Protein of Clinical Significance in Patients with Acute Coronary Syndromes?
L. OLTRONA, R. PIROLA
Clinicians have become increasingly sophisticated in their application of car- diac biomarkers in the management of acute coronary syndromes. In the 1950s, clinical investigators first reported that proteins released from necrot- ic cardiac myocytes could be detected in the serum and could aid in the diagnosis of acute myocardial infarction. The ensuing 40 years witnessed progressive improvement in the cardiac tissue-specificity of biomarkers of myocardial necrosis and a corresponding enhancement in the clinical sensi- tivity and specificity of their use for establishing the diagnosis of acute myocardial infarction.
In recent years, novel biochemical markers have been demonstrated to play a pivotal role in diagnosis, risk stratification, and guidance of treatment of acute coronary syndromes, complex clinical conditions with multiple causes: as such, treatment is likely to be most effective when directed at the underlying cause of the disease. Five principal causes of acute coronary syn- dromes have been described: (1) plaque rupture with acute thrombosis, (2) progressive mechanical obstruction, (3) inflammation, (4) secondary unsta- ble angina, and (5) dynamic obstruction (coronary vasoconstriction) [1]. It is rare that any of these contributors exists in isolation. However, patients with acute coronary syndromes may vary substantially with respect to the mixture of contributions from each of these major mechanisms and are like- ly to benefit from different therapeutic strategies [1]. Moreover, the risk of subsequent death and/or recurrent ischaemic events among patients with acute coronary syndromes also varies widely, depending on the presence or absence of irreversible myocyte injury, the haemodynamic consequences of ischaemia and/or infarction, and the extent and tempo of atherosclerotic
Dipartimento CardioVascolare De Gasperis, Niguarda Hospital, Milan, Italy
vascular disease. With the emergence of novel, sensitive biomarkers of inflammation, myocyte necrosis, vascular damage, and haemodynamic stress, it is becoming possible to characterise non-invasively the participa- tion of different contributors in any individual patient.
There is solid evidence from numerous studies that the unstable patient with elevated troponins has a nine-fold increased risk for myocardial infarc- tion or death in the next 30 days [2]. Consequently, the American College of Cardiology/American Heart Association guidelines [3] as well as the European Society of Cardiology Task Force Report [4] incorporated troponin measurements into their diagnostic algorithms for patients with acute coro- nary syndromes.
Over the past decade, the emergence of convincing evidence for the value of cardiac troponin in guiding therapy has dramatically accelerated the inte- gration of cardiac biomarkers into clinical decision making for patients with acute coronary syndromes. Concurrently, advances in our understanding of the pathogenesis and consequences of acute coronary atherothrombosis have stimulated the development of new biomarkers and created the oppor- tunity for an expanded role of multiple biomarkers, some old and others new, in the classification and individualisation of treatment for acute coro- nary syndromes [5–7]. For example, detection of cardiac troponin in the blood of patients with non-ST-elevation acute coronary syndromes is not only indicative of myocardial necrosis, but is also associated with the pres- ence of intracoronary thrombus and distal embolisation of platelet microag- gregates [8]. These pathobiological links to elevated levels of cardiac tro- ponin are likely to underlie, at least in part, the value of this biomarker in targeting potent antithrombin and antiplatelet therapy.
Inflammation has an essential role in the pathogenesis of atherosclerosis [9] and is also a consequence of myocardial damage. Elevated markers of inflammatory activity are associated with an increased risk of future cardio- vascular events in healthy individuals [10, 11] and in patients with stable [12] and unstable coronary artery disease [13–16]. High-sensitivity testing for C-reactive protein (CRP) has emerged as a convenient tool for detecting low-level systemic inflammation that portends a higher risk of developing atherothrombotic vascular disease [17] and poor short- and long-term prog- nosis in patients after acute coronary syndromes [14, 16]. Although the pre- cise mechanistic links between inflammation and risk in acute coronary syn- dromes are not conclusively established, it is plausible that elevated levels of circulating markers of inflammation reflect an intensification of focal inflammatory processes that destabilise vulnerable plaques [17]. Moreover, growing evidence implicates CRP as a mediator, in addition to a marker, of atherothrombosis [18].
