Biomarkers in acute myocardial injury

Biomarkers in acute myocardial injury DEVIN W. KEHL, NAVAID IQBAL, ARRASH FARD, BEN A. KIPPER, ALEJANDRO DE LA PARRA LANDA, and ALAN S. MAISEL SAN DIEGO, CALIF

Acute coronary syndrome (ACS) is a significant cause of morbidity and mortality worldwide. The proper diagnosis of ACS requires reliable and accurate biomarker assays to detect evidence of myocardial necrosis. Currently, troponin is the gold standard biomarker for myocardial injury and is used commonly in conjunction with creatine kinase-MB (CK-MB) and myoglobin to enable a more rapid diagnosis of ACS. A new generation of highly sensitive troponin assays with improved accuracy in the early detection of ACS is now available, but the correct interpretation of assay results will require a careful consideration of assay characteristics and the clinical setting prior to incorporation into routine practice. B-type natriuretic peptides, copeptin, ischemia-modified albumin, heart-type fatty-acid-binding protein, myeloperoxidase, C-reactive protein, choline, placental growth factor, and growthdifferentiation factor-15 make up a promising group of other biomarkers that have shown the ability to improve prognosis and diagnosis of ACS compared with traditional markers. (Translational Research 2012;159:252–264) Abbreviations: ACS ¼ acute coronary syndrome; AMI ¼ acute myocardial infarction; BNP ¼ B-type natriuretic peptide; CAD ¼ coronary artery disease; CK-MB ¼ creatine kinase-MB; CRP ¼ C-reactive protein; cTn ¼ troponin; cTnI ¼ troponin I; cTnT ¼ troponin T; CV ¼ coefficient of variation; ECG ¼ electrocardiogram; ED ¼ emergency department; GDF-15 ¼ growth-differentiation factor-15; H-FABP ¼ heart-type fatty-acid-binding protein; hs-Tn ¼ high sensitivity troponin; hs-TnI ¼ high sensitivity troponin I; hs-TnT ¼ high sensitivity troponin T; IMA ¼ ischemia-modified albumin; MI ¼ myocardial infarction; MPO ¼ myeloperoxidase; NPV ¼ negative predictive value; NSTEMI ¼ non-ST-elevation myocardial infarction; NT-proBNP ¼ N-terminal pro-B-type natriuretic peptide; PlGF ¼ placental growth factor; PPV ¼ positive predictive value; ROC AUC ¼ area under the receiver operating characteristic curve; sCD40L ¼ soluble CD40 ligand; STEMI ¼ ST-elevation myocardial infarction

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he evaluation of acute chest pain has traditionally been a challenge. Delayed diagnosis and therapy not only increase cost but also lead to serious cardiac events and mortality.1,2 The accurate and rapid diagnosis of acute coronary syndrome (ACS) is therefore From the Department of Medicine, University of California at San Diego, San Diego, Calif; Veterans Affairs San Diego Healthcare System, San Diego, Calif. Submitted for publication October 31, 2011; accepted for publication November 15, 2011. Reprint requests: Devin W. Kehl, MD, Department of Medicine, University of California at San Diego, 200 West Arbor Drive, MC 8425, San Diego, CA 92103; e-mail: [email protected]. 1931-5244/$ - see front matter Ó 2012 Mosby, Inc. All rights reserved. doi:10.1016/j.trsl.2011.11.002

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critically important. Although injury to the myocardium can occur from multiple mechanisms, of greatest concern is prolonged ischemic injury leading to cellular necrosis, which defines myocardial infarction (MI) (Fig 1). The diagnosis of acute myocardial infarction (AMI) requires a clinical picture suggestive of myocardial ischemia, including symptoms of ischemia, characteristic changes on electrocardiogram (ECG), new Q waves on ECG, or imaging consistent with new loss of myocardium or new wall motion abnormality, coexistent with a rise or fall in cardiac biomarkers indicative of myocardial necrosis with at least 1 value above the 99th percentile of the upper limit of normal.3 The earliest biomarkers of myocardial injury included aspartate aminotransferase as well as lactate dehydrogenase and its isoenzymes,4 but their use was limited by poor specificity for myocardial necrosis. Specificity improved with

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Fig 1. Schematic representation of the pathogenesis of MI and its consequences. The biomarkers implicated in each process are listed next to the appropriate bubble.

the next generation of markers including creatine kinase-MB (CK-MB), which is abundant in the heart but still is found in other tissues.5 Currently, the gold standard biomarker for MI is cardiac troponin (cTn). However, an abundance of recent research has led to the identification of multiple new markers of myocardial injury, in addition to advances in cTn assays to allow for extremely high sensitivity. This review will serve to (1) summarize the current diagnostic and prognostic use of established biomarkers, including cTn, CK-MB, and myoglobin, used routinely in clinical practice for the diagnosis of MI; (2) discuss the recent emergence of highsensitivity cTn (hs-Tn) assays and the challenges raised with their implementation, and (3) discuss additional biomarkers of myocardial injury whose use is less established or in development. TROPONIN

The most widely established and useful biomarker for myocardial injury is cTn. The cTn complex is made up of 2 subunits—C, I, and T—which together control calcium mediated interaction of actin and myosin, leading to the contraction and relaxation of striated muscle.6 Troponin I (cTnI) and troponin T (cTnT) are expressed only in cardiac muscle,6 which allows these biomarkers to achieve extremely high specificity for myocardial damage (Fig 1).7,8 cTn subunits are detectable in the peripheral circulation when damage to the cardiac myocyte first leads to the release of cytoplasmic cTn, which accounts for 3% to 5% of cTnI and 7% of

cTnT levels9,10; the release of bound cTn subunits contributes to the continued rise in peripheral levels.6 After infarction, cTn remains detectable for days (4–7 days for cTnI and 10–14 days for cTnT),7 cleared from the circulation primarily by the reticuloendothelial system,11 and fragmented into molecules that are cleared renally.12 Although cTn elevation persists for days, initial detection is delayed after myocardial injury, as necrosis typically requires 2–4 h to occur in the setting of ischemia.3 Consequently, cTnT and cTnI are detectable only after this latency period following the onset of injury,7 and recommendations call for serial measurements to be drawn at presentation and again after 6–9 h from the onset of symptoms.3 Early studies of the diagnostic performance of conventional cTn assays demonstrated poor sensitivity in the initial period after the onset of symptoms suggestive of ACS. In an early study of patients with suspected ACS presenting to the emergency department (ED) within 24 h of symptom onset, the sensitivity of cTnI and cTnT at the initial presentation for AMI was 3.7% and 33.3%, respectively, which improved to 82% and 89% after 6 h and to 89% and 96% after 12 h.13 The specificities of both markers were high with initial specificity of 98% for cTnI and 89% for cTnