Introduction

  
     Patients presenting to the emergency department with chest pain often represent a clinical dilemma as well as an economic problem. It has become an accepted practice, that all patients with symptoms suggestive of an acute coronary syndrome should be admitted to a coronary care unit. Less than 30% of patients admitted to rule out myocardial infarction (MI) ultimately have a diagnosis of MI.1 In patients presenting with chest pain to the emergency department, less than one third have an acute coronary syndrome, of which only 10% are diagnosed as acute MI and 20% unstable angina (UA).2 Thus, a large number of patients are admitted to intensive care units “unnecessarily”, putting strain to often limited space and resources. It is estimated that 4% to 5% of patients with evolving MI are sent home inappropriately.3,4

    Therefore, it is important to develop a strategy which could reliably separate patients at high risk of subsequent acute coronary event, and who need monitoring and aggressive treatment, from those with little or no risk, who could be treated in a conservative, “non-intensive” manner or discharged.

    New markers, such as cardiac isoforms of troponins (T and I) have been shown to be more specific and more sensitive indicators of myocardial damage. The purpose of this article is to review the diagnostic and prognostic utility of conventional and newer markers of cardiac injury in the evaluation of patients with acute chest pain syndromes.


Traditional Indicators of Myocardial Necrosis: Overview


    The electrocardiogram


   For decades, the clinical presentation and ECG findings on admission were the basis of risk stratification and decision-making.

   ST segment elevations or new left bundle branch block are highly reliable in the identification of patients with acute MI (~ 95% will develop infarction), and the management of these patients is now relatively well defined.

   The ECG provides a specific diagnosis in only ~40% of patients with acute MI and only ~5% of all patients presenting with chest pains to the emergency room.1

   In patients with chest pain at rest but no ST-segment elevation on the electrocardiogram (ECG), the diagnoses of unstable angina (UA) and non-Q-wave myocardial infarction (NQMI) are usually considered together because they cannot be distinguished clinically or angiographically. Testing for elevated levels of a serum cardiac marker makes distinction between these two conditions possible.

   However, it is possible to reasonably stratify the risk of these patients on the basis of clinical presentation and ECG findings, defining a group with <5% probability of a cardiac event.5 A classification system of unstable angina proposed by Braunwald6 and prospectively validated7,8 allows identification of patients into low, medium, and high-risk,9 with reasonable accuracy, but overlaps are unavoidable.

    One of the most important adverse prognostic indicators, both in UA and NQMI, is the presence of ST segment depression.10 ST depression has a greater impact on long-term prognosis than cardiac enzyme levels. High-risk patients, especially when presenting with ST depression, should be monitored and intensively treated. The approach to patients considered at low risk for a cardiac event is controversial, and can vary from discharge, admission to a step-down unit,11 or observation in a short-stay unit,12 to full CCU admission. Other innovations include early triage by myocardial scintigraphy,13 or echocardiography14 in the emergency department, or early stress test.15,16 These approaches have not been validated in large series of patients. They are also time-consuming and expensive.


Serum markers: creatine kinase, CK-MB


   For more than 2 decades, creatine kinase (CK) and its more cardiac specific isoenzymes (CK-MB) were the gold standard in confirming the diagnosis of acute MI, i.e., to distinguish between UA and NQMI.

   Creatine kinase is widely distributed throughout the body. As a result, elevations in total plasma CK levels lack specificity for cardiac damage. The MB fraction of CK (CK-MB) has high specificity for cardiac tissue, and its measurement increases specificity. Hence, CK-MB has been the preferred marker for many years.18 Both total CK and CK-MB begin to rise four to six hours after the onset of infarction, but they are not elevated in all patients until about 12 hours.19,20

   Definitive diagnosis of acute MI for all patients requires 12 hours, thus, acute MI cannot be excluded early by normal CK-MB levels.

   Consequently, if the possibility of MI is great enough, the patient has to be admitted to an intensive care unit for an evaluation to rule out the diagnosis.

   Most patients with acute MI have a typical rising and falling pattern of activity. Peak activity is seen at 18 to 24 hours with a return to baseline levels by 36 to 40 hours. However, a positive result is relatively specific, particularly in patients with ischemic symptoms, when skeletal muscle damage is not present.


