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Troponins and acute coronary syndrome

Megan Rensburg, MB ChB, MMed (Path), FC Path (Chem)

Consultant Chemical Pathologist, National Health Laboratory Service and Stellenbosch University, Tygerberg Hospital

Correspondence to: M Rensburg (rensburg@sun.ac.za)

Cardiac muscle injury is defined as the disruption of normal cardiac myocyte membrane integrity resulting in the loss of intracellular constituents such as troponin, creatine kinase, and myoglobin into the extracellular space. The mechanism of injury includes trauma, toxins and viral infections, but ischaemia or infarction – due to an imbalance between the supply and demand of oxygen – is the most common cause.1

Acute coronary syndrome (ACS) constitutes a large spectrum of clinical conditions, ranging from unstable angina pectoris to acute myocardial infarction (AMI).

Diagnosis of acute myocardial infarction

The diagnosis of AMI was traditionally made using the combination of chest pain, electrocardiographic (ECG) manifestations, and elevations in serum or plasma of cardiac biomarkers. The biomarkers tradionally requested are troponins and creatine kinase – MB fraction (CK-MB). Clinical symptoms such as chest pain are frequently atypical or absent, and ECG changes may be nonspecific or absent. This has resulted in the diagnosis of AMI becoming more dependent on the measurement of biomarkers.

Because of their greater sensitivity and specificity,1 cardiac troponins (cTn) are the biomarkers of choice for the evaluation and management of patients with ACS, and in the diagnosis of AMI. Guidelines set in 2007 by the National Academy of Clinical Biochemistry and the European Society of Cardiology/American College of Cardiology stated that ‘in the presence of a clinical history suggestive of ACS, the following is considered indicative of myocardial necrosis consistent with myocardial infarction: an elevation in cTn concentrations above the 99th percentile of a healthy population, accompanied by an assay imprecision of ≤ 10% …’.2 , 3 In addition, a rising and/or falling troponin pattern is an important component of the universal definition of AMI.3

Troponin biochemistry

Cardiac troponins consist of three proteins known as cTnC, cTnI and cTnT based on their function: C for calcium-binding, I for inhibition of actin-myosin interactions, and T for tropomyosin binding to facilitate contraction.2 , 3 cTn is released in the setting of irreversible damage to the myocyte and starts rising in blood 4 - 6 hours after cell death, peaks at approximately 18 - 24 hours and remains detectable for up to 14 days. This time frame is observed when using non-high-sensitivity cTn assays.1

‘Highly sensitive’ cTn

The ever-increasing sensitivity of cTn assays has led to the development of ‘highly sensitive’ cTn (hsTn) assays, capable of measuring cTn levels below the 99th percentile in a healthy population. Use of these hsTn assays makes it possible to detect low levels of cTn even in healthy subjects.4 A rise in cTn can be observed 2 - 3 hours after the onset of an AMI, leading to earlier diagnosis and therapeutic intervention.1 Serial changes documented by a second measurement will help to differentiate acute cardiac disorders (showing a rise and/or fall) from chronic cardiac disease, which will usually exhibit constant cTn levels.5 The improved sensitivity involves sacrificing reduced specificity, leading to additional diagnostic challenges for clinicians.6 With the increased use of hsTn assays and the application of the 99th percentile as the decision limit for AMI, a substantial increase in detection of patients with elevated cTn levels will be observed, and a high percentage of patients will be misclassified. It should be emphasised that AMI is not the only cause of myocyte necrosis, and therefore non-ischaemic causes of troponin elevation should be kept in mind.3 The high sensitivity of cTn, even in the presence of minimal cardiac myocyte necrosis, means that these markers may become ‘positive’ even in the absence of thrombotic ACS. Below is a list of causes of elevated cTn in the absence of ACS.

Causes of elevated cTn other than ACS1

• Cardiac causes

• cardiac contusion (trauma)

• cardiac surgery

• cardioversion

• endomyocardial biopsy

• acute and chronic heart failure

• aortic dissection

• aortic valve disease

• hypertrophic cardiomyopathy

• myocarditis

• endocarditis

• coronary vasospasm

• post-cardiac transplantation

• post-percutaneous coronary inter-vention

• tachyarrhythmia

• bradyarrythmia

• rhabdomyolysis with myocyte
necrosis.

• Non-cardiac causes

• critically ill patients

• pulmonary embolism

• severe pulmonary hypertension

• renal failure

• stroke

• subarachnoid haemorrhage

• cardiotoxic drugs, e.g. amiodarone

• sepsis

• extensive burns

• extreme exertion

• infiltrative disease, e.g. amyloidosis.

• False-positive

• heterophilic antibodies

• rheumatoid factors

• fibrin clots

• microparticles

• analyser malfunction.

Ongoing research is in the process of best defining algorithms on how to interpret data from hsTn assays in clinical practice. These include development of rule-out and rule-in algorithms as well as optimising the timing of the second measurement.5

Potential uses for hsTn

• Earlier diagnosis of patient with ACS, especially AMI.

• Risk stratification of patients with stable coronary artery disease; the higher the hsTn level, the higher the incidence of cardiovascular events.5

• Detection of non-ischaemic causes of elevated cTn.

Summary

• Correlate biochemical marker levels with the clinical scenario (e.g. chest pain, ECG).

• Observe cTn kinetics – a rise and/or fall in levels.

• Take note of the non-ischaemic causes of elevated cTn levels.

• hsTn can be a useful cardiac biomarker.

References

1. UpToDate. Troponins and creatine kinase as biomarkers of cardiac injury. http://www.uptodate.com.ez.sun.ac.za/contents/troponins-and-creatine-kinase-as-biomarkers-of-cardiac-injury (accessed 19 March 2012).

2. Mohammed AA, Januzzi JL. Clinical applications of highly sensitive troponin assays. Cardiology in Review 2010;18(1):12-19.

3. Tandini A, Cemri M. Troponin elevation in conditions other than acute coronary syndromes. Vascular Health and Risk Management 2011;7:597-603.

4. Mahajan VS, Jarolim P. How to interpret elevated cardiac troponin levels. Circulation 2011;124:2350-2354.

5. Twerenbold R, Reichlina T, Reiter M, Mueller C. High-sensitive cardiac troponin: friend or foe? Swiss Medical Weekly 2011;141:w13202.

6. Jeremias A, Gibbon CM. Narrative Review: Alternative causes for elevated cardiac troponin levels when Acute Coronary Syndromes are excluded. Ann Intern Med 2005;142(9):786-791.