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Cardiac troponins are regulatory proteins of the thin actin filaments of the cardiac muscle. Troponin T and troponin I are highly sensitive and specific markers of myocardial injury. Serial measurement of troponin I or troponin T has become an important tool for risk stratification of patients presenting with acute coronary syndromes. The joint committee of the European Society of Cardiology, the American College of Cardiology, and the American Heart Association has recently accepted their measurement in serum as the standard biomarker for the diagnosis of acute myocardial infarction and for diagnosis and management of acute coronary syndromes.1,2 Cardiac troponins, however, are raised in many patients presenting with conditions other than acute coronary syndromes (box). To ignore this fact will lead to unjustified, potentially harmful investigations and increases medical costs. In sepsis, for example, cardiac troponins are raised in up to 85% of patients in the absence of any acute coronary syndromes.3 Doctors need to be aware that troponins are biochemical markers that replace neither electrocardiograms nor clinical investigation.
In the setting of an acute coronary syndrome raised cardiac troponins identify patients with a risk of death that is several times higher than in patients without troponin elevation in the subsequent weeks.4 In addition, cardiac troponins have also been reported to predict mortality in heart failure, sepsis, renal failure, stroke, pulmonary embolism, and in critically ill patients without coronary artery disease.
Cardiac troponins are detected in serum or heparin plasma by using monoclonal antibodies against several different epitopes of the troponin T or I molecule. These antibodies have negligible cross reactivity to skeletal muscle.5 Cardiac troponins I and T start to rise within 3-4 hours after myocardial infarction and remain raised for 4-10 days because of a gradual degeneration of myofibrils with release of the troponin complex.6,7
Several manufacturers offer different immunological tests with different cut-off values and different sensitivities for the detection of troponins. In contrast to the different assays of troponin I, which are not standardised, troponin T is assessed by using a single assay. Therefore, the results are directly comparable between different laboratories over the world. The new third generation troponin T test has a clinically relevant cut-off point (upper limit of normal) of about 0.1 μg/l and a 95% sensitivity for the detection above 0.01 μg/l.5 Newer tests for troponin I show cut-off points between 0.1 μg/l and 2 μg/l, with a detection level around 0.007 μg/l.8 Nevertheless, for all biochemical tests doctors should evaluate cut-off levels provided by the manufacturers in their own population of patients.
Several mechanisms leading to raised troponins are assumed: the best known reason is myocardial ischaemia in the setting of acute coronary syndromes or myocardial infarction.9 However, recovery of left ventricular ejection fraction after troponin positive sepsis, septic shock, or myocarditis shows that other mechanisms for raised troponins may be relevant, too. One may be leaking of cardiac troponins from myocyte cell membranes. Tumour necrosis factor α has been shown to increase the permeability of endothelial monolayers to macromolecules and lower weight solutes.10 Permeability may change similarly at the level of myocyte cell membranes, leading to leakage of cardiac troponins. Experimental evidence for this hypothesis was provided by Piper et al,11 who showed reversible membranous bleb formation in rat cardiomyocytes during limited periods of hypoxia and a consecutive release of myocardial enzymes in cell supernatant. In rat cardiomyocytes, only 15 minutes of mild ischaemia have been shown to be enough to cause the release of troponin I, an interval too short to induce cell death.12
Conditions associated with raised cardiac troponins (analytical causes excluded)
Cardiac diseases and interventions
Cardiac surgery w3 w4
Cardioversion and implantable cardioverter defibrillator shocks w5 w6
Closure of atrial septal defectsw7
Heart failurew10 w11
Percutaneous coronary interventionw16 w17
Post cardiac transplantationw18
Critically ill patientsw23 w24
High dose chemotherapyw25 w26
Primary pulmonary hypertensionw27
Pulmonary embolismw28 w29
Subarachnoid haemorrhagew37 w38
Sepsis and septic shockw40-42
Ultra-endurance exercise (marathon)w45-47
A further mechanism for a rise in troponins may be related to coagulation in the capillary bed during sepsis, leading to reversible myocardial hypoxia and apoptosis associated with leakage of cardiac troponins into the serum. However, experimental evidence proving this hypothesis does not exist to date.
The most important question is not whether diseases presented in the box represent myocardial damage or not but rather whether raised troponins reflect reversible or irreversible myocardial injury and how necrosis could be distinguished from reversible myocardial damage. Further experimental studies are required to clarify this point, which has in recent years been considered in numerous clinical studies that showed that raised troponins are predictors for mortality or worse clinical outcome independently of acute coronary syndromes and myocardial infarction.w1 w9 w23 w24 w27 w28 w31 w35 w41 w43 However, raised cardiac troponins alone will never allow us to make a clinical diagnosis, but they are an important contribution to a complex clinical picture, be it in the context of acute coronary syndromes or other conditions. Above all they contain prognostic information for most of these conditions that may be relevant for the management of patients
Additional references w1-w47 are on bmj.com
Competing interests: None declared.