David M. Nemer, Hicham Skali
Hospital Medicine Clinics
Background- What is Troponin?: Troponin is an intracellular regulatory protein complex associated with the contractile apparatus of skeletal and cardiac myocytes. It is composed of 3 protein subunits: troponin I (cTnI), troponin T (cTnT), and troponin C. Cardiac myocytes express structurally unique isoforms of cTnI and cTnT as compared with skeletal myocytes. Irreversible injury of cardiac myocytes leading to cell death (myocardial necrosis) results in the release of cTnI and cTnT into the circulation. Highly specific immunoassays have been developed for the detection of these cardiac-specific proteins in peripheral blood (with minimal cross-reactivity to skeletal troponin). In prior decades, consensus opinion held that an elevation in cardiac troponins (cTns) exclusively signified irreversible myocardial cell death. However, the potential for release of cTns in the setting of reversible myocyte injury is now a topic of considerable debate. This issue is made even more controversial by the advent of increasingly sensitive assays that can reliably detect low levels of cTn in a majority of apparently disease-free individuals. and Although this debate is ongoing, cTn remains the preferred biomarker of myocardial necrosis due to its superior performance in the diagnosis and prognosis of cardiac conditions.
What are the differences between assays for cardiac troponin I and troponin T? Following release from cardiac myocytes, cTnI exists in different forms (free or bound to other types of cTn) in the circulation as well as in multiple isoforms (oxidized, reduced, or phosphorylated). In the development of immunoassays for cTnI detection, various manufacturers have used detection antibodies directed against different epitopes of the multiple cTnI forms. As a result, there is a lack of standardization between cTnI assays from different manufacturers, and absolute concentrations of cTnI cannot be compared between different assays. Because of the existence of an international patent, cTnT assays in widespread use have been produced by a single manufacturer. As a result, the uniform use of a single current generation cTnT assay across clinical care centers allows for direct comparison of absolute concentrations. Of note, all cTnI and cTnT assays meet the same performance specifications, and no distinction is made in terms of their diagnostic and prognostic utility when used for the clinical indications discussed later.
What is the difference between sequential generations of cardiac troponin assays? The US Food and Drug Administration (FDA) first approved the use of a cTn assay for clinical care in 1994. Since that time, manufacturers have produced successive assay generations with progressive improvement in analytical performance. This improvement is characterized by the ability to detect increasingly lower concentrations of circulating cTn while maintaining similar test accuracy and precision. Accordingly, each improvement in assay performance has led to earlier detection of increasing cTn levels following the onset of myocardial necrosis. Furthermore, the most recently developed assays can detect circulating cTn levels in up to 90% of healthy individuals as compared with less than 50% for earlier generation assays. There is currently no widely accepted classification scheme for the multitude of cTn assays. As a result, manufacturers describe their commercial assays using terms that do not have standardized meanings according to analytical performance. For example, newer-generation assays with lower limits of detection have generally been described as “high sensitivity” cardiac troponin (hs-cTn) assays, although strict criteria defining “high sensitivity” do not exist. In 2012 the International Federation of Clinical Chemistry suggested that the term “high sensitivity” be reserved for only those assays that detect cTn in greater than 50% of healthy subjects, and preferably in more than 95%. However, manufacturers have not yet adopted such standard terminology. One proposed classification scheme for cTn assays is presented in Table 1, generated from the combined suggestions of Jarolim and Apple.1Although several hs-cTn assays are available for use in other countries, thus far none has been cleared by the FDA for clinical use in the United States.