Abstract
Elucidation of the physiologically distinct subunits of troponin in 1973 greatly facilitated our understanding of cardiac contraction. Although troponins are expressed in both skeletal and cardiac muscle, there are isoforms of troponin I/T expressed selectively in the heart. By exploiting cardiac-restricted epitopes within these proteins, one of the most successful diagnostic tests to date has been developed: cardiac troponin (cTn) assays. For the past decade, cTn has been regarded as the gold-standard marker for acute myocardial necrosis: the pathological hallmark of acute myocardial infarction (AMI). Whilst cTn is the cornerstone for ruling-out AMI in patients presenting with a suspected acute coronary syndrome (ACS), elevated cTn is frequently observed in those without clinical signs indicative of AMI, often reflecting myocardial injury of ‘unknown origin’. cTn is commonly elevated in acute non-ACS conditions, as well as in chronic diseases. It is unclear why these elevations occur; yet they cannot be ignored as cTn levels in chronically unwell patients are directly correlated to prognosis. Paradoxically, improvements in assay sensitivity have meant more differential diagnoses have to be considered due to decreased specificity, since cTn is now more easily detected in these non-ACS conditions. It is important to be aware cTn is highly specific for myocardial injury, which could be attributable to a myriad of underlying causes, emphasizing the notion that cTn is an organ-specific, not disease-specific biomarker. Furthermore, the ability to detect increased cTn using high-sensitivity assays following extreme exercise is disconcerting. It has been suggested troponin release can occur without cardiomyocyte necrosis, contradicting conventional dogma, emphasizing a need to understand the mechanisms of such release. This review discusses basic troponin biology, the physiology behind its detection in serum, its use in the diagnosis of AMI, and some key concepts and experimental evidence as to why cTn can be elevated in chronic diseases.
Highlights
Intensive investigation into the mechanisms of striated muscle contraction during the late 50 s and early 60 s led to evidence of a protein that resembled tropomyosin and regulated the calcium sensitivity of the actomyosin contractile apparatus
After the onset of myocardial ischaemia, cardiac myocyte death can occur within 15 min, with histological evidence of necrosis appearing within 4–6 h.24 cardiac troponin (cTn) is released from the myocardium a few hours following a period of ischaemia and is detectable in the venous circulation once the interstitial fluid from the infarct zone has been cleared by the cardiac lymphatics.[34] cTnI/T are released in free-forms and as noncovalent ternary and binary complexes (Figure 2)
The rationale behind the cTn assay was relatively simple: myocardial necrosis leads to membrane disruption causing troponin release which is detected in serum
Summary
Intensive investigation into the mechanisms of striated muscle contraction during the late 50 s and early 60 s led to evidence of a protein that resembled tropomyosin and regulated the calcium sensitivity of the actomyosin contractile apparatus This finding subsequently led to the discovery of troponin by Ebashi and Kodama in 1965. Elucidation of the physiologically distinct subunits of troponin by Greaser and Gergely[1] in 1973 has facilitated a quantum-leap in our understanding of the molecular physiology underpinning cardiac contraction Consequent to their findings, one of the most successful diagnostic investigations to date has been developed: the cardiac troponin (cTn) assays. The literature suggests cTn can be released with reversible cell injury in the absence of necrosis or cell death This has been prompted (and reinforced by), observations of increased cTn in clinical situations whereby there is no obvious coronary syndrome, such as extreme exercise. This review addresses the biology of troponin, the physiology behind its detection in serum, its clinical utilization as a biomarker of AMI and myocardial injury, as well as the experimental evidence behind cTn elevation in several chronic conditions
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