eMedicine Specialties > Emergency Medicine > Cardiovascular

Use of Cardiac Markers in the Emergency Department

Author: Donald Schreiber, MD, CM, Associate Professor of Surgery (Emergency Medicine), Stanford University School of Medicine
Coauthor(s): Suzanne M Miller, MD, Clinical Instructor, Emergency Medicine, George Washington University School of Medicine and Health Sciences; Attending Physician, Department of Emergency Medicine, INOVA Fairfax Hospital; Chief Executive Officer, MDadmit
Contributor Information and Disclosures

Updated: Jul 8, 2009

Introduction

The role of cardiac markers in the diagnosis, risk stratification, and treatment of patients with chest pain and suspected acute coronary syndrome (ACS) has continued to evolve. The clinical evaluation of patients with possible acute coronary syndrome is often limited by atypical symptoms. In most patients, the initial electrocardiogram (ECG) is nondiagnostic. Despite increased vigilance on the part of emergency physicians and high admission rates to exclude acute myocardial infarction (AMI), the rate of missed myocardial infarction (MI) continues to hover at 1.5-2%.

A recent consensus guideline from the American College of Cardiology (ACC) and the European Society of Cardiology (ESC) has redefined acute myocardial infarction. Cardiac markers and cardiac troponin, in particular, are central to the new definition of acute myocardial infarction.

According to these guidelines, the diagnosis of acute myocardial infarction is now based on any one of the following criteria:1,2

  • A rise, fall, or both of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischemia with at least one of the following1 :
    • Ischemic symptoms
    • New pathologic Q waves on ECG
    • Ischemic ECG changes (new ST-T changes or new left bundle-branch block)
    • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
  • For percutaneous coronary interventions in patients with normal baseline troponin levels, elevations of these cardiac biomarkers greater than 3 times the 99th percentile upper reference limit.
  • Sudden, unexpected cardiac death involving cardiac arrest with suspected associated ischemic symptoms, and accompanied by presumably new ST-segment elevation or new left bundle-branch block and/or evidence of fresh thrombus at coronary angiography and/or at autopsy
  • Pathological changes of acute myocardial infarction

This is a significant change from the original World Health Organization classification of AMI. Patients with elevated troponin levels but negative creatine kinase-MB (CK-MB) who were formerly diagnosed with unstable angina or minor myocardial injury are now reclassified as non–ST-segment elevation MI (NSTEMI) even in the absence of diagnostic ECG changes. The adoption of this new standard for the definition of myocardial infarction has important implications for the utilization of cardiac biomarkers in the emergency department evaluation of patients with possible acute coronary syndrome. Studies on the pathophysiology of unstable angina and AMI have established a common pathway that is initiated by acute plaque rupture. A series of thrombotic events ensues, which results in thrombus formation. The subsequent clinical events of infarction or ischemia depend on the degree of occlusion and the presence, if any, of collateral blood flow.

Based on the pathophysiological evidence, the term acute coronary syndrome (ACS) is now used to represent the entire clinical spectrum from new-onset angina to acute myocardial infarction with ST-segment elevation (STEMI). The clinical approach now focuses on risk stratification, and cardiac markers assume a central role in the diagnostic algorithm.

Current Cardiac Markers in Acute Coronary Syndrome

Cardiac troponins

The troponins are regulatory proteins found in skeletal and cardiac muscle. The 3 subunits that have been identified include troponin I (TnI), troponin T (TnT), and troponin C (TnC). The genes that code for the skeletal and cardiac isoforms of troponin C (TnC) are identical; thus, no structural difference exists between them. However, the skeletal and cardiac subforms for troponin I (TnI) and troponin T (TnT) are distinct, and immunoassays have been designed to differentiate between them. This explains the unique cardiospecificity of the cardiac troponins. Skeletal TnI and TnT are structurally different. No cross-reactivity occurs between skeletal and cardiac TnI and TnT with the current assays.

Early studies on the release kinetics of the cardiac troponins indicate that they were not early markers of myocardial necrosis. The early generation troponin assays yielded positive results within 4-8 hours after symptom onset, similar in timing to the release of CK-MB; however, they remain elevated for as long as 7-10 days post-MI.

Initial studies on the cardiac troponins revealed a subset of patients with rest unstable angina in whom CK-MB levels were normal but who had elevated troponin levels. These patients had higher adverse cardiac event rates (death, acute myocardial infarction [AMI]) in the 30 days after the index admission and a natural history that closely resembled patients with NSTEMI. The table in Media file 1 outlines many of the initial studies on troponins in acute coronary syndrome.


Use of cardiac markers in the ED. Studies on trop...

Use of cardiac markers in the ED. Studies on troponins in acute coronary syndrome.

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Use of cardiac markers in the ED. Studies on trop...

Use of cardiac markers in the ED. Studies on troponins in acute coronary syndrome.

An elevated troponin level also enabled risk stratification of patients with acute coronary syndrome and identified patients at high risk of adverse cardiac events (ie, death, MI) up to 6 months after the index event.3,4

Antman evaluated troponin I (TnI) in patients with ACS in the TIMI IIIB trial.3 Patients without ST-segment elevation were considered for thrombolytic therapy. The study revealed that the initial TnI level on admission correlated with mortality at 6 weeks. CK-MB levels, although sensitive and specific for the diagnosis of AMI, were not predictive of adverse cardiac events and had no prognostic value.

