Diagnosis of Acute Coronary Syndromes

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Previously considered to be separate disease entities, the acute coronary syndromes (ACS) are somewhat arbitrarily divided on the basis of their electrocardiographic manifestations and are now thought to arise from a common disease process. Based on a number of factors, the severity of the ACS and, consequently, their attendant clinical risk may vary. The management of patients with ACS should vary accordingly.

Early Evaluation of the Patient with Suspected ACS

Any patient presenting with chest pain should undergo a rapid clinical assessment using the clinical history, physical examination, and a 12-lead electrocardiogram (ECG) to guide subsequent management. This process should be complete within 10 minutes of presentation, such that the managing clinician should be able to determine if the patient is presenting with an overall picture of cardiac or non-cardiac chest pain. Factors suggestive of non-cardiac chest pain include atypical symptoms, unusual locations of the chest discomfort, variable reproducibility with exertion, reproducibility with palpation of the chest wall, and relief with therapeutic interventions that improve gastroesophageal pain. Unfortunately, a significant percentage of patients with chest pain have a variable mixture of typical and atypical symptoms; as such, it is necessary to depend on diagnostic testing to help to adequately distinguish between patients with cardiac discomfort and those with non-cardiac pain. Among the diagnostic tools available to the clinician for such a situation are ECG and cardiac biomarkers.

The ECG is time-tested, portable, highly specific for diagnosis of coronary ischaemia, and powerfully prognostic for patients with ACS.1,2 Unfortunately, limitations of ECG include variable sensitivity - the study is dependent on the presence of coronary ischaemia at the time of performance and operator skill in correct interpretation - and may be negative in settings of coronary ischaemia involving the high lateral wall of the left ventricle (i.e. circumflex territory ischaemia). Thus, the ECG has poor negative predictive value in excluding the presence of coronary ischaemia.

Cardiac biomarkers have become a mainstay for the diagnostic and prognostic evaluation of patients with chest pain. Among the currently accepted markers for this indication are the necrosis markers, myoglobin, creatine kinase isoenzymes, and the troponins. At present, each of these assays is widely available for the rapid evaluation of the patient with suspected ACS.

Myoglobin is an oxygen-carrying haem protein found in the cytosol of myocytes, and, as a function of this 'shallow' storage pool, is detectable very rapidly in the setting of muscle cell injury. Indeed, detectable values for myoglobin may be seen within an hour of onset of myocardial necrosis, prior to the detection of other necrosis markers. Also, myoglobin has been shown to be an independent predictor of adverse outcomes in subjects with ACS.3 However, the lack of specificity for cardiac injury has limited the universal adoption of myoglobin for evaluation of chest pain patients.

Other markers of cardiac necrosis currently in use include the MB isoenzyme of creatine kinase, as well as the troponins (I and T). Both classes of markers are structural proteins found within the contractile apparatus of the sarcomere, although a small pool of cytosolic troponin is also present within the cardiomyocyte. Creatine kinase MB was the time-honoured marker of choice for detection of myocardial necrosis, and levels of creatine kinase MB are related to the risk of mortality in chest pain patients;4 however, the lack of cardiac specificity of creatine kinase MB - together with the superior sensitivity of the troponins of both diagnosis and prognostication in patients with chest pain - has led to the adoption of the troponins as the biochemical 'gold standard' for detection of myocardial necrosis.5

In addition to the data demonstrating the primacy of the troponins not only for detection of cardiac injury consequent to coronary ischaemia, but also for estimating prognosis for adverse outcomes in this setting, it is now recognised and accepted that elevated serum troponin values in patients with non-serotonin-segment elevation (NSTE) ACS may also reflect the presence of intracoronary thrombus, as well as the severity of microvascular occlusions 'downstream' to a platelet-rich intracoronary thrombus.6,7 As agents with potent effects on this pathologic process are now available, troponin levels may also be utilised to assist in therapeutic decision-making. Other, more novel biomarkers useful for the evaluation, triage, and therapeutic decision-making for patients with chest pain include ischaemia-modified albumin (IMA) and the natriuretic peptides.

In the presence of tissue ischaemia, circulating albumin undergoes a conformational change that renders it unable to bind transition metals. This ischaemia-rendered change yields a compound known as IMA, which is rapidly detectable following the onset of coronary ischaemia and, importantly, is elevated in states of coronary ischaemia not only with, but also without, cardiac injury.8,9

The currently accepted strength of IMA lies in its negative predictive value of excluding the presence of ischaemia; accordingly, IMA may be useful for rapid triage of a chest pain patient to a lower likelihood pathway for management of non-coronary chest discomfort. A large multicenter trial examining the value of IMA for chest pain evaluation is about to be launched.

The natriuretic peptides, including b-type natriuretic peptide (BNP) and its amino-terminal cleavage pro-fragment (NT-pro-BNP), are markers of myocardial wall stress and have been adopted as markers for heart failure due to their exquisite relationship to this process. However, both BNP and NT-pro-BNP are released in the setting of ACS, as coronary ischaemia itself is a situation directly leading to the presence and severity of myocardial wall stress in the absence of overt heart failure. As has been demonstrated in a wide variety of ACS - ranging from NSTE ACS to ST-elevation myocardial infarction (STEMI) - both BNP and NT-pro-BNP potently predict the risk for death from ACS, and both markers appear superior to the troponins in stratifying risk for death from ACS, although the troponins appear superior in identifying risk of reinfarction.10,11 Among patients with elevations of both troponin and natriuretic peptides, it has therefore been suggested that more aggressive management strategies (such as more routine use of revascularization techniques) might be accompanied by more favourable outcomes for such highest risk patients.12

Following a rapid, thorough evaluation of the patient with chest pain, the clinician should be able to decide whether a patient has cardiac or non-cardiac chest pain. For those with suspected or proven ACS, the physician should then consider the class of ACS - NSTE ACS or STEMI - with therapeutic efforts based on the correct diagnosis and level of risk. 


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