Disadvantages of CK-MB


    False Positives


   Although the determination of CK-MB/CK ratio greatly improves diagnostic accuracy, false positive results can occur in a number of conditions. CK-MB can be released from skeletal muscle, resulting in elevation of serum CK-MB concentration with skeletal muscle injury. It may be difficult to detect possible MI when there is concurrent skeletal muscle damage. Myocardial injury can occur after cardiopulmonary resuscitation, cardioversion, defibrillation, cardiac and non-cardiac surgical procedures, and blunt chest trauma with possible cardiac contusion.

   False positive results may also occur in various clinical settings: myopathies, skeletal muscle injury, central nervous system damage, hypothyroidism, and renal failure.


   Delayed diagnosis and poor
   prognostic index


    A distinct disadvantage of CK-MB is the late diagnostic window. The typical rise and fall pattern takes about 10 - 30 hours, requiring serial determinations over a 24-hour period. This explains the low early diagnostic sensitivity on admission in patients with suspected MI, which is only about 50%.21

   Its prognostic power is limited as well. Patients with elevated CK-MB (NQMI), have a worse short- and long-term prognosis than UA with ST depression, but adverse outcomes are frequent in both groups, with large overlap.22 It has virtually no value in predicting cardiac events in low-risk subsets, i.e., in those without ST-T depressions and only mild or marginal rises of CKMB.


    Lack of discriminative value in
    coronary reperfusion


   Coronary reperfusion is associated with an increased rate as well as well as an increased amount of washout of CK and CK-MB relative to the amount depleted from the myocardium (release ratio).23 When enzyme is washed out early due to restoration of blood flow, the percentage of CK that is found in the plasma relative to that depleted from the heart, can be as high as twice what occurs under normal circumstances.24 The more rapid egress of CK into plasma with reperfusion results in higher and earlier peak values. A time to peak of less than four hours is good evidence of referfusion. Unfortunately, in 80% to 90% of cases, peak values occur between 4 and 16 hours, providing little or no discriminative value.

    The more rapid release and an increased release ratio of CK-MB prevents its use to compare infarct size between patients with reperfusion and those treated conventionally.


The Ideal Marker of Cardiac Necrosis


    The extent of myocardial necrosis is an important determinant of the risk of death.15,25 It is therefore desirable to identify a serum marker whose release bears a close relation to the degree of myocardial damage. Such a marker should be more sensitive than current markers, should be completely cardiac-specific, detectable early after the onset of necrosis, i.e., measurable in a time frame that permits treatment to minimize further necrosis, easy to measure (preferably at the bedside), and provide prognostic information.26,27

    CK and CK-MB do not fulfill all the above-mentioned requirements. The desire for improved specificity in the diagnosis of myocardial injury led to the search for more cardiac-specific markers of myocardial necrosis.

 

Table 1. Time Course of serum markers in acute MI

Troponins


    Specificity and diagnostic utility


    Troponin I (cTnI) and troponin T (cTnT) are regulatory proteins that control the calcium-mediated interaction of actin and myosin. The cardiac forms of these proteins are products of specific genes, and therefore, have the potential to be unique for the heart. They are not present in smooth muscle28 and in the blood of healthy individuals. A finding of cardiac troponin T and I is therefore highly specific for myocardial injury.29,30

   Studies on cardiac troponin I have failed to find any cTnI outside of the heart at any stage of neonatal development.29,31 In contrast, cardiac troponin T is expressed to a minor extent in skeletal muscle. Elevations have been found in some patients with renal impairment and hemodialysis,32 but this probably represents expressed fetal isoforms in skeletal muscle. However, the present cTnT assay does not detect these forms.33,34 Thus, its specificity should be comparable to that of cTnI.

    Both markers are released into the circulation about 4 - 6 hours after the onset of necrosis with a peak at 12 - 24 hours, a time course similar to that with CK-MB. They remain in the circulation up to 1 week.35 (Table 1)

   Quantitative tests for troponins require laboratory processing, but sensitive and rapid qualitative tests, which can be performed at the bedside, and which require only 20 - 30 minutes are now available.36,37 All these qualities place the troponins in a favorable position with regard to their diagnostic potential.