Data from a meta-analysis indicate that an elevated troponin level in patients without ST-segment elevation is associated with a nearly 4-fold increase in the cardiac mortality rate. For the composite end point of death or AMI, an elevated troponin was associated with an odds ratio of 3.3 (95% confidence interval [CI], 2.4-4.5).5

Other studies by Ohman et al (1996) and Stubbs et al revealed that an elevated troponin level at baseline was an independent predictor of mortality even in patients with chest pain and acute myocardial infarction (AMI) with ST-segment elevation who were eligible for reperfusion therapy.6,7

The troponin level also has prognostic value. The TIMI IIIB, GUSTO IIa, GUSTO IV ACS, and Fragmin During Instability in Coronary Artery Disease (FRISC) trial all demonstrated a direct correlation between the level of TnI or TnT and the mortality rate and adverse cardiac event rate in acute coronary syndrome.3,8,9,10,6 These studies have confirmed the use of the cardiac troponins TnI and TnT in risk stratification and therapeutic decision making.

The cardiac troponins are sensitive, cardiospecific, and provide prognostic information for patients with acute coronary syndrome. They have become the cardiac markers of choice for patients with acute coronary syndrome.

With the introduction of increasingly sensitive and precise troponin assays, up to 80% of patients with acute myocardial infarction (AMI) will have an elevated troponin within 2-3 hours of emergency department arrival. Before these improvements in the troponin assays, it usually took between 6 and 9 hours to rule patients out and often later than with CK-MB. However, with this improved clinical performance in the newest cardiac troponin assays, the so-called rapidly rising cardiac biomarkers such as myoglobin or CK-MB isoforms have little clinical utility.11,12,13,14

As a result, some authorities have called for a troponin standard alone and recommend eliminating CK-MB. The authors are aware of institutions that have discontinued the use of CK-MB in favor of measuring troponin alone.15

The latest 2007 American College of Cardiology (ACC) guidelines for NSTEMI recommend serial troponins be obtained for a definitive rule out at baseline and 6-9 hours later. To establish the diagnosis of acute myocardial infarction, only one elevated level above the established cutoff is required. The demonstration of a rising or falling level is needed to distinguish persistently elevated troponin levels (eg, in some patients with renal failure) from those patients with acute myocardial infarction.

Creatine kinase-MB isoenzymes

Prior to the introduction of cardiac troponins, the biochemical marker of choice for the diagnosis of acute myocardial infarction (AMI) was the CK-MB isoenzyme. The criterion most commonly used for the diagnosis of AMI was 2 serial elevations above the diagnostic cutoff level or a single result more than twice the upper limit of normal. Although CK-MB is more concentrated in the myocardium (approximately 15% of the total CK), it also exists in skeletal muscle. The cardiospecificity of CK-MB is not 100%. False-positive elevations occur in a number of clinical settings, including trauma, heavy exertion, and myopathy.

Familiarity with the release kinetics of CK-MB is also important for the clinician. CK-MB first appears 4-6 hours after symptom onset, peaks at 24 hours, and returns to normal in 48-72 hours. Its value in the early and late (>72 h) diagnosis of AMI is limited. However, its release kinetics can assist in diagnosing reinfarction if levels rise after initially declining in the time period after AMI.

The Thrombolysis in Myocardial Infarction (TIMI) IIIB trial showed that CK-MB levels, although sensitive and specific for the diagnosis of AMI, were not predictive of adverse cardiac events and had no prognostic value.

In the CRUSADE registry, a review of almost 30,000 patients revealed that discordant troponin and CK-MB results occurred in 28% of patients. However, patients who were troponin negative (Tn-) but CK-MB positive (CKMB+) had in-hospital mortalities (3%) that were not significantly increased from patients who were negative for both biomarkers (2.7%, odds ratio [OR] 1.02; 95% CI, 0.75-1.38).16  Similar findings have been noted in other studies.

In a report of more than 10,000 patients with acute coronary syndrome (ACS) from the multicenter GRACE registry, 1110 (10.4%) were Tn-positive/CK-MB-negative and 822 (7.7%) were Tn-negative/CK-MB-positive (false positives).17 In-hospital mortality was highest when both Tn and CK-MB were positive (7.7%), intermediate in Tn-positive/CK-MB-negative patients (3.9%), and lowest in patients in whom both markers were negative and those who were Tn-negative/CK-MB-positive (1.7% and 2.3%, respectively). Thus, an isolated CK-MB elevation has limited prognostic value in patients with a non-ST elevation ACS.

Relative index, CK-MB, and total CK

The relative index calculated by the ratio of CK-MB (mass)/total CK X 100 can assist the clinician in differentiating false-positive elevations of CK-MB arising from skeletal muscle. A ratio less than 3 is consistent with a skeletal muscle source. Ratios greater than 5 are indicative of a cardiac source. Ratios between 3 and 5 represent a gray zone. No definitive diagnosis can be established without serial determinations to detect a rise.

