Cardiac Markers
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Cardiac markers are used in the diagnosis and risk stratification of patients with chest pain and suspected acute coronary syndrome (ACS). The cardiac troponins, in particular, have become the cardiac markers of choice for patients with ACS. Indeed, cardiac troponin is central to the definition of acute myocardial infarction (MI) in the consensus guidelines from the European Society of Cardiology (ESC) and the American College of Cardiology (ACC): These guidelines recommend that cardiac biomarkers should be measured at presentation in patients with suspected MI, and that the only biomarker that is recommended to be used for the diagnosis of acute MI at this time is cardiac troponin due to its superior sensitivity and accuracy. [1, 2, 3, 4]
For example, patients with elevated troponin levels but negative creatine kinase-MB (CK-MB) values 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 electrocardiogram (ECG) changes.
Similarly, only 1 elevated troponin level above the established cutoff is required to establish the diagnosis of acute MI, according to the ACC guidelines for NSTEMI. [4, 5, 6]
These changes were instituted following the introduction of increasingly sensitive and precise troponin assays. Up to 80% of patients with acute MI will have an elevated troponin level within 2-3 hours of emergency department (ED) arrival, versus 6-9 hours or more with CK-MB and other cardiac markers.
Accordingly, some have advocated relying solely on troponin and discontinuing the use of CK-MB and other markers. [7, 8, 9, 10, 11] Nevertheless, CK-MB and other markers continue to be used in some hospitals to rule out MI and to monitor for additional cardiac muscle injury over time.
Note that 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. ACC/American Heart Association (AHA) guidelines recommend immediate reperfusion therapy for qualifying patients with ST-segment elevation MI (STEMI), without waiting for cardiac marker results. [12, 13]
Go to Myocardial Infarction and Complications of Myocardial Infarction for more complete information on these topics.
The troponins are regulatory proteins found in skeletal and cardiac muscle. Three subunits have been identified: troponin I (TnI), troponin T (TnT), and troponin C (TnC). The genes that encode 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 troponin TnT are distinct, and immunoassays have been designed to differentiate between them.
Two different reference ranges are used in troponin assays. The upper percentile reference limit gives the upper limit of what can be expected in a normal, healthy, adult population, while the coefficient of variation (CV) is the percent variation in assay results that can be expected when the same sample is repeatedly analyzed.
According to European Society of Cardiology (ESC)/American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/ World Heart Federation (WHF) guidelines, MI refers specifically to myocardial necrosis due to myocardial ischemia. However, although elevations in the serum levels of TnI, TnT, and CK-MB indicate the presence of injury-associated necrosis of myocardial cells, such elevations do not point to the underlying mechanism of the necrosis. While myocardial necrosis occurs in MI, it can also be a product of predominantly nonischemic myocardial injury, as occurs in association with heart failure, arrhythmia, myocarditis, renal failure, pulmonary embolism, and percutaneous or surgical coronary procedures. [14]
The sensitivity, specificity, and precision of the different commercially available troponin assays vary considerably. These differences are related to a lack of standardization, the use of 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, and its 99th percentile cutoffs and the 10% CV are well established. However, up to 20-fold variation has occurred in 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 96 (28%) 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. [15]
In a similar reanalysis of the TACTICS-TIMI 18 trial, 3 different TnI 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) acute MI cutoffs. (The WHO cutoffs define acute MI using CK-MB and report troponin levels as either a higher “acute MI level” or a lower “intermediate level” that is correlated with “leak” or “minor myocardial injury.”)
Using the 10% CV cutoff identified, an additional 12% more cases were identified relative to the WHO acute MI cutoff. The 99th percentile cutoff identified an additional 10% of cases relative to the 10% CV cutoff, as well as a 22% increase in the number of cases over the WHO acute MI cutoff. Nevertheless, 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. [16, 17]
The National Academy of Clinical Biochemistry (NACB) 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 CV that is less than 10%.
However, most TnI assays are imprecise at the 99th percentile reference limit. [18] 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.
In addition, studies have shown that populations within the 99th percentile reference limit include patients with low troponin levels who nevertheless have an elevated cardiac risk, and that the true 99th percentile cutoff for a healthy patient population is actually a factor of 10-50 lower. Accordingly, these investigations suggest that higher sensitivity or ultrasensitive troponin assays are necessary. [17] 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.
