Cardiac marker

Cardiac marker

Types

Types include:

Test	Sensitivity and specificity	Approximate peak	Description
Troponin test	The most sensitive and specific test for myocardial damage. Because it has increased specificity compared with CK-MB, troponin is a superior marker for myocardial injury.	12 hours	Troponin is released during MI from the cytosolic pool of the myocytes. Its subsequent release is prolonged with degradation of actin and myosin filaments. Differential diagnosis of troponin elevation includes acute infarction, severe pulmonary embolism causing acute right heart overload, heart failure, myocarditis. Troponins can also calculate infarct size but the peak must be measured in the 3rd day. realesed in 2-4 hours and persists for up to 7 days.
CPK-MB test	It is relatively specific when skeletal muscle damage is not present.	10-24 hours	CK-MB resides in the cytosol and facilitates high energy phosphates into and out of mitochondria. It is distributed in a large number of tissues even in the skeletal muscle. Since it has a short duration, it cannot be used for late diagnosis of acute MI but can be used to suggest infarct extension if levels rise again. this usually back to normal in 2-3 days.
Lactate dehydrogenase (LDH)	LH is not as specific as troponin.	72 hours	Lactate dehydrogenase catalyses the conversion of pyruvate to lactate. LDH-1 isozyme is normally found in the heart muscle and LDH-2 is found predominately in blood serum. A high LDH-1 level to LDH-2 suggest MI. LDH levels are also high in tissue breakdown or hemolysis. It can mean cancer, meningitis, encephalitis, or HIV. this usually back to normal 10-14 days.
Aspartate transaminase (AST)			This was the first used.[2] It is not specific for heart damage, and it is also one of the liver function tests.
Myoglobin (Mb)	low specificity for myocardial infarction	2 hours	Myoglobin is used less than the other markers. Myoglobin is the primary oxygen-carrying pigment of muscle tissue. It is high when muscle tissue is damaged but it lacks specificity. It has the advantage of responding very rapidly,[3] rising and falling earlier than CK-MB or troponin. It also has been used in assessing reperfusion after thrombolysis.[4]
Ischemia-modified albumin (IMA)	low specificity		IMA can be detected via the albumin cobalt binding (ACB) test, a limited available FDA approved assay. Myocardial ischemia alters the N-terminus of albumin reducing the ability of cobalt to bind to albumin. IMA measures ischemia in the blood vessels and thus returns results in minutes rather than traditional markers of necrosis that take hours. ACB test has low specificity therefore generating high number of false positives and must be used in conjunction with typical acute approaches such as ECG and physical exam. Additional studies are required.
Pro-brain natriuretic peptide			This is increased in patients with heart failure. It has been approved as a marker for acute congestive heart failure. Pt with < 80 have a much higher rate of symptom free survival within a year. Generally, pt with CHF will have > 100.
Glycogen phosphorylase isoenzyme BB

Cardiac Enzymes

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There are several enzymes that are released when heart cells are damaged.  A specific, sensitive marker that is present in 1-2 hours after the cardiac muscle injury continues to be sought.

Troponin T and I These are contractile proteins of the myofibril. The cardiac isoforms are very specific for cardiac injury and are not present in serum from healthy people. Current guidelines from the American College of Cardiology Committee state that cardiac troponins are the prefered markers for detecting myocardial cell injury. Troponin I (cTnI) or T (cTnT) are the forms frequently assessed.  § Rises 2 - 6 hours after injury § Peaks in 12 - 16 hours § cTnI stays elevated for 5-10 days, cTnT for 5-14 days

Creatine Kinase (creatine phosphokinase) This enzyme is found in heart muscle (CK-MB), skeletal muscle (CK-MM), and brain (CK-BB).  Creatine kinase is increased in over 90% of myocardial infarctions. However, it can be increased in muscle trauma, physical exertion, postoperatively, convulsions, delirium tremens and other conditions. Time sequence after myocardial infarction § begins to rise 4-6 hours § peaks 24 hours § returns to normal in 3-4 days Creatine Phosphokinase Isoenzymes § MM fraction  - skeletal muscle § MB fraction - heart muscle § BB fraction - brain MB fraction § Rises and returns to normal sooner than total CK § Rises in 3-4 hours § Returns to normal in 2 days CK - MB subforms This test is becoming more popular. MB2 is released from heart muscle and converted in blood to MB1. A level of MB2 equal or greater than 1.0 U/L and an MB2/MB1 ratio equal or greater than 1.5 indicates myocardial infarction.