The CK-MB/CK relative index was introduced to improve the specificity of CK-MB elevation for myocardial infarction. However, sensitivity for acute myocardial infarction falls when concurrent cardiac injury and skeletal muscle injury is present. In an ED-based study to evaluate the CK-MB relative index compared to the absolute CK-MB, specificity was increased (96% vs 93%) but with a loss of sensitivity (52% to 47%).18 The utilization of the CK-MB/CK relative index works if patients have only myocardial infarction or only skeletal muscle injury but not both. Therefore, in the combined setting of acute myocardial infarction (AMI) and skeletal muscle injury (rhabdomyolysis, heavy exercise, polymyositis), the fall in sensitivity is significant.

The diagnosis of AMI must not be based on an elevated relative index alone. The relative index may be elevated in clinical settings when either the total CK or the CK-MB is within normal limits. The relative index is only clinically useful when both the total CK and the CK-MB levels are increased.

Myoglobin

Myoglobin has attracted considerable interest as an early marker of myocardial infarction (MI). It is a heme protein found in skeletal and cardiac muscle. Its low molecular weight accounts for its early release profile. Myoglobin typically rises 2-4 hours after onset of infarction, peaks at 6-12 hours, and returns to normal within 24-36 hours.

Rapid myoglobin assays are available, but, overall, they suffer from lack of cardiospecificity. Serial sampling every 1-2 hours can increase the sensitivity and specificity. A rise or delta of 25-40% over 1-2 hours is strongly suggestive of acute myocardial infarction (AMI). In most studies, myoglobin only achieved a 90% sensitivity for AMI. The negative predictive value of myoglobin is not high enough to exclude the diagnosis of AMI. The original studies that evaluated myoglobin used the original World Health Organization (WHO) definition of AMI that was based on a CK-MB standard. With the adoption of a troponin standard for AMI in the new European Society of Cardiology (ESC)/American College of Cardiology (ACC) definition, the sensitivity of myoglobin for AMI is substantially reduced. This significantly diminishes its utility and a number of studies have convincingly shown that the use of contemporary cardiac troponin assays render the use of myoglobin measurements unnecessary.14,12

Creatine kinase-MB isoforms

The CK-MB isoenzyme exists as 2 isoforms: CK-MB1 and CK-MB2. Laboratory determination of CK-MB actually represents the simple sum of the isoforms CK-MB1 and CK-MB2. CK-MB2 is the tissue form and initially is released from the myocardium after MI. It is converted peripherally in serum to the CK-MB1 isoform. This occurs rapidly after symptom onset.

The CK-MB isoforms may be analyzed using high-voltage electrophoresis. Automated analyzers with rapid turnaround times are available. The ratio of CK-MB2/CK-MB1 is calculated. Normally, the tissue CK-MB1 isoform predominates; thus, the ratio characteristically is less than 1. A result is positive if CK-MB2 is elevated and the ratio is more than 1.7.

The release kinetics of the CK-MB isoforms are rapid. CK-MB2 is detected in serum within 2-4 hours after onset and peaks at 6-9 hours. It is an early marker for AMI. Two large studies evaluating its use revealed a sensitivity of 92% at 6 hours after symptom onset compared with 66% for CK-MB and 79% for myoglobin.19,20  The major disadvantage of this assay is that it is relatively labor intensive for the laboratory.

What Is the Best Marker Strategy?

Understanding the release kinetics of each of the cardiac markers underscores the importance of the time from symptom onset. Given the recent ACC/ESC guidelines for the diagnosis of AMI, cardiac troponins are clearly the best marker.

Furthermore, the introduction of newer cardiac troponin assays with increased sensitivity and lower cutoff levels have rendered traditional early markers such as myoglobin and CK-MB isoforms unnecessary.15,12,14  

The American College of Emergency Physicians (ACEP) advocates 3 level B Recommendations for the best cardiac marker strategy to rule out NSTEMI in the ED.21

  • A single negative CK-MB, troponin I, or troponin T measured 8-12 hours after symptom onset
  • A negative myoglobin in conjunction with a negative CK-MB mass or negative troponin I measured at baseline and at 90 minutes in patients presenting less than 8 hours after symptom onset
  • A negative 2-hour delta CK-MB in conjunction with a negative 2-hour delta troponin I in patients presenting less than 8 hours after symptom onset

Unfortunately, the ACEP does not specifically recommend either the 99th percentile, the 10% coefficient of variation (CV) or the WHO AMI cutoffs for definitive rule out. The 90-minute rule-out utilizing myoglobin recommended by the ACEP was based on a study that used myoglobin in conjunction with either CK-MB or TnI.22 The CK-MB/myoglobin protocol yielded a sensitivity of only 92% at 90 minutes. The myoglobin/TnI combination yielded a sensitivity of only 97% at 90 minutes. The ACEP authors cited problems with the relative lack of specificity for myoglobin and the fact that many of the studies were not based on the most recent guidelines for the diagnosis of myocardial infraction adopted by the ACC/ESC. It is difficult to comprehend the ACEP clinical policy that accepts a missed MI rate of 3%-8%.

The ACEP’s recommendation on the utility of delta CK-MB and delta troponin I are based on determining the change (the delta) in the level of troponin I or CK-MB on samples drawn 2 hours apart. A delta troponin I evaluation as recommended by Fesmire et al is partially based on their scientific work using older second-generation troponin I assays and outdated WHO AMI cutoffs in a retrospective study. The ACEP’s recommendations for delta troponin I, therefore, appears to be based on very limited data using only one commercial assay and on other small studies with significant methodological limitations. Overall, the ACEP’s recommendation to use a delta troponin I in conjunction with a delta CK-MB may not be generalizable to other commercially available troponin assays. Caution must be used when using the ACEP’s recommendations in ED patients with chest pain and suspected acute coronary syndrome (ACS).

