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Troponin

The troponin complex consists of three subunits: troponin T (tropomyosin binding), troponin I (inhibitory), and troponin C (calcium binding). This complex is located on the actin filament and regulates the calcium mediated interaction of actin and myosin filaments during muscular contraction. Most troponin T and I molecules are bound to the contractile proteins, but a small fraction (3 - 6%) remains free in the cytoplasm. Both troponin T and I have amino acid sequences that differ between adult skeletal and cardiac muscle. Immunoassays are now available that can specifically measure cardiac troponin T and I in plasma. Troponin C has no potential as a cardiac specific marker because its amino acid sequence is identical in skeletal and cardiac muscle.

Following cardiac injury, there is an early release of troponin from the cytoplasmic pool followed by a persistent release of the bound fraction from muscle fibers that are being degraded. Troponin levels become elevated within 2 to 3 hours after the onset of chest discomfort, peak at 18-24 hours, and remain elevated for up to 14 days. The half life of circulating troponin is approximately 2 hours.

In 80% of patients a rule in diagnosis of myocardial ischemia can be made in 2 to 3 hours, but a definitive rule-out diagnosis requires 12 hours. Because it remains elevated for such a long time, troponin is beneficial in detecting infarctions in late presenting patients. Troponin may reach concentrations that are 5 to 50 fold higher than the upper limit of normal.

Elevated troponin is found in 30 to 40% of patients with unstable angina. It appears to be a better risk indicator in angina than CK-MB. Patients with unstable angina who have normal CK-MB and increased troponin have a 30% likelihood of ischemic complications such as acute MI or cardiac death. The long term (>5 months) outcome of these patients is similar to patients diagnosed with acute myocardial infarction.

Patients with atypical, minimal ECG changes and normal troponin values have very few serious cardiac events. Patients with relatively mild arrhythmia such as atrial fibrillation may have only elevated CK-MB, while patients with prolonged arrhythmia may exhibit elevations of both CK-MB and troponin.

The most recent guidelines suggest that samples be obtained at baseline, at 6 hours, and again at 12 hours in occasional patients in whom suspicion is very high. A 3 hour sample is helpful in evaluating patients in the emergency department. Two normal troponin levels indicate a dischargeable patient.

Approximately10% of patients with an acute coronary syndrome has normal troponin and increased CK-MB, which is most likely due to skeletal muscle injury. These patients have excellent outcomes, confirming the lack of specificity of CK-MB for heart disease. Elevated troponin and normal CK-MB suggest either unstable angina or late admission after an acute infarction.

Prognosis after acute myocardial infarction is closely related to the extent of myocardial damage. Peak values obtained at 72 to 96 hours provide the best estimate of infarct size. A 20% change in troponin values is suggestive of reinfarction.

Interventional therapy affects plasma troponin levels less than CK-MB. Troponin levels do not usually increase after electrical cardioversion, even in patients with elevated total CK and CK-MB secondary to skeletal muscle injury. Elevations are more common in patients who have undergone direct current shock or prolonged resuscitation, or both. Postpercutaneous coronary intervention troponin values are useful only if the baseline troponin value is within the normal range or remains unchanged over time. If the baseline value is normal, a 3-fold increase is consistent with a postprocedure acute myocardial infarction.

During cardiac surgery, low levels of troponin (<10 ng/mL) are encountered due to cardioplegia, prolonged cross clamping of the aorta and direct trauma to the heart. Higher levels correlate with more significant myocardial injury.

Increase in the concentration of troponin in patients with renal failure indicates cardiac damage. These patients have a higher long term risk for death than patients with normal troponin values. Troponin I values do not change significantly before and after dialysis.

Many physicians have noticed elevated troponin concentrations in patients without demonstrable myocardial infarction. In one study, 15% of critically ill patients in an ICU, who were not admitted for ischemic heart disease, had elevated troponin. Two thirds of these patients did not have recognized heart disease. An increase in plasma troponin concentration is indicative of myocardial injury, but is not synonymous with MI or an ischemic injury. The most common nonischemic causes of elevated plasma troponin concentration include:

• Myocarditis
• Pericarditis
• Congestive heart failure
• Hypertension
• Pulmonary embolism
• Cardiac contusion (blunt cardiac trauma)
• Amyloidosis
• Chemotherapy
• Sepsis
• Shock
• Renal failure
• Chemotherapy

Congestive heart failure often produces subendocardial injury due to increased ventricular wall stress. Hypertension is often associated with left ventricular hypertrophy and subendocardial injury. Pulmonary embolism often produces right ventricular injury. Pacemaker wires, ablation, implantable cardioverter defribillator discharges and cardioversion all induce cardiac injury. Recent investigations suggest that infection with cardiotrophic viruses may occur more frequently than previously suspected and that only a small subset of patients progress to overt myocarditis or heart failure. Troponin elevations are common in patients with sepsis and may be secondary to hypotension, septic emboli, high doses of vasoactive drugs or the effects of cytokines. Shock can produce cardiac injury as a result of tachycardia and hemodynamic compromise. Several chemotherapeutic agents including adriamycin, doxorubicin, 5-fluorouracil and Herceptin are cardiotoxic. Renal failure is often accompanied by chronic low level elevations of troponin secondary to left ventricular hypertrophy or dialysis induced cardiac injury. Treatment of GI bleeding with pressor medications has also been associated with elevated troponin concentrations. If the clinical circumstance suggests that an ischemic mechanism is unlikely, these other causes of cardiac injury should be considered. Transient elevations of troponin that occur within 24 hours after extreme exercise do not appear to indicate acute myocardial injury.

Negligible concentrations of troponin are present in the plasma of healthy adults. Therefore, reference ranges are very low and slight elevations usually indicate myocardial damage. Troponin can be used for both risk stratification during an acute cardiac event and diagnosis of myocardial infarction. The reference range is the cutoff point between individuals without heart disease and patients with some degree of myocardial ischemia. The latter group has the same long-term risk of adverse outcomes as patients presenting with acute myocardial infarction.

Several international expert panels including the European Society of Cardiology, the American College of Cardiology, and the American Heart Association have recommended that increased troponin be defined as a value above the 99^th percentile concentration of a healthy population. Total imprecision of should be <10% at the 99^th percentile reference limit.

A 99^th percentile reference limit of 0.04 ng/mL has frequently been cited for troponin I measured on the Beckman Coulter Access immunoassay analyzer. However, in our experience too many patients without ischemic heart disease had slightly elevated troponin values when plasma samples, collected in green topped Greiner plastic tubes, were measured on a Beckman Coulter DXi analyzer. Therefore, the following reference intervals were established.

 

 

Preanalytical variables such as short sample, inadequate mixing of the blood, incomplete centrifugation, and tilting of tubes after centrifugation can result in falsely elevated results.

Specimen requirement is a 4 mL green top (heparin) tube of blood.