    For diagnostic use, detectability of troponin T has been considered abnormal. This has raised concerns about false positives, even though it improves the sensitivity of the test. False positive results are a particular problem in patients with end-stage renal disease on hemodialysis, 29% of whom have elevated cTnT levels without evidence of myocardial injury.38,39 In comparison to cTnT, the serum concentration of cTnI is not increased in patients with end-stage renal disease in the absence of myocardial damage.

   Increases in the troponins have also been observed in patients with a clinical picture suggestive of UA.40-45 Studies have shown that cTnT assay can identify minor myocardial cell damage in up to 30% of patients with UA whose CK-MB values remained within normal limits.40,41 Thus, the increased sensitivity of these assays enables clinicians to identify patients with biochemical necrosis, who do not meet the criteria for acute MI by conventional serum markers.

   For patients with NQMI, elevations in troponin levels may represent a previous infarct occurring in the days prior to admission that is now associated with recurrent chest pain in an unstable pattern. 42

   Troponin measurements are helpful in evaluating patients in which CK-MB may be elevated due to release from skeletal muscle, such as may occur following cardiopulmonary resuscitation or electrical cardioversion. For example, one study of 38 patients undergoing elective cardioversion using a median cumulative energy of 300 J found that only 3 patients had minimal elevations of cTnI (0.8 to 1.5 ug/L) suggestive of subtle myocardial injury.46 Therefore, substantial elevations of cTnI suggest the presence of myocardial injury from causes unrelated to direct current cardioversion.

   Troponins have been shown to improve the specificity of diagnosis in patients with possible perioperative infarction or myocardial contusion and in those who are critically ill.47- 49


    Prognostic value


   Of extreme importance is the recent finding that elevated serum plasma troponins carry potent prognostic information in patients with UA and both NQMI and Q-wave MI. Patients with elevated levels of either cTnT or cTnI have a much higher incidence of adverse cardiac events than those with negative findings.42,43,50-53 The prognostic information provided by these proteins appears to be independent of the classification of the patient’s presentation as UA or NQMI. In the large GUSTO IIA Troponin Substudy, which consisted of more than 800 patients with UA and nonspecific ECG changes, increased baseline levels of troponin T were highly predictive of cardiac events at 30 days. Troponin T level was more strongly correlated with 30 day’s survival than electrocardiographic criteria or CK-MB level.54

   The TRIM trial55 found that both markers provided equivalent independent prognostic information for cardiac death or myocardial infarction at 30 days.

   In a meta-analysis of patients with UA, both markers had comparable sensitivity (63%) and specificity (91%) for detecting myocardial infarction. When analyzed for prognosis, the risk ratio for MI or cardiac death was 4.2 for troponin I and 2.7 for troponin T.56

   Measurement of troponin T beyond the initial presentation at 8 - 16 hours has an added short-term prognostic value in the same group of patients. More patients had positive test later in the course of their hospitalization than on admission.57 A retrospective analysis of 1404 patients in the TIMI IIIB study found that high levels of troponin I were associated with a significantly higher mortality at 42 days and that mortality increased for each 0.1mcg/L rise in troponin, level.51

   Troponin I levels were an independent risk factor even when adjusting for baseline characteristics such as ST depression and age. Although predictive of short-term outcome, troponins also have long-term prognostic value, and determine a group of patients with high cardiac event rates at 5 - 12 months.52,58,59 Most of these studies were performed on relatively high-risk populations of patients. However, the prognostic power of troponins appears to be maintained in lower risk patients as well, where a positive test identifies patients with increased risk of future cardiac events and a high prevalence of coronary artery disease on angiography.60


    Use in the evaluation of chest pain in
    the emergency room


    Since troponins have proven prognostic value in unstable coronary syndromes, could they be used in the emergency department for early triage of patients? The challenge in this setting is not simply to rule out myocardial infarction, but rather to distinguish patients with acute unstable coronary lesions from those with either stable coronary disease (CAD), or no CAD. Can troponins be used to distinguish those who can be safely discharged and evaluated further on an outpatient basis?

