Volume 3  Issue 1  Summer 2005

Cardiac Troponins

Troponins of cardiac origin are regulatory proteins that control the calcium mediated interaction of Actin and Myosin. The troponin complex consists of three subunits: Troponin T, which binds to Tropomyosin and facilitates contractions; Troponin I, which binds to Actin and inhibits Actin/Myosin interaction; and Troponin C, which binds the calcium ions ⁽¹⁾. The amino acid sequence of the skeletal and cardiac isoforms of Troponin T and Troponin I are sufficiently dissimilar and therefore detectable by monoclonal antibody assay ⁽²⁾. Troponin C is not used clinically because both cardiac and smooth muscle share Troponin C isoforms.

Cardiac troponins can be released from the myocyte to the blood due to both reversible and irreversible cell damage. In prolonged ischemia, cells are irreversibly damaged as the cell membrane degrades, followed by the gradual release of myofibril-bound cytosolic complexes ⁽¹⁾. However, the notion that troponin is increased only after irreversible myocardial necrosis has recently been challenged by the observation that some patients with unstable angina have only transient troponin elevations with values returning to baseline within a few hours ⁽³⁾. This pattern of troponin increase may not be consistent with permanent myocardial damage. It is therefore conceivable that myocardial troponin can also be released in the setting of increased membrane permeability ⁽⁴⁾. With increased membrane permeability, smaller troponin fragments could be released into the systemic circulation. In this setting, myocyte damage may not be permanent and necrosis does not occur.

In theory, the background noise levels of Troponin I and T in the circulation of a healthy person are near zero (unlike creatinine kinase, which is present at detectable levels in healthy people and elevated in the presence of skeletal muscle disease or injury). A much lower threshold of troponin released compared to creatinine kinase can be utilized to define myocardial infarction. However, analytic variability results in the cut offs being set so as to achieve maximum predicative value (sensitivity vs. specificity).

Because of the improvements in both sensitivity and specificity, the American College of Cardiology/European Society of Cardiology have redefined acute myocardial infarction based preferentially on serial measurements of Troponin⁽⁵⁾. The consequence of this change in definition is that a greater proportion of patients with non-ST segment elevation acute coronary syndrome are classified as having non-ST segment elevation myocardial infarction instead of unstable angina⁽⁶⁾. Troponin is so sensitive for the detection of myocardial injury that non-coronary processes that cause minor myocardial damage (e.g., perimyocarditis, pulmonary embolus with right ventricular strain, and severe acute heart failure) also can result in an elevated troponin level and sometimes present a clinical challenge.

Troponins have proven utility as prognostic markers. In patients who have non-ST segment elevation acute coronary syndrome and who were studied in the Thrombolysis in Myocardial Infarction (TIMI) IIIB Trial, graded elevations in Troponin I at baseline were strongly and independently correlated with increasing mortality⁽⁷⁾. In Global Use of Strategies to Open Occluded Arteries (GUSTO) IIA Trial, an elevated Troponin T level at baseline was an independent predictor of death at 30 days across the spectrum of acute coronary syndrome ⁽⁸⁾.

Patients with a detectable troponin level at baseline were more likely to have three-vessel or left main coronary artery disease on coronary angiography compared to patients without a detectable troponin level. This finding explains why patients with elevated troponin level at baseline were more likely to benefit from an early invasive strategy ⁽⁹⁾. Studies have shown that patients in the (TACTICS) - TIMI 18 Trial, with even minor elevations of Troponin T (0.01 to 0.05 ng/mL) or Troponin I (0.01 to 0.04 ng/mL), experienced considerable reductions in death or ischemic complications if their non-ST segment elevation acute coronary syndrome was treated with an early invasive strategy ⁽¹⁰⁾.

Practical clinical issues with troponin relate to the background noise that is seen in almost all assays. Some of the major studies are predicated on absolute cut-off values which are not readily achievable in the real world. ProMedica Laboratories uses Beckman's Troponin I Kit. Based on the variation of the assay, we have established the negative cut-off at 0.04 ng/mL. Values less than 0.04 ng/mL are not readily reproducible and range from 0.01 to 0.04 ng/mL can be noted on repeat testing. The lab has established a gray zone between 0.05 and 0.49 ng/mL which indicates that, in all probability, there is evidence of myocardial injury as identified by troponin leaking through the myofibril membrane. Definitive evidence of myocardial necrosis is a Troponin I of greater than 0.49 ng/mL. Thus, there is some conflicting data within the literature versus the real world. It is our strong belief that any value greater than 0.04 ng/mL is indicative of myocardial injury; however, the value does not necessarily correlate with non-ST segment elevation myocardial infarction.

