Cardiac Troponin

Cardiac troponins I and T are regulatory proteins on the thin filament of cardiac muscle. They sit in the contractile apparatus, with a small free cytosolic pool, and they enter the blood when myocytes are injured. Cardiac specific isoforms exist for both, which makes them the most specific biomarkers of myocardial injury. Current assays are high sensitivity (hs-cTnI and hs-cTnT), defined by a measurable value in more than half of healthy people and an imprecision of 10% or less at the 99th percentile upper reference limit. Results are reported in ng/L.

Myocardial injury is present when a value exceeds the 99th percentile. It is acute when a rise or fall is shown on serial samples, and chronic when values are persistently raised and stable (variation under 20%). Myocardial infarction needs acute injury together with clinical evidence of ischaemia: symptoms, new ischaemic ECG change, pathological Q waves, new regional wall motion abnormality or a coronary thrombus.

Chest pain accounts for 5 to 10% of emergency attendances, and only 10 to 20% of these patients have myocardial infarction. With high sensitivity assays, a raised troponin is found in a large share of unselected hospital patients, and most of these are not type 1 infarction. The test is strong at excluding infarction and weak at identifying its cause.

Indications. Suspected acute coronary syndrome, chest pain, dyspnoea, syncope or arrhythmia of unclear cause, suspected myocarditis or pericarditis, suspected pulmonary embolism with right heart strain, aortic dissection, monitoring of cardiotoxic therapy, perioperative surveillance in high risk surgery, and risk assessment in heart failure and kidney disease.

Specimen. Serum, or heparin or EDTA plasma, depending on the assay. Draw at presentation and again at 1 to 3 hours with a rapid strategy (0 and 1 hour or 0 and 2 hours), or at 3 to 6 hours with a conventional assay. Samples should be taken from the arm opposite any infusion. Haemolysis alters some assays.

Upper reference limits. The 99th percentile is assay specific and sex specific, and local values take precedence. Typical values are about 14 ng/L for hs-cTnT overall (about 9 ng/L in women and 16 ng/L in men) and about 26 ng/L for one common hs-cTnI method overall (about 16 ng/L in women and 34 ng/L in men). Sex specific limits detect infarction in women that a single overall limit misses.

Kinetics. Values begin to rise within 1 to 3 hours of myocyte injury, peak at 12 to 24 hours, and remain raised for 7 to 10 days (troponin I) or 10 to 14 days (troponin T). Late presentation therefore keeps the test useful for several days, and a persistently raised value after an infarct does not signal a new event.

Rapid rule out and rule in.

• Rule out: a very low value at presentation (assay specific, typically under 5 ng/L) in a patient whose symptoms began at least 3 hours earlier excludes infarction with a negative predictive value over 99%. A low first value with a very small change at 1 or 2 hours has the same effect.
• Rule in: a high first value (assay specific, for example 52 ng/L or more for hs-cTnT) or a large absolute change at 1 or 2 hours (for example 5 ng/L or more for hs-cTnT) gives a positive predictive value of 70 to 75% for infarction.
• Observe: patients who are neither ruled out nor ruled in need a third sample at 3 hours and clinical assessment.
• Where the baseline is already raised, a relative change of 20% or more indicates acute injury.

Type 1 myocardial infarction. Atherosclerotic plaque rupture or erosion with coronary thrombosis. Value rises and falls, with ischaemic symptoms or ECG change.

Type 2 myocardial infarction and supply demand mismatch. Tachyarrhythmia, severe hypertension, hypotension and shock, severe anaemia, hypoxaemia and respiratory failure, sepsis, coronary spasm, spontaneous coronary artery dissection, coronary embolism.

Non-ischaemic acute myocardial injury.

• Myocarditis and pericarditis with myocardial involvement, takotsubo syndrome, acute heart failure, cardiac contusion, cardioversion, ablation, cardiac surgery, endomyocardial biopsy.
• Pulmonary embolism, aortic dissection, stroke and subarachnoid haemorrhage, sepsis and critical illness, burns, extreme endurance exercise.
• Cardiotoxic drugs: anthracyclines, trastuzumab, fluorouracil, immune checkpoint inhibitors (myocarditis can be fulminant), cocaine and amphetamines.

Chronic myocardial injury. Chronic kidney disease, left ventricular hypertrophy, heart failure, cardiomyopathies, cardiac amyloidosis, diabetes, older age. Values are stable, and small fluctuations of under 20% do not indicate a new event.

Features that favour type 1 infarction. Typical ischaemic pain, ECG change, a large rise and fall, and a regional wall motion abnormality matching a coronary territory.

Critical values and findings needing immediate action. Triggers vary by laboratory.

• A raised or rising troponin with ongoing chest pain, ST elevation, new left bundle branch block or haemodynamic instability. ST elevation is treated at once and does not wait for the result.
• Troponin rise with ventricular arrhythmia, heart block, acute heart failure, new murmur or cardiogenic shock.
• Troponin rise with tearing chest or back pain, pulse deficit or widened mediastinum (aortic dissection).
• Troponin rise during immune checkpoint inhibitor therapy, which needs urgent exclusion of myocarditis.

Interferences and pitfalls.

• Presentation within 3 hours of onset can give a normal first value, so a second sample is essential.
• Heterophile antibodies and human anti-animal antibodies cause false positives. A raised value that does not change over several samples in a well patient suggests interference.
• High dose biotin interferes with sandwich assays and can lower the result.
• Macrotroponin (troponin bound to immunoglobulin) produces a persistent, stable raised value.
• In skeletal muscle disease (myositis, dystrophy, rhabdomyolysis), hs-cTnT can be raised from regenerating skeletal muscle, and troponin I is more specific.
• Haemolysis lowers hs-cTnT and can raise some troponin I results.
• Assays are not interchangeable, and thresholds from one assay cannot be applied to another. Point-of-care assays are less sensitive than laboratory assays.
• Kidney failure raises baseline values through reduced clearance and chronic myocardial injury, and still carries prognostic weight.

Special groups.

• Women: lower sex specific limits are needed, and symptoms may be atypical.
• Older adults and people with diabetes: atypical presentation is common, and baseline values are higher.
• Children: troponin is used for myocarditis, Kawasaki disease and cardiac injury, with age specific limits.
• Neonates: values are higher in the first days, and rise with perinatal asphyxia.
• Pregnancy: mild rises can occur in pre-eclampsia and peripartum cardiomyopathy.
• Athletes: marathon and endurance exercise raise values for 24 to 48 hours.
• Regions: rheumatic heart disease, Chagas disease and viral myocarditis are significant causes.

Follow up tests. 12-lead ECG with serial recordings, repeat troponin, echocardiography, coronary angiography or CT coronary angiography, cardiac MRI, natriuretic peptides, D-dimer and CT pulmonary angiography, CT aortography, full blood count, urea and electrolytes, glucose and HbA1c, lipid profile, C-reactive protein, thyroid function tests, creatine kinase, viral and autoimmune screens, and polyethylene glycol precipitation for macrotroponin.