification of high-risk patients who present with symptoms suggestive of acute coronary syndrome to the Emergency Department. NPV, negative predictive value; PPV, positive predictive value, LoD, limit of detection; URL, upper reference limit; MI, myocardial infarction; hs, high sensitivity. N.L.M. is supported by a Research Excellence Award (RE/18/5/34216) and a Chair Award (CH/F/21/90010) from the British Heart Foundation. Conflict of interest: F.S.A. is a consultant at HyTest Ltd, AWE Medical, and an associate editor of Clinical Chemistry. He serves on the advisory boards of Werfen, Siemens Healthineers, and Qorvo; has received honoraria for speaking at industry conferences such as Siemens Healthineers and Beckman Coulter; and is a principal investigator on industry-funded grants (non-salaried) on cardiac biomarkers received from the Hennepin Healthcare Research Institute, Abbott Diagnostics, Abbott POC, BD, Beckman Coulter, Ortho-Clinical Diagnostics, Roche Diagnostics, Siemens Healthcare, and Quidel. N.L.M. reports research grants awarded to the University of Edinburgh from Abbott Diagnostics and Siemens Healthineers outside the submitted work and honoraria from Abbott Diagnostics, Siemens Healthineers, Roche Diagnostics, and LumiraDx. C.M. has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the University Hospital Basel, the University of Basel, Abbott, Beckman Coulter, Brahms, Idorsia, Novartis, Ortho Diagnostics, Quidel, Roche, Siemens, Singulex, and Sphingotec outside the submitted work. He has also received speaker honoraria/consulting honoraria from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, BMS, Novartis, Osler, Roche, and Sanofi, all paid to the institution. None.
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: British Heart Foundation
OpenAlex ID: W4226524027