One of the medicolegal pitfalls for the clinician is to mistakenly rule out NSTEMI on the basis of a single negative determination of troponin in the early 3- to 6-hour time frame after symptom onset. The troponins are recommended for evaluation of patients who present more than 24 hours after symptom onset. Lactic dehydrogenase (LDH) isoenzymes no longer are recommended and should be abandoned.

Cardiac markers are not necessary for the diagnosis of patients who present with ischemic chest pain and diagnostic ECGs with ST-segment elevation. These patients may be candidates for thrombolytic therapy or primary angioplasty. Treatment should not be delayed to wait for cardiac marker results, especially since the sensitivity is low in the first 6 hours after symptom onset. The 2007 Focused Update of the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend immediate reperfusion therapy for qualifying patients with STEMI without waiting for cardiac marker results.23

In other patients with definite or possible acute coronary syndrome (ACS), serial evaluation of the cardiac markers is essential to diagnose acute myocardial infarction (AMI). The following table outlines the recommended sampling frequency after ED admission for the various cardiac markers.

Table 1. Cardiac Markers - Sampling Frequency

Open table in new window

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Table
 Baseline3-4 h6-9 h12-24 h>24 h
CK-MB isoforms, myoglobinxxx  
CK-MB, TnI, TnTxxxX only if very high risk 
Late presenters
(TnI, TnT)		    x
 Baseline3-4 h6-9 h12-24 h>24 h
CK-MB isoforms, myoglobinxxx  
CK-MB, TnI, TnTxxxX only if very high risk 
Late presenters
(TnI, TnT)		    x

The sample time at 3-4 hours is useful in the ED or chest pain observation unit where rapid triage and early diagnosis are essential. In other patients admitted for ACS, biomarkers drawn at the 3- to 4-hour time interval are not as important as the 6- to 9-hour sample. The recent ACC/AHA guidelines for the treatment of patients with unstable angina and NSTEMI recommend a baseline sample upon ED arrival and a repeat sample 6-9 hours after presentation. Few studies on the "time to positivity" have been performed, but serial samples that become positive in the 12- to 24-hour time window are unlikely unless the patient has ongoing symptoms of ischemia after admission. AMI can be essentially ruled out in patients with negative serial marker results through the 6- to 9-hour period after presentation. This latter recommendation from the ACC/AHA guidelines represents a significant change in the standard of care for ruling out AMI.

The Role of Cardiac Markers in Therapeutic Decisions for Acute Coronary Syndrome

Although cardiac markers are crucial from a diagnostic and prognostic viewpoint, clinical investigations have begun to show their use as an indicator for specific therapeutic interventions in acute coronary syndrome (ACS). Current therapeutic strategies in ACS have been restricted primarily to clinical indications (eg, ischemic chest pain) or ECG changes (eg, ST-segment elevation or depression). Currently, no validated therapeutic algorithms are based on an isolated positive marker result in the absence of other clinical or ECG findings.

Subgroup analysis of the low molecular weight heparin (LMWH) trials (Efficacy and Safety of Subcutaneous Enoxaparin in Non Q-wave Coronary Events [ESSENCE], FRISC) has demonstrated a decreased cardiac event rate in patients with a positive result for troponin T (TnT) and who were treated with an LMWH.24,25

In the Platelet Receptor Inhibition for Ischemic Syndrome (PRISM) trial, patients with an elevated troponin I (TnI) who were treated with tirofiban (a glycoprotein GIIB/IIIA inhibitor that markedly reduces platelet aggregation) demonstrated a significant decrease in cardiac events compared with patients without an elevated TnI level. No significant difference in outcomes was found for patients without TnI elevations who were treated with tirofiban when compared with placebo (see Media file 3).26


Use of cardiac markers in the ED. Cardiac event r...

Use of cardiac markers in the ED. Cardiac event rates in the platelet receptor inhibition for ischemic syndrome (PRISM) study based on troponin I results.

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Use of cardiac markers in the ED. Cardiac event r...

Use of cardiac markers in the ED. Cardiac event rates in the platelet receptor inhibition for ischemic syndrome (PRISM) study based on troponin I results.

Bhatt and Topol showed that patients who were treated with the GIIB/IIIA inhibitor eptifibatide within 6 hours of symptom onset obtained the greatest benefit. In Bhatt and Topol's subgroup analysis of the PURSUIT trial, patients with an elevated troponin level also had better responses to therapy than those whose troponin result was negative (see Media file 4).27

Use of cardiac markers in the ED. Effect of time ...

Use of cardiac markers in the ED. Effect of time to treatment in patients with acute coronary syndrome (ACS) who are treated with the GIIb/IIIa inhibitor eptifibatide.

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Use of cardiac markers in the ED. Effect of time ...

Use of cardiac markers in the ED. Effect of time to treatment in patients with acute coronary syndrome (ACS) who are treated with the GIIb/IIIa inhibitor eptifibatide.

The recent Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18 (TACTICS-TIMI 18) trial assessed the benefit of an early invasive treatment strategy versus a conservative treatment strategy for patients with unstable angina (UA) and NSTEMI. All patients received aspirin, heparin, and the GIIb/IIIa inhibitor tirofiban. Patients in the early invasive arm were catheterized and revascularized within 4-48 hours. Patients with elevations in TnI or TnT had a statistically significant reduction in death, MI, or rehospitalization for ACS in 6 months with early invasive therapy. Patients without elevated troponin levels had no detectable benefit from invasive therapy versus conservative management.28,29

In a subset analysis of the TACTICS-TIMI 18 data, Kleiman and colleagues demonstrated that an elevation of CK-MB did not benefit the early invasive group when compared with the conservative management group. However, early invasive therapy did benefit the subgroup of patients with elevated troponin levels but normal CK-MB levels.30

These studies confirm that a positive troponin result alone is an independent predictor of high risk. Therapy with LMWHs and/or GIIB/IIIA inhibitors appears to confer the most benefit on those patients with elevated cardiac troponins levels who are at high risk.

Laboratory Medicine and the Troponins

Technological advances have dramatically altered the clinical laboratory assays for the cardiac troponins. With the introduction of third-generation assays, the cutoff detection limit for troponin T (TnT) has fallen 100-fold from 1 ng/mL to 0.01 ng/mL. Cross-reactivity with skeletal muscle has been eliminated in the current generation of troponin T assays. The clinician has benefited greatly from the introduction of rapid point-of-care (POC) devices, whole-blood analyzers, and faster laboratory turnaround times.

Point of care assays

National Academy of Clinical Biochemistry (NACB) recommendations specify that cardiac markers be available on an immediate basis 24 hours per day, 7 days per week, with a turnaround time of 1 hour.31 Point-of-care (POC) devices that provide rapid results should be considered in hospitals whose laboratories cannot meet these guidelines.

POC assays for CK-MB, myoglobin, and the cardiac troponins TnI and TnT are available. Only qualitative TnT assays are available as POC tests, but both quantitative and qualitative POC TnI assays are currently marketed. In a recent multicenter trial, the creatine kinase-MB, myoglobin, and troponin I (CHECKMATE) study, the time to positivity was significantly faster for the POC device than for the local laboratory (2.5 h vs 3.4 h).32 In another multicenter study that evaluated the iStat POC TnI assay in comparison to the central laboratory in 2000 ED patients with suspected ACS, POC testing reduced the length of stay by approximately 25 minutes for patients who were discharged from the ED.33,34 The sensitivity of current POC assays coupled with the benefit of rapid turnaround time make the POC assays attractive clinical tools in the ED.

Troponin cutoff levels

In order to utilize the current recommendation regarding cutoffs, the emergency physician must understand certain basic principles in laboratory medicine. The level of detection of an assay is the lowest level that the assay can detect, although the precision at this point may be inadequate. The 99th percentile upper reference limit is the upper normal limit of the assay derived from a presumably normal healthy population. Ninety-nine percent of a healthy adult population has levels below this cutoff. Levels below the 99th percentile upper reference limit are presumably normal, but this cutoff ultimately depends on the sensitivity and level of detection for the assay.

In the case of many current troponin assays, studies have shown that in actual fact these 99th percentile reference limits include a heterogeneous patient population that includes "true" normals but also other patients with low levels who have elevated cardiac risk. These studies have suggested that, in fact, the true 99th percentile cutoff for a healthy patient population is actually a factor of 10-50 lower. These investigations suggest that higher sensitivity or ultrasensitive troponin assays are necessary.35 The advantage of ultrasensitive troponins is based on the premise that lower cutoff levels achieve higher sensitivity that will allow earlier diagnosis often within 90 minutes of presentation.

The coefficient of variation (CV) is defined as the variation in the assay result when the same sample is repeatedly analyzed. The CV is expressed as a percentage. For example, if the CV is 20% at the 0.2 ng/mL level, then the normal variation in the laboratory if the same blood sample was repeatedly analyzed would be 0.16-0.24 ng/mL. In general, the CV rises as the assay level falls. At the lowest levels, the CV can be high, rendering the assay imprecise at that point. A 10% CV is considered acceptable. Ideally, the CV would be less than 10% at the 99th percentile sensitivity level but that is generally not the case for most troponin assays. For most current troponin assays, the cutoff at which the 10% CV limit is achieved is usually higher than the 99th percentile cutoff.

The sensitivity, specificity, and precision of the different commercially available troponin assays vary considerably. These differences are related to a lack of standardization, different monoclonal antibodies, the presence of modified TnI and TnT in the serum, and variations in antibody cross-reactivity to the various detectable forms of TnI that result from its degradation. Only one manufacturer produces the TnT assay, so variation is thereby eliminated. The 99th percentile cutoffs and the 10% CV are well established for the troponin T assay. However, up to 20-fold variation has occurred in TnI results obtained with the multitude of commercial TnI assays currently available, each with their own 99th percentile upper reference limits and 10% CV levels.