To optimize the assay’s use in the ED, it is important to be familiar with the particular troponin assay available in the laboratory and to know whether the cutoff is set at the 10% CV level or the 99th percentile upper reference limit.
NACB recommendations specify that cardiac markers be available on an immediate basis 24 h/d, 7 d/wk, with a turnaround time of 1 hour. [19] 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 multicenter trial, the time to positivity was significantly faster for the POC device than for the local laboratory (2.5 h vs 3.4 h). [20]
In another multicenter study, which evaluated the i-STAT POC TnI assay in comparison with the central laboratory in 2000 patients with suspected ACS, POC testing reduced the length of stay by approximately 25 minutes for patients who were discharged from the ED. [21, 22] The sensitivity of current POC assays coupled with the benefit of rapid turnaround time make the POC assays attractive clinical tools in the ED.
In addition to its use in the diagnosis of MI, an elevated troponin level can identify patients at high risk for adverse cardiac events. [23, 24] Specifically, data from a meta-analysis indicated that an elevated troponin level in patients without ST-segment elevation is associated with a nearly 4-fold increase in the cardiac mortality rate. [25] In patients without ST-segment elevation who were being considered for thrombolytic therapy, initial TnI levels on admission correlated with mortality at 6 weeks, but CK-MB levels were not predictive of adverse cardiac events and had no prognostic value. [23]
Other studies revealed that an elevated troponin level at baseline was an independent predictor of mortality, even in patients with chest pain and acute MI with ST-segment elevation who were eligible for reperfusion therapy. [26, 27]
Data from the ARTEMIS study, comprising 1137 diabetic patients with stable coronary artery disease (CAD) and 649 normoglycemic patients, found that high levels (≥14 ng/L) of highly sensitive TnT (hs-TnT) was an independent strong predictor of cardiac death or hospitalization for heart failure in patients with diabetes and CAD (as were B-type natriuretic peptide, highly sensitive C-reactive protein [hs-CRP], and soluble suppressor of tumorigenicity-2 [sST2] in a multivariate analysis). [28] In the nondiabetic group, only hs-CRP and sST2 were predictive for these outcomes.
Data from the Acute Decompensated Heart Failure National Registry (ADHERE) involving information from 23,696 patients hospitalized with acute heart failure showed that increased levels of troponin and creatinine were the strongest predictors of in-hospital worsening heart failure. [29]
Finally, the TIMI IIIB, GUSTO IIa, GUSTO IV ACS, and FRISC trial all demonstrated a direct correlation between the level of TnI or TnT and the mortality rate and adverse cardiac event rate in ACS. [23, 26, 30, 31, 32]
Prior to the introduction of cardiac troponins, the biochemical marker of choice for the diagnosis of acute MI was the CK-MB isoenzyme. The criterion most commonly used for the diagnosis of acute MI 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, it also exists in skeletal muscle and false-positive elevations occur in a number of clinical settings, including trauma, heavy exertion, and myopathy.
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 acute MI is limited. However, its release kinetics can assist in diagnosing reinfarction if levels rise after initially declining following acute MI.
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 but CK-MB positive had in-hospital mortality rates that were not significantly increased from patients who were negative for both biomarkers. [33]
Similarly, in a report of more than 10,000 patients with ACS from the multicenter GRACE registry, in-hospital mortality was highest when both troponin and CK-MB were positive, intermediate in troponin-positive/CK-MB-negative patients, and lowest in patients in whom both markers were negative and in those who were troponin-negative/CK-MB-positive. [34] Thus, an isolated CK-MB elevation has limited prognostic value in patients with a non-ST elevation ACS.
The relative index calculated by the ratio of CK-MB (mass) to total CK can assist in differentiating false-positive elevations of CK-MB arising from skeletal muscle. A ratio of less than 3 is consistent with a skeletal muscle source, while 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 MI falls when concurrent cardiac injury and skeletal muscle injury is present. In an ED-based study to evaluate the CK-MB relative index compared with the absolute CK-MB, specificity was increased, but with a loss of sensitivity. [35]
The CK-MB/CK relative index is useful if patients have only an MI or only skeletal muscle injury, but not if they have both. Therefore, in the combined setting of acute MI and skeletal muscle injury (rhabdomyolysis, heavy exercise, polymyositis), the fall in sensitivity is significant.
Note that the diagnosis of acute MI must not be based on an elevated relative index alone, because 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.
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 rapidly after symptom onset.
Normally, the tissue CK-MB1 isoform predominates; thus, the CK-MB2/CK-MB1 ratio is typically less than 1. A result is positive if the CK-MB2 is elevated and the ratio is greater than 1.7.
CK-MB2 can be detected in serum within 2-4 hours after onset and peaks at 6-9 hours, making it an early marker for acute MI. 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. [36, 37] The major disadvantage of this assay is that it is relatively labor intensive for the laboratory.
Myoglobin is a heme protein found in skeletal and cardiac muscle that has attracted considerable interest as an early marker of MI. 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 have a lack of cardiospecificity. Serial sampling every 1-2 hours can increase the sensitivity and specificity; a rise of 25-40% over 1-2 hours is strongly suggestive of acute MI. However, in most studies, myoglobin only achieved 90% sensitivity for acute MI, so the negative predictive value of myoglobin is not high enough to exclude the diagnosis of acute MI.
The original studies that evaluated myoglobin used the WHO definition of acute MI that was based on a CK-MB standard. With the adoption of a troponin standard for acute MI in the ACC/ESC definition, the sensitivity of myoglobin for acute MI is substantially reduced. This significantly diminishes its utility, and a number of studies have indicated that contemporary cardiac troponin assays render the use of myoglobin measurements unnecessary. [8, 10]
In patients with definite or possible ACS, serial evaluation of cardiac markers is essential to diagnosing acute MI.
The American College of Emergency Physicians (ACEP) recommends 3 different testing strategies for ruling out NSTEMI in the ED. [38] One strategy is to use a single negative CK-MB, TnI, or TnT measured 8-12 hours after symptom onset.
Another strategy is to use negative myoglobin in conjunction with a negative CK-MB mass or negative TnI measured at baseline and at 90 minutes in patients presenting less than 8 hours after symptom onset.
A third approach is to use a negative 2-hour delta CK-MB in conjunction with a negative 2-hour delta TnI in patients presenting less than 8 hours after symptom onset.
Note that ACEP does not specify whether to use the 99th percentile cutoff, the 10% CV cutoff, or the WHO acute MI cutoffs for troponin.
The 90-minute rule-out with myoglobin recommended by ACEP was based on a study that used myoglobin in conjunction with either CK-MB or TnI. [39] The CK-MB/myoglobin protocol yielded a sensitivity of 92% at 90 minutes, and the myoglobin/TnI combination yielded a sensitivity of 97% at 90 minutes.
ACEP acknowledges the relative lack of specificity for myoglobin and that many of the myoglobin studies did not define MI per the ACC/ESC guidelines. Nevertheless, it is difficult to comprehend the ACEP clinical policy that accepts a missed MI rate of 3-8%.
ACEP’s recommendations on the use of delta CK-MB and delta TnI are based on determining the change in the level of TnI or CK-MB on samples drawn 2 hours apart. However, the delta TnI evaluation is partially based on the use of older TnI assays and outdated WHO acute MI cutoffs in a retrospective study. Therefore, ACEP’s recommendation to use a delta TnI in conjunction with a delta CK-MB may not be generalizable to other commercially available troponin assays. Caution must be used when using ACEP’s recommendations in ED patients with chest pain and suspected ACS.
The following table outlines the recommended sampling frequency after ED admission for the different cardiac markers.
Table 1. Sampling Frequency of Cardiac Markers (Open Table in a new window)
Baseline
3-4 h
6-9 h
12-24 h
>24 h
CK-MB isoforms, myoglobin
X
X
X
CK-MB, TnI, TnT
X
X
X
X
(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 interval are not as important as they are at the 6- to 9-hour mark. The 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 window are considered unlikely, unless the patient has ongoing symptoms of ischemia after admission. Acute MI can therefore be ruled out in patients with negative serial marker results through the 6- to 9-hour period after presentation.