Myoglobin Found in striated muscle. Damage to skeletal or cardiac muscle releases myoglobin into circulation. Time sequence after myocardial infarction § Rises fast (2 hours) after myocardial infarction § Peaks at 6 - 8 hours § Returns to normal in 20 - 36 hours Have false positives with skeletal muscle injury and renal failure.

Lactic Dehydrogenase This enzyme is no longer used to to diagnose myocardial infarction.

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

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 ACS 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 AMI. Cardiac markers are central to the new definition of AMI.

According to these bodies, AMI is now defined as a typical rise and fall of biochemical markers (eg, troponin, creatine kinase–MB [CK-MB]), with at least one of the following:

• Ischemic symptoms
• New pathologic Q waves on ECG
• Ischemic ECG changes (ST-segment elevation or depression)
• Coronary artery intervention
• Pathologic findings of AMI

This is a significant change from the original World Health Organization classification of AMI. Patients with elevated troponin levels but negative CKMB 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.

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, that 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 AMI 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

Creatine kinase-MB isoenzymes

Prior to the introduction of cardiac troponins, the biochemical marker of choice for the diagnosis of 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. However, conflicting data from the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) IIb trial suggested that an elevated CKMB correlated with an increased mortality rate. The utility of CK-MB in risk stratification and therapeutic decision making in patients with ACS is unclear.

Relative index, CKMB, 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 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 useful when both the total CK and the CK-MB levels are increased.

Myoglobin

Myoglobin has attracted considerable interest as an early marker of 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 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 ACS.

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. The major disadvantage of this assay is that it is relatively labor intensive for the laboratory.

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 TnC are identical; thus, no structural difference exists between them. However, the skeletal and cardiac subforms for TnI and 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.

Studies on the release kinetics of the cardiac troponins indicate that they are not early markers of myocardial necrosis. They appear in serum 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, AMI) in the 30 days after the index admission and a natural history that closely resembled patients with non Q-wave MI. An elevated troponin level enabled risk stratification of patients with ACS and identified patients at high risk of adverse cardiac events (ie, death, MI) up to 6 months after the index event.

The table in Media file 1 outlines many of the initial studies on troponins in ACS.

Antman evaluated TnI in patients with ACS in the TIMI IIIB trial. 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.

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 in patients with chest pain and suspected AMI with ST-segment elevation who were eligible for reperfusion therapy.

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).

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 in ACS. 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, are cardiospecific, and provide prognostic information for patients with ACS. They have become the cardiac markers of choice for patients with ACS.

Some authorities have called for a troponin standard alone and recommend eliminating CK-MB, and a contributor to this article is aware of institutions that have discontinued use of CK-MB in favor of measuring troponin alone.

What Is the Best Marker?

Understanding the release kinetics of each of the cardiac markers underscores the importance of the time from symptom onset. The best marker depends on the time from onset of symptoms. The earliest markers are myoglobin and the CK-MB isoforms. CK-MB and troponins are ideal in the intermediate period of 6-24 hours. It is important that the clinician realize that the troponins are not early markers. Only 35% of patients with NSTEMI have positive troponins at baseline evaluation. 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 2004 ACC/American Heart Association (AHA) guidelines recommend immediate reperfusion therapy for qualifying patients with STEMI without waiting for cardiac marker results.

In other patients with definite or possible ACS, serial evaluation of the cardiac markers is essential to diagnose AMI. The following table outlines a recommended sampling frequency after ED admission.

Table 1. Cardiac Markers - Sampling Frequency

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Table

	Baseline	2-4 h	6-12 h	12-24 h	>24 h
Early (CKMB isoforms, myoglobin)	X	X	X
Intermediate (CK-MB, TnI, TnT)	X	X	X	X
Late (TnI, TnT)					X
	Baseline	2-4 h	6-12 h	12-24 h	>24 h
Early (CKMB isoforms, myoglobin)	X	X	X
Intermediate (CK-MB, TnI, TnT)	X	X	X	X
Late (TnI, TnT)					X

The sample time at 2-4 hours is useful primarily in chest pain observation units in which rapid triage and early diagnosis are essential. In other patients admitted for ACS, markers drawn at the 2- to 4-hour time interval are not as important as the 6- to 12-hour sample. The recent ACC/AHA guidelines for the treatment of patients with unstable angina and NSTEMI recommend a baseline sample on ED arrival and a repeat sample 6-12 hours after symptom onset. 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 12-hour period after symptom onset. 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 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 TnT and who were treated with an LMWH.