However, many practical aspects of optimising the sampling protocols in
the emergency unit and combining troponin measurements with other markers in the clinical routine setting still need to be clarified. There is gen- eral consent that a single test for troponins on the arrival of the patient to the hospital is insufficient because a single test can miss 10–15% of at-risk patients. The timing of the second test has not yet been clearly defined. The European Society of Cardiology (ESC) recommends repeating troponin test- ing 6–12 h after arrival in the emergency unit [4]. The American version asks for a repeat test 8–12 h after the onset of pain – a minor, but sometimes decisive difference in perception in the work-up of the individual patient [3].
Previous studies before the era of troponins had suggested a 12-h rule-out strategy [19]. Troponins have helped to shorten and to improve the diagnos- tic work-up. A prospective study using troponin T and troponin I bedside tests proposed an interval of 6 h to identify high-risk patients [20].
The World Health Organization (WHO) has traditionally defined myocar- dial infarction as requiring the presence of at least two out of three diagnos- tic criteria, namely, an appropriate clinical presentation, typical changes in the electrocardiogram (ECG), and raised ‘cardiac’ enzymes, essentially total CK or its MB iso-enzyme (CK-MB) activities [21]. In 2000, the ESC and American College of Cardiology (ACC) committee published its consensus recommendations for a new definition of myocardial infarction [22]. In par- ticular, the ESC/ACC definition of acute myocardial infarction requires the rise and fall of the biochemical marker of myocardial necrosis together with other criteria, comprising ischaemic symptoms, the development of patho- logical Q waves, ischaemic ECG changes, or a coronary artery intervention [22]. Thus, according to the WHO definition, an acute myocardial infarction could be diagnosed without biochemical evidence of myocardial necrosis, while the ESC/ACC criteria stipulate that the biomarkers be elevated and subsequently be shown to fall in the appropriate clinical context. Quite simultaneously with the ESC/ACC re-definition of myocardial infarction, other expert committees published companion documents, according to which, in patients with no ST-segment elevation at ECG, but with ischaemic symptoms, a positive cardiac troponin result identifies those who have non- ST-segment elevation myocardial infarction (NSTEMI) and who could bene- fit from aggressive medical therapy [3, 4]. The new consensus documents have therefore based the new definition of myocardial infarction on bio- chemical grounds – a choice that was guided by the advent of new markers of myocardial necrosis, such as cardiac troponins [23–25]. The superior clin- ical value of troponin comes from its higher sensitivity to smaller myocar- dial injury and its virtually total specificity for cardiac damage [26]. Despite the ability to detect quantitatively smaller degrees of myocardial necrosis, cardiac troponins need 4–10 h after symptom onset to appear in serum, at about the same time as CKMB elevations become detectable, and peak at
12–48 h, then remaining abnormal for several days [27]. In applying the results of cardiac troponin testing to the defining of myocardial infarction, one should keep in mind that these markers actually reflect myocardial necrosis but do not indicate its mechanism. Thus, an elevated value in the absence of clinical evidence of ischaemia should prompt a search for other causes of cardiac damage. Many non-ischaemic pathophysiological condi- tions can cause myocardial necrosis and therefore elevations in cardiac tro- ponin concentrations Strictly speaking, even in the ‘troponin era’, the diag- nosis of myocardial infarction remains clinical. Measurement of cardiac tro- ponin provides a valuable diagnostic test for myocardial infarction only when used together with other clinical information. Ideally, three measure- ments of cardiac troponin are suggested, with a sampling frequency of hos- pital admission, 6 and 12 h later, to demonstrate changing values.
From the point of view of risk definition, too, troponin measurements can be used less than optimally [28–30]. The data are clear and have shown for many years that the predictive accuracy of troponin measurements requires more than one measurement [2, 24, 31]. Thus, markers that rise ear- lier than troponin might be more predictive than a solitary admission tro- ponin value, but not more predictive if an additional troponin value is included in the analysis. In some situations where immediate events are the outcomes of interest, such a strategy might be reasonable [7].
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