    In a study of 773 consecutive patients with acute chest pain without ST segment elevations, Hamm et al61 found troponin T and I strong independent predictors of cardiac events. A negative troponin test result was associated with a low risk for cardiac events, 1.1% and 0.3% for cTnT and cTnI, respectively. Troponins T and I tests were performed on admission, and four or more hours later, so that one sample was taken at least 6 hours after the onset of pain. Although the authors concluded that patients who test negative could be safely discharged from the emergency department, they nevertheless urge greater caution in those with ST depression, despite negative troponin values. In this subgroup, short-term events were not completely negligible (2.8% or 1.4%), and one of the 20 deaths in their study occurred in a patient who had negative troponins T and I.

   In another study, a more heterogeneous population involving more than 1000 patients presenting to the emergency department with acute chest pain was studied, using cardiac troponin I.62 Although cTnI was an independent predictor of major cardiac events, the positive predictive valve was not high. More important, negative troponin I values obtained during the first 24 hours did not ensure a benign course. Six percent of all patients with negative troponin I test had a major cardiac complication. In patients without MI and negative test, complications occurred in 5%. In the 94 patients with cardiac complication, only 47% had abnormal troponin I value. They found that the admission ECG was the strongest predictor for a major cardiac complication. The authors do not support the routine use of cardiac troponin I for emergency department triage of patients with chest pain.

    Both studies demonstrated that troponins are an important addition for the evaluation of patients with chest pain in the emergency department, but should not be utilized as the sole criteria. Both indicate that ECG ischemia increases short-term risk appreciably, irrespective of negative troponin values. Serial measurements that include a point at least 6 hours after onset of symptoms are fundamental.

   Therefore, based on currently available data, troponins are of uncertain value in the evaluation of patients with chest pain presenting to the emergency room who have a non-diagnostic ECG.


    Aid To Clinical Decision-Making


    Current treatment of patients with unstable coronary syndromes consists of aspirin, B-blockers and intravenous heparin.63 Based on evidence from the VANQUISH study,64 an aggressive interventional approach is not recommended. Intervention is reserved only for patients with a high degree of clinical instability; otherwise it should be deferred after pre-discharge exercise testing is performed and inducible ischemia documented.

   There is some early evidence that elevated troponin levels in patients with unstable coronary syndromes could indicate complex lesion morphology.65 Should we, then, adopt a different therapeutic approach in these patients? Indeed, the FRISK trial66 showed that in patients who had a positive test for troponin T, administration of low molecular weight heparin significant reduced cardiac events when compared to placebo. This is the first trial, which provides a possibly useful alternative management strategy for this high-risk subgroup. On the other hand, another study with a thrombin inhibitor did not confer any advantage over heparin in the troponin positive group.67

   Recently, glycoprotein IIb/IIIa antagonists have been shown to be superior to heparin in the treatment of unstable coronary syndromes, both in the medical68-70 and coronary intervention group.71,72 However, no data are currently available on whether these agents may be more beneficial than standard or low-molecular-weight-heparin in troponin positive patients with acute coronary syndromes. Similarly, there are no data whether a more invasive approach with early angiography and intervention should be adopted in these patients. This question will be tackled in an ongoing large FRISC II study, but until its results are published, the above mentioned conservative strategy should be recommended.


CONCLUSION


Troponins are a highly valuable addition in the diagnosis and evaluation of patients with acute coronary syndromes - both in the emergency department and in the hospital. They improve our diagnostic accuracy with unprecedented sensitivity and specificity. Both tests provide improved specificity when compared to the other marker proteins for acute MI that are currently in use. However, considerable controversy exists as to which troponin will become the marker of choice in the future.

In addition, troponins are powerful, independent prognostic indicators, which enable more precise risk stratification of patients and thus, their use greatly facilitates the decision-making process.
When utilized judiciously, they may be cost-effective, and ease the strain on our resources by assigning low risk patients to less expensive diagnostic and treatment methods, without affecting mortality and morbidity. High-risk patients might have improved outcomes from more aggressive therapy – either medical or interventional. Although definitive strategies are as yet to be established, they will certainly contribute largely in the development of appropriate, high quality, and cost-effective therapy.



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