Clinical trials have demonstrated the benefits of using cardiac markers as an indicator for specific therapeutic interventions in ACS. However, this use remains investigational; 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 trials with low molecular weight heparin (LMWH) showed a decreased cardiac event rate in patients with a positive result for TnT and who were treated with an LMWH. [40, 41]
Similarly, in the PRISM trial, patients with an elevated TnI who were treated with the glycoprotein (GP) IIb/IIIa inhibitor tirofiban (Aggrastat) demonstrated a significant decrease in cardiac events compared with patients without an elevated TnI level. No significant difference in outcomes was seen in patients without TnI elevations who were treated with tirofiban when compared with placebo. [42]
In the PURSUIT trial, patients who were treated with the GP IIb/IIIa inhibitor eptifibatide (Integrilin) within 6 hours of symptom onset obtained the greatest benefit, and subgroup analysis showed that patients with an elevated troponin level also had better responses to therapy than did those whose troponin result was negative. [43]
Finally, in the TACTICS-TIMI 18 trial, patients with elevations in TnI or TnT had a significant reduction in death, MI, or rehospitalization for ACS within 6 months after being treated with early invasive therapy consisting of aspirin, heparin, tirofiban, and catheterization/revascularization within 4-48 hours. [44, 45] Subset analysis noted 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. [46]
These studies suggest that a positive troponin result alone is an independent predictor of high risk for adverse cardiac events, and that therapy with LMWHs and/or GP IIb/IIIa inhibitors appears to confer the most benefit on patients with elevated cardiac troponins levels.
Patients with chronic renal failure (CRF) who are on hemodialysis are at increased risk of coronary artery disease and acute ACS, and cardiovascular disease accounts for about 50% of deaths in these patients. Early studies revealed a high prevalence of elevated cardiac troponin levels in patients with CRF, and especially of TnT. However, the clinical significance of an elevated TnT level is unclear.
Biochemical studies have demonstrated that the troponin elevation originates from the myocardium and is not related to the myopathy associated with renal failure. Yet, patients with CRF frequently have chronic congestive heart failure (CHF) and hypertension, which may independently elevate the troponin level. In addition, data suggest that elevated troponin levels in asymptomatic patients may reflect subclinical microinfarctions that are clinically distinct from ACS.
Large prospective studies have confirmed the association between TnT elevation and cardiac mortality in patients with CRF. The GUSTO IV ACS trial showed that patients with renal insufficiency and an elevated TnT had the highest overall risk of the composite endpoint of death or acute MI, [47] and 2 other prospective studies reported that an elevated TnT—but not TnI—increased the risk of long-term mortality. [48, 49] Whether elevated TnT increases cardiac risk in the short term (ie, 30 d) is unclear, but patients without short-term risk may not require hospitalization and potentially could be managed on an outpatient basis.
It has been suggested that chronically elevated troponin levels represent chronic structural cardiovascular disease, such as prior MI, chronic CHF, or hypertension in the setting of CRF. If true, these patients are at higher cardiac risk compared with the normal, healthy patient population and troponin remains a useful marker in the setting of CRF. [50, 51]
Note that 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 CRF and possible ACS is nondiagnostic for acute MI in the absence of other findings. Serial determinations are usually required, with a focus on a rise in the troponin level.
Ascertaining whether an elevated troponin in patients with CRF represents true acute MI or a false-positive result can be difficult. In 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 and in the absence of any other findings indicative of ACS, the elevated troponin result is more likely to be false positive for acute MI.
A number of studies have demonstrated that TnT can be used for risk stratification of patients with CHF without ischemia. Specifically, 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. [52]
Isolated studies have shown evidence of MI and elevated TnI levels in patients with subarachnoid hemorrhage. [53] 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 also been documented in other nonischemic cardiac disease states, such as tachyarrhythmias, hypertension, myocarditis, and myocardial contusion.
Investigations into emerging cardiac markers are focusing on increasing diagnostic sensitivity and specificity and on improving prognostic capability.
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 ACS. 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, and left anterior descending artery involvement. [44] These data suggest that increased BNP levels may correlate with greater severity of myocardial ischemia and could partially explain the association between increased BNP levels and adverse outcomes.
Data from OPUS-TIMI 16 and TACTICS-TIMI 18 demonstrated that baseline elevations of TnI, C-reactive protein (CRP), and BNP levels in patients with NSTEMI were independent predictors of the composite endpoint of death, MI, or CHF. [54] The PROMPT-TIMI 35 trial demonstrated that transient myocardial ischemia during exercise testing was associated with an immediate rise in BNP levels. [55] 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.