In the Platelet Receptor Inhibition for Ischemic Syndrome (PRISM) trial, patients with an elevated 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).

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).

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.

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.

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 patients with the highest 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 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. 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). The high 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

The recent ACC/ESC guidelines for ACS recommend that the cutoff level for troponin be set at a point that is greater than the 99th percentile reference limit with a coefficient of variation (CV) of less than or equal to 10%. The CV is defined as the variation in the result when the same sample is repeatedly analyzed. In general, the CV rises as the sensitivity cutoff level falls. Ideally, the CV would be less than 10% at the 99th percentile sensitivity level but that is generally not the case for troponin assays. The 10% CV level is usually higher. The NACB also recommends that the 10% CV level be used for clinical decision making.

The original troponin assays also defined an AMI level and a second lower level that correlated with "leak." Based on the current knowledge of the pathophysiology of ACS, this practice should be abandoned. By definition, any elevated measure of troponin in the appropriate clinical setting is a myocardial infarction.

From a clinical point of view, the current generation of TnT and the current generation of TnI assays do not differ in their diagnostic sensitivity and specificity. The Troponin T assay is manufactured by a solitary company, and the 99th percentile limits and 10% CV levels have been standardized. However, a 20-fold variation among the many different commercial TnI assays has been reported when the same patient blood sample is analyzed. TnI undergoes extensive modification in serum after release. Terminal residues are cleaved, and various degrees of protein binding occur. The different antibodies used in many of the different TnI assays, explain the different analytical results that are obtained. Unfortunately, no standardization of the TnI assay has been established, and results with one assay cannot necessarily be extrapolated to another. Some assays have performed better than others and have demonstrated higher sensitivities.

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 laboratory should set the troponin cutoff point at the 10% CV level.

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 of TnT-positive results has been reported in asymptomatic patients with chronic renal failure who are on hemodialysis. TnI and CKMB levels are also elevated in chronic failure but less frequently. 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 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 ACS. Patients with 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. 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. Two other prospective studies have reported that an elevated TnT but not TnI portended an increased long-term mortality risk. 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 be worked up as outpatients.

Dialysis does not affect TnT or TnI levels. Predialysis and postdialysis levels are essentially unchanged. CKMB, however, is dialyzable, and levels are decreased postdialysis. Therefore, a single elevated TnT level in patients with CRF and possible ACS is nondiagnostic 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, it can be difficult to ascertain whether or not an elevated troponin in patients with chronic renal failure represents true myocardial necrosis/infarction or a false-positive result. 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 6-12 hours. In low-risk asymptomatic patients, the clinician may decide that the elevated troponin result is false positive 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. At 1 year, patients with CHF and elevated TnT levels more than 0.05 ng/mL have a 60% incidence of adverse cardiac events.

Isolated studies have shown evidence of MI and elevated TnI levels in patients with subarachnoid hemorrhage. 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 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 coronary artery disease, including the following:

• Pacing, automated implantable cardioverter-defibrillator
• Tachyarrhythmias
• Hypertension
• Myocarditis
• Myocardial contusion
• Acute and chronic congestive heart failure
• Cardiac surgery
• Renal failure
• Pulmonary embolism
• Subarachnoid hemorrhage
• Sepsis
• Hypothyroidism
• Shock

Emerging Cardiac Markers

Many markers have been investigated in 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. This 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, CRP, and BNP levels in patients with NSTEMI were independent predictors of the composite endpoint of death, MI, or CHF. The PROMPT-TIMI 35 trial demonstrated that transient myocardial ischemia during exercise testing was associated with an immediate rise in BNP levels. 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. 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. 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 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.

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 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. 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.

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. Anwarrudin et al calculated that the combination of IMA, myoglobin, CK-MB, and TnI increased the sensitivity to 97% for detecting myocardial ischemia. 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 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.

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