There is a problem with the use of a single troponin measurement in patients who present very early because it is not sufficient to exclude a myocardial infarction of recent (less than six hours) onset. With shorter times to catheterization across the spectrum of acute coronary syndrome, there often is insufficient time to obtain a second troponin measurement prior to percutaneous coronary intervention. Although cytosolic release of troponin precedes its release from the myofilament, approximately 10-20% of patients with non-ST segment elevation acute coronary syndrome⁽⁹⁾ and more than half of patients with ST-segment elevation acute myocardial infarction⁽¹⁰⁾ will have a positive troponin level four to six hours after initial negative assays. The ACC/ESC Committee Consensus document states that "any amount of myocardial damage . . . implies an impaired clinical outcome for the patient" and there is "no discernable threshold below which an elevated value of cardiac troponin would be deemed harmless" ⁽⁷⁾. However, the ACC/AHA Guidelines indicate that the myocardial necrosis signified by troponin elevation may not necessarily be due to atherosclerotic coronary artery disease and that myocardial infarction should therefore be diagnosed in conjunction with other supportive evidence. The implementation of these new guidelines in clinical practice has led to a substantial increase in the frequency of myocardial infarction diagnosis.

Mortality at 30 days was significantly higher among patients with elevated troponin levels at presentation than among patients with no biomarkers detected, but it was not as high as among patients with elevated creatinine kinase/MB levels. In several studies of acute coronary syndromes, troponin elevation has likewise been associated with a worse prognosis. Furthermore, the risk of subsequent death appears to be related to the degree of troponin elevation. There are statistically significant increases in mortality with increasing levels of troponin and the relative risk for death is 7.8 in the group with the highest troponin level ⁽⁸⁾.

While the presence of thrombus and impaired epicardial blood flow are both associated with troponin elevations, impaired myocardial perfusion is a more robust and independent predictor of troponin elevation among patients with acute coronary syndrome. Among patients with a highest pretest probability or clinical suspicion of thrombotic coronary artery disease, the diagnostic and prognostic value of troponin is clear. However, troponin testing is now also being used as a screening tool among patients with low pre-test probability of thrombotic coronary artery disease. Given the high sensitivity of cardiac troponin for detecting even minimal myocardial cell necrosis, these markers may become "positive" even in the absence of thrombotic acute coronary syndrome. This may occasionally be related to a spurious troponin elevation (usually easily detectable by obtaining a second sample), but may also be due to several non-thrombotic cardiac and systemic diseases. In many instances, these troponin elevations may arise from ischemia, with or without significant coronary artery disease or microcirculatory dysfunction rather than supply-side thrombotic ischemia ⁽¹¹⁾.

Conclusion
Troponin is a highly sensitive biomarker that aides in the detection of myocardial cell damage. It is often, but by no means always, caused by thrombotic obstruction and impaired myocardial perfusion in the context of an acute coronary syndrome. This marker is frequently "positive" in other disease states in the absence of thrombotic acute coronary syndromes. Therefore, while troponin is a sensitive biomarker to "rule out" non-ST segment elevation myocardial infarction, it is less useful to "rule in" this event because it is not specific for acute coronary syndromes. As a result, if troponin testing is applied indiscriminately in broad populations that have a low pretest probability of thrombotic disease, the positive predictive value of the marker is greatly diminished. Although troponin elevation in a patient with suspected acute coronary syndrome may guide management decisions, such as the need for anti-thrombotic, anti-platelet, and interventional therapies, no data supports these therapies in the management of patients with a non-thrombotic syndrome.

FOR MORE INFORMATION CONTACT DR. SUSAN SHAPIRO AT 419-534-3505

Prepared by F. Michael Walsh, M.D., Consultants in Laboratory Medicine

Table. Nonthrombotic Causes and Presumed Mechanism for Elevated Cardiac Troponin Level ⁽¹¹⁾

Diagnosis	Mechanism
Demand ischemia
Sepsis/systemic inflammatory Resonse syndrome Hypotension Hypovolemia Supreaventricular tachycardia/atrial fibrillation Left ventricular hypertrophy	Myocardial depression/supply-demand mismatch Decreased perfusion pressure Decreased filling pressure/output Supply-demand mismatch Subendocardial ischemia
Myocardial ischemia
Coronary vasospasm Intracranial hemorrhage or stroke Ingestion of sympathomimetic agents	Prolonged ischemia with myonecrosis Imbalance of autonomic nervous system Direct adrenergic effects
Direct myocardial damage
Cardiac contusion Direct current cardioversion Cardiac infiltrative disorders Chemotherapy Myocarditis Pericarditis Cardiac transplantation	Traumatic Traumatic Myocyte Compression Cardiac toxicity Inflammatory Inflammatory Inflammatory/immune-mediated
Myocardial strain
Congestive heart failure Pulmonary embolism Pulmonary hypertention or Emphysema Strenuous exercise	Myocardial wall stretch Right ventricular stretch Right ventricular stretch Ventricular stretch
Chronic renal insufficiency	Unknown

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