Preinterventional levels of mid-regional (MR) pro-adrenomedullin (MR-proADM), MR-pro-A-type natriuretic peptide (MR-proANP), and N-terminal pro-natriuretic peptide (NT-proBNP) also appear to have potential prognostic utility for adverse events within 1 year of patients with severe aortic valve stenosis who undergo transcatheter aortic valve implantation (TAVI). [56] In a prospective study of 100 consecutive patients with aortic stenosis who were treated with TAVI, preintervention levels of these markers as well as highly sensitive troponin T (hs-TnT) were not predictive of 30-day outcome but were associated with cardiovascular events and all-cause mortality at 1 year.
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 the primary and secondary prevention levels.
Data indicate that CRP is a useful prognostic indicator in patients with ACS, as elevated CRP levels are independent predictors of cardiac death, acute MI, 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 (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. Early studies showed significantly increased MPO levels in patients with angiographically documented coronary artery disease [57] ; these findings spurred further investigation into MPO as a novel cardiac marker.
In 604 sequential patients presenting to the ED with chest pain, elevated MPO levels independently predicted increased risk for major adverse cardiac events, including MI, reinfarction, need for revascularization, or death at 30 days and at 6 months. [58] Among the patients who presented to the ED with chest pain but who were ultimately ruled out for MI, an elevated MPO level at presentation predicted subsequent major adverse cardiovascular outcomes. In a subgroup of patients with negative baseline TnT, 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. However, further validation studies on MPO in the general ED chest pain population are needed to determine its sensitivity and specificity, as well as its negative and positive predictive values. [59, 60]
Ischemia modified albumin (IMA) is a novel marker of ischemia that is produced when circulating serum albumin contacts ischemic heart tissues. IMA can be measured by the albumin cobalt binding assay that is based on IMA’s inability to bind to cobalt. [61] A rapid assay with a 30-minute laboratory turnaround time has been developed and marketed as the first commercially available US 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 for as long as 12 hours.
Studies on the use of IMA in patients with chest pain in the ED found sensitivities that ranged from 71-98% and specificities of 45-65%, with a negative predictive value of 90-97% for ACS. [62]
A multimarker approach in one study, using a combination of ECG findings, TnT levels, and IMA levels, achieved a sensitivity of 95% for ACS, [63] while a second study calculated that the combination of IMA, myoglobin, CK-MB, and TnI increased the sensitivity to 97% for detecting myocardial ischemia. [64]
However, IMA levels are 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 IMA’s use in the ED diagnosis of ACS when the ECG and cardiac troponins levels are nondiagnostic.
Overview
What is the efficacy of cardiac markers?
Where are troponin cardiac markers found?
What reference ranges are used in cardiac troponin assays?
What is the role of troponin cardiac markers in the diagnosis of myocardial infarction (MI)?
How does the sensitivity, specificity, and precision cardiac troponin assays vary?
How can cardiac troponin assays be optimized for use in the emergency department (ED)?
What is the indication for cardiac marker point-of-care (POC) assays?
What is the prognostic value of cardiac troponin?
How is creatine kinase-MB (CK-MB) used as a cardiac marker?
How is the creatine kinase-MB (CK-MB) relative index used as a cardiac marker?
How are creatine kinase-MB (CK-MB) isoforms used as cardiac markers?
How is myoglobin used as a cardiac marker?
How are troponins used as cardiac markers in chronic renal failure (CRF)?
What are troponins used as cardiac markers in nonischemic heart disease?
What is the focus of emerging cardiac markers?
How are B-type natriuretic peptide (BNP) cardiac markers characterized and what do they indicate?
How are C-reactive protein (CRP) cardiac markers characterized and what do they indicate?
How are myeloperoxidase (MPO) cardiac markers characterized and what do they indicate?
How are ischemia modified albumin (IMA) cardiac markers characterized and what do they indicate?
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Baseline
3-4 h
6-9 h
12-24 h
>24 h
CK-MB isoforms, myoglobin
X
X
X
CK-MB, TnI, TnT
X
X
X
X
(only if very high risk)
Late presenters
(TnI, TnT)
X
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: Nothing to disclose.
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, Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director for Emergency Medicine, Sanz Laniado Medical Center, Netanya, Israel
Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, New York Academy of Medicine, New York Academy of Sciences, Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Edward Bessman, MD, MBA Chairman and Clinical Director, Department of Emergency Medicine, John Hopkins Bayview Medical Center; Assistant Professor, Department of Emergency Medicine, Johns Hopkins University School of Medicine
Edward Bessman, MD, MBA 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.
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; ProceduresConsult.com Royalty Other
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
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