Getting to the heart of myocardial infarction

Dina Packham explains how high sensitivity and precision in the detection of cardiac troponin T is used to detect or exclude myocardial infarction in the early stages

CARDIOVASCULAR disease is the leading cause of death worldwide – a high proportion of these deaths is due to heart disease, specifically coronary heart disease, of which myocardial infarction is a major manifestation.

Myocardial infarction (MI) or acute myocardial infarction (AMI) occur when the blood supply to part of the heart is interrupted or decreased (ischaemia), causing damage or death to cardiac myocytes (heart muscle cells). Symptoms of MI may include pain or discomfort to the chest, radiating to the left arm, neck and jaw. In addition there may be shortness of breath, nausea, vomiting palpitations or sweating. These symptoms are not specific and can be misdiagnosed. Furthermore, MI may also occur with atypical or no symptoms. Consequently, the detection of MI in the emergency room cannot rely on clinical symptoms alone.

Advances in scientific knowledge and technology led to the redefinition of AMI by worldwide experts from the European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA) and the World Heart Federation (WHF). Their redefinition and guidelines for the detection of AMI were published in an expert consensus document in 20071.

Among the criteria for the diagnosis of AMI, they recommend the detection of a rise and/or fall of cardiac biomarkers (preferably troponin), with at least one value above the 99th percentile of the upper reference limit (URL) for the normal reference population, together with evidence of myocardial ischaemia (at least one of the following):
•    symptoms of ischaemia
•    ECG changes indicative of new ischaemia
•    Development of pathological Q waves in the ECG
•    Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

Myocardial cell death is marked by the release of a number of different proteins into the blood, including myoglobin, the cardiac troponins T and I (cTn T and cTn I), creatine kinase (CK) and lactate dehydrogenase (LDH). These biomarkers can be measured easily using a variety of clinical assays.

The preferred biomarker for myocardial necrosis is cTn I or T, because of its specificity to myocardial tissue and its high sensitivity1. Even slight elevations of cTn may indicate some degree of damage to the heart. An increased value for cTn is defined as a measurement exceeding the 99th percentile of a normal reference population and detection of a rise and/or fall of cTn (in the clinical setting of acute myocardial ischaemia)1.

Elevations in cardiac biomarkers reflect myocardial necrosis but they do not reveal the aetiology. Consequently, raised cTn levels in the absence of clinical evidence of ischaemia requires investigation for other causes of myocardial injury, such as myocarditis, aortic dissection, pulmonary embolism, congestive heart failure or renal failure1.

The cardiac troponins can also be used as biomarkers in the diagnosis of a recurrent MI and in the diagnosis of MI following percutaneous coronary interventions (PCI) or coronary artery bypass grafting (CABG).  In the latter, an increase in cTn levels is an indicator of poor outcome1.

Blood samples for the measurement of cTn should be drawn during the initial assessment (often several hours after the onset of symptoms) and again six to nine hours later. An elevated cTn level in one of these samples (indicating a rise or fall in cTn levels) is required for the diagnosis of MI. This demonstration of a rise and/or fall in cTn is necessary to distinguish background elevated troponin levels (for example, due to chronic renal failure) from elevations caused by MI1. (It should be noted that this pattern is not an absolute requirement if the patient presents 24 hours or more after the onset of symptoms1.) Levels of cTn may remain elevated for 7-14 days after the onset of MI.

A number of commercial assays are available for the measurement of cTn in serum or plasma.  It is recommended that the optimal assay precision (coefficient of variation) at the 99th percentile URL should be < 10%.

Until recently, cTn assays lacked sensitivity at the time of presentation and did not have the required level of precision at lower concentrations above the 99th percentile. However, a highly sensitive cTn T assay is now available (the Elecsys TnT hs assay, Roche Diagnostics) that demonstrates excellent precision in the range of 0.003-10 ng/ml cTn T in serum or plasma and meets the required precision level of < 10% CV at the 99th percentile URL2.

Such sensitivity and precision is of enormous value in the assessment of patients presenting with cardiac symptoms – both in the early detection and in the early exclusion of AMI. The performance of this new assay is enhanced by its robustness against interfering factors; ensuring highly accurate results and consistency in patient follow up. Furthermore, with results in as little as nine minutes, it also delivers unprecedented speed and turnaround of results, which are essential for emergency samples.

In a recent study, the Elecsys hs TnT assay identified nearly 20% more patients with a final diagnosis of non-STEMI compared to a conventional cTn T assay and enabled an earlier diagnosis of non-STEMI2.  

Dr Richard Body, Emergency Medicine Specialist at Manchester Royal Infirmary, recently commented: “From my point of view as an emergency physician, high sensitivity cardiac troponin assays have great promise for the early exclusion of AMI. In our initial evaluation of the Elecsys hs TnT assay, it was possible to exclude AMI with 100% sensitivity using a cTn T ‘rule out’ cut-off of <3pg/ml. Our findings confirm those of Reichlin et al who compared several high sensitivity troponin assays3. In his study, the Elecsys assay was the only one to have 100% sensitivity at any cut-off, offering a great advantage for emergency physicians who want to rule out AMI as soon as possible after presentation.”

High sensitivity and precision in the detection of cTnT is also helpful in the risk stratification of patients presenting with acute coronary syndrome (particularly in the risk assessment of chronic renal failure patients), providing a valuable aid in the selection of patients who may require more intensive therapy and intervention.

Raised cTn levels have been associated with recurrent coronary ischaemic events and poor outcome. Even very small elevations in cTn have been associated with an increased risk of an adverse outcome in patients with acute coronary syndromes4.

In another recent study, very low levels of troponin T were detectable in the majority of patients with stable coronary artery disease. These levels, which were well below the limit of detection of previous assays, were strongly associated with the incidence of cardiovascular death and heart failure5.

The aim of the ESC/ACCF/AHA/WHF task force for the redefinition of myocardial infarction was to have “a substantial impact on the identification, prevention and treatment of cardiovascular disease throughout the world.” The advent of a new generation of high sensitive assays for cTn that allows the early diagnosis or exclusion of AMI and risk stratification of patients is a valuable diagnostic and prognostic tool for physicians in the assessment of patients presenting with cardiac symptoms and will undoubtedly contribute to the achievement of this goal.