In the GUSTO IV study, a relatively insensitive point-of-care TnI assay was used to screen patients for study eligibility. In a subsequent study, the blood samples were reanalyzed using the 99th percentile cutoff of a far more sensitive central laboratory TnT assay. The more sensitive 99th percentile cutoff of this TnT assay identified an additional 28% (96 out of 337 patients) with a positive TnT result but negative point-of-care TnI. These patients had higher rates of death or MI at 30 days (odds ratio [OR], 4.3).36

In a similar reanalysis of the TACTICS-TIMI18 trial, 3 different troponin I cutoffs were compared on 1821 patients to evaluate the 30-day risk of death or MI: the 99th percentile, 10% CV, and the World Health Organization (WHO) AMI cutoffs. Using the 10% CV cutoff identified, an additional 12% more cases (213/1821) were identified relative to the WHO AMI cutoff, and the 99th percentile cutoff identified an additional 181 cases (10%) relative to the 10% CV cutoff and a 22% increase in the number of cases over the WHO AMI cutoff. The odds ratios for the adverse cardiac event rates of death or MI at 30 days were similar for all 3 cutoffs suggesting that the lower cutoffs detected more patients with cardiovascular risk without sacrificing specificity.29,35

For these reasons, the National Academy of Biochemistry working with the ACC/ESC guidelines has recommended adoption of the 99th percentile upper reference limit as the recommended cutoff for a positive troponin result. Ideally, the precision of the assay at this cutoff level should be measured by a coefficient of variation that is <10%. However, most TnI assays are imprecise at the 99th percentile reference limit.37 Some have therefore recommended that the cutoff level be raised to the slightly higher 10% CV level instead of the 99th percentile reference limit to ensure adequate assay precision. Fortunately, the newest assays have achieved a 10% CV even at the 99th percentile upper reference limit. Therefore, there is considerable variation because of this lack of standardization between troponin assays.

The emergency physician must be familiar with the particular troponin assay available in the laboratory and ensure that high-sensitivity assays are being used. Furthermore, the emergency physician must know if the cutoff is set at the slightly higher 10% CV level or the lower 99th percentile upper reference limit.

Certain hospitals may be still using the outdated WHO AMI cutoffs. These cutoffs were based on the original WHO definition of AMI using CK-MB. At these hospitals, the troponin level is interpreted as a higher "AMI level" and a second lower "intermediate level" that is correlated with "leak" or "minor myocardial injury". Based on the current knowledge of the pathophysiology of acute coronary syndrome (ACS), this practice should be abandoned. By definition, any elevated measure of troponin above the 10% CV or 99th percentile upper reference limit in the appropriate clinical setting is a myocardial infarction as defined by the American College of Cardiology (ACC)/European Society of Cardiology (ESC).

Troponins in Chronic Renal Failure and in Nonischemic Heart Disease

Cardiac markers in chronic renal failure

Cardiovascular disease accounts for about 50% of deaths in patients with chronic renal failure (CRF) who are on hemodialysis. These patients are at increased risk of coronary artery disease and acute ACS. The use of cardiac markers to risk-stratify this patient subgroup has been evaluated. Early studies revealed a high prevalence of elevated cardiac troponin levels in patients with CRF. A very high prevalence (30-70%) of TnT-positive results has been reported in asymptomatic patients with chronic renal failure who are on hemodialysis. TnI is also elevated in chronic renal failure but less frequently (<5%). The etiology of the CK-MB elevation is directly related to renal clearance.

Biochemical studies have demonstrated that the troponin elevation originates from the myocardium (and, therefore, is not a true false-positive result) and is not related to the myopathy associated with renal failure. TnT level is elevated more frequently than TnI level. Recent data suggest that elevated troponins levels in asymptomatic patients may reflect subclinical microinfarctions that are clinically distinct from acute coronary syndrome (ACS). Patients with chronic renal failure (CRF) frequently have chronic congestive heart failure and hypertension that may independently elevate the troponin level.

The clinical significance of an elevated TnT level has been debated. The largest prospective studies have confirmed the association between TnT elevation and cardiac mortality.33 The GUSTO IV ACS trial revealed that patients with renal insufficiency and an elevated TnT had the highest overall risk of the composite endpoint of death or AMI.38 Two other prospective studies have reported that an elevated TnT but not TnI portended an increased long-term mortality risk.39,40 Whether the increased cardiac risk is in the short term (ie, 30 d) or only the long term is unclear. Patients without short-term risk may not require hospitalization and potentially could have workup completed on an outpatient basis. 

It has been suggested that chronically elevated troponin levels represent chronic structural cardiovascular disease such as prior myocardial infarction, chronic CHF, or hypertension in the setting of chronic renal failure. These patients are at higher cardiac risk than the normal healthy patient population. Troponin is still a useful diagnostic marker in the setting of chronic renal failure.41,42

Dialysis does not affect TnT or TnI levels. Predialysis and postdialysis levels are essentially unchanged. CK-MB, however, is dialyzable, and levels are decreased postdialysis. Therefore, a single elevated TnT level in patients with chronic renal failure (CRF) and possible acute coronary syndrome (ACS) is nondiagnostic for acute myocardial infarction (AMI) in the absence of other findings. The specificity of TnI is higher than TnT in this setting but not conclusive for AMI. Serial determinations are usually required, looking for a rise in the troponin level.

Therefore, ascertaining whether or not an elevated troponin in patients with chronic renal failure represents true acute myocardial necrosis/infarction or a false-positive result can be difficult. In those patients with cardiac risk factors who are deemed clinically to be at moderate-high risk for ACS, the prudent approach would be to observe and perform serial cardiac markers over 6-9 hours. In low-risk asymptomatic patients, the clinician may decide that the elevated troponin result is false positive for AMI in the absence of any other findings indicative of ACS.

Troponins in nonischemic heart disease

Outcome analyses on a variety of clinical conditions have shown that any degree of myocardial injury is associated with increased morbidity and mortality rates. An elevated troponin level is a sensitive marker of occult myocardial injury and necrosis, even in nonischemic states.

A number of studies have demonstrated that TnT enables risk stratification of patients with congestive heart failure (CHF) without ischemia. Elevated cardiac troponins are associated with decreased left ventricular ejection fraction and poor prognosis in patients with CHF and are related to the severity of heart failure.43

Isolated studies have shown evidence of MI and elevated TnI levels in patients with subarachnoid hemorrhage.44 Vasoactive peptides released during acute subarachnoid hemorrhage induce deep T-wave inversions on ECG that indicate myocardial injury. Similarly, TnT has been shown to be an independent predictor of outcome in patients with pulmonary embolism. Right ventricular strain or infarction from acute pulmonary hypertension causes the elevated troponin level.

Elevated troponin levels have been documented in other disease states and situations that are not associated with atherosclerotic epicardial coronary artery disease, including the following:

Emerging Cardiac Markers

Many markers have been investigated in acute coronary syndromes (ACSs). Cardiac markers are the holy grail of laboratory medicine. The search for the ideal cardiac marker with 100% sensitivity and 100% specificity continues. A select few are reviewed here.

B-type natriuretic peptide

B-type natriuretic peptide (BNP) is secreted primarily by the ventricular myocardium in response to wall stress, including volume expansion and pressure overload. Multiple studies have demonstrated that BNP may also be a useful prognostic indicator in ACS. The TIMI study group performed several investigations showing that the BNP level predicted cardiac mortality and other adverse cardiac events across the entire spectrum of ACSs. The mortality rate nearly doubled when both TnI and BNP levels were elevated.

In the TACTICS-TIMI 18 trial, an elevated BNP level was associated with tighter culprit stenosis, higher corrected TIMI frame count (CTFC), and left anterior descending (LAD) artery involvement.45 These data suggested that increased BNP levels may correlate with greater severity of myocardial ischemia and partially explain the association between increased BNP levels and adverse outcomes.
 
Using data from the Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction (OPUS-TIMI) 16 and the TACTICS-TIMI 18 studies, Sabatine and colleagues demonstrated that baseline elevations of troponin I, C-reactive protein (CRP), and BNP levels in patients with NSTEMI were independent predictors of the composite endpoint of death, MI, or CHF.46 The PROMPT-TIMI 35 trial demonstrated that transient myocardial ischemia during exercise testing was associated with an immediate rise in BNP levels.47  In addition, the severity of ischemia was directly proportional to the elevation in BNP.

The presence of acute CHF in patients with ACS is a well-known predictor of adverse cardiac events and higher risk. Therefore, it is not surprising that an elevated BNP level, as a marker of CHF, is also predictive of adverse cardiac events in patients with ACS. Although BNP has been validated as a diagnostic marker for CHF, insufficient data are available to evaluate the use of BNP as a diagnostic cardiac marker for ACS in the ED.

C-reactive protein

CRP, a nonspecific marker of inflammation, is considered to be directly involved in coronary plaque atherogenesis. Extensive studies beginning in the early 1990s showed that an elevated CRP level independently predicted adverse cardiac events at both the primary and secondary prevention levels. A CRP level is useful to evaluate a patient's cardiac risk profile.

Current data indicate that CRP is a useful prognostic indicator in patients with ACS. Elevated CRP levels are independent predictors of cardiac death, AMI, and CHF. In combination with TnI and BNP, CRP may be a useful adjunct, but its nonspecific nature limits its use as a diagnostic cardiac marker for ACS in the ED.

Myeloperoxidase

Myeloperoxidase (MPO) is a leukocyte enzyme that generates reactant oxidant species and has been linked to prothrombotic oxidized lipid production, plaque instability, lipid-laden soft plaque creation, and vasoconstriction from nitrous oxide depletion. Past studies showed significantly increased MPO levels in patients with angiographically documented coronary artery disease.48 These findings spurred further investigation into MPO as a novel cardiac marker.

Brennan and colleagues assessed the value of MPO as a predictor of cardiovascular risk in 604 sequential patients presenting to the ED with chest pain.49 Elevated MPO levels independently predicted increased risk of major adverse cardiac events including MI, reinfarction, need for revascularization, or death at 30 days and 6 months. Among the patients who presented to the ED with chest pain but who were ultimately ruled out for myocardial infarction, an elevated MPO level at presentation predicted subsequent major adverse cardiovascular outcomes. In a subgroup of patients with negative baseline troponin T, MPO levels were significantly elevated at baseline, even within 2 hours after symptom onset.

MPO may be a useful early marker in the ED based on its ability to detect plaque vulnerability that precedes ACS. Further validation studies on MPO in the general ED chest pain population are needed to determine its sensitivity, specificity, positive predictive value, and negative predictive value.50,51

Ischemia modified albumin

Current cardiac markers, including troponin and CK-MB, are sensitive for myocardial necrosis. They are markers of cell death that occurs in acute myocardial infarction (AMI). However, most patients with ACS have myocardial ischemia without infarction. A cardiac marker that is sensitive for myocardial ischemia would be an attractive addition to the diagnostic algorithm.

A novel marker of ischemia, ischemia modified albumin (IMA), is produced when circulating serum albumin contacts ischemic heart tissues. IMA can be measured by the albumin cobalt binding (ACB) assay that is based on IMA's inability to bind to cobalt.52 A rapid assay with a 30-minute laboratory turnaround time has been developed and marketed as the first commercially available Food and Drug Administration (FDA) approved marker of myocardial ischemia.

Based on investigations of myocardial ischemia induced by balloon inflation during percutaneous coronary intervention, IMA levels rise within minutes of transient ischemia, peak within 6 hours, and can remain elevated as long as 12 hours. Studies on the use of IMA in patients with chest pain in the ED have found sensitivities that ranged from 71-98%, and specificities of 45-65%, with a negative predictive value (NPV) of 90-97% for ACS.53

Sinha and colleagues reported that a multimarker approach using the combination of ECG findings, the TnT levels, and the IMA levels achieved a sensitivity of 95% for ACS.54 Anwarrudin et al calculated that the combination of IMA, myoglobin, CK-MB, and TnI increased the sensitivity to 97% for detecting myocardial ischemia.55 However, IMA level is also elevated in patients with cirrhosis, certain infections, and advanced cancer, which reduces the specificity of the assay. Further validation and outcome studies are required to evaluate its use in the ED diagnosis of ACS when the ECG and cardiac troponins levels are nondiagnostic.

Conclusion

The diagnosis of acute coronary syndrome (ACS) is frequently difficult and is based primarily on clinical suspicion. Cardiac markers cannot be used, particularly in the early hours after symptom onset, to reliably exclude the disease.

Cardiac markers have high positive predictive values; thus, clinicians must not ignore positive results in clinical settings compatible with ACS.

The astute clinician must also consider the other life-threatening etiologies of chest pain besides ACS, such as aortic dissection and pulmonary embolism, for which cardiac markers have no diagnostic value.

Multimedia

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Media file 1: Use of cardiac markers in the ED. Studies on troponins in acute coronary syndrome.
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Use of cardiac markers in the ED. Studies on troponins in acute coronary syndrome.

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Media file 2: Use of cardiac markers in the ED. Troponin I levels and cardiac mortality in acute coronary syndrome.
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Use of cardiac markers in the ED. Troponin I levels and cardiac mortality in acute coronary syndrome.

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Media file 3: Use of cardiac markers in the ED. Cardiac event rates in the platelet receptor inhibition for ischemic syndrome (PRISM) study based on troponin I results.
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Use of cardiac markers in the ED. Cardiac event rates in the platelet receptor inhibition for ischemic syndrome (PRISM) study based on troponin I results.

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Media file 4: Use of cardiac markers in the ED. Effect of time to treatment in patients with acute coronary syndrome (ACS) who are treated with the GIIb/IIIa inhibitor eptifibatide.
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Use of cardiac markers in the ED. Effect of time to treatment in patients with acute coronary syndrome (ACS) who are treated with the GIIb/IIIa inhibitor eptifibatide.

Keywords

cardiac markers, chest pain, acute coronary syndrome, ACS, acute myocardial infarction, AMI, myocardial infarction, MI, troponin, myoglobin, cardiac troponin, creatine kinase–MB, CK-MB, biochemical marker, non–ST-segment elevation MI, NSTEMI, ST-segment elevation, STEMI

 


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References
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Further Reading

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Keywords

cardiac markers, chest pain, acute coronary syndrome, ACS, acute myocardial infarction, AMI, myocardial infarction, MI, troponin, myoglobin, cardiac troponin, creatine kinase–MB, CK-MB, biochemical marker, non–ST-segment elevation MI, NSTEMI, ST-segment elevation, STEMI

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Contributor Information and Disclosures

Author

Donald Schreiber, MD, CM, Associate Professor of Surgery (Emergency Medicine), Stanford University School of Medicine
Donald Schreiber, MD, CM is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Abbott Point of Care Inc Research Grant and Speaker''''''''''''''''s Bureau Speaking and teaching; Bristol-Myers Squibb Inc Honoraria Speaking and teaching; Sanofi-Aventis, Inc Honoraria Speaking and teaching; Nanosphere Inc Grant/research funds Research; Singulex Inc Grant/research funds Research

Coauthor(s)

Suzanne M Miller, MD, Clinical Instructor, Emergency Medicine, George Washington University School of Medicine and Health Sciences; Attending Physician, Department of Emergency Medicine, INOVA Fairfax Hospital; Chief Executive Officer, MDadmit
Suzanne M Miller, MD is a member of the following medical societies: American Academy of Emergency Medicine and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Edward Bessman, MD, Chairman, Department of Emergency Medicine, John Hopkins Bayview Medical Center; Assistant Professor, Department of Emergency Medicine, Johns Hopkins University
Edward Bessman, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Gary Setnik, MD, Chair, Department of Emergency Medicine, Mount Auburn Hospital; Assistant Professor, Division of Emergency Medicine, Harvard Medical School
Gary Setnik, MD is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine
Disclosure: SironaHealth Salary Management position; South Middlesex EMS Consortium Salary Management position

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

David FM Brown, MD, Assistant Professor, Division of Emergency Medicine, Harvard Medical School; Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital
David FM Brown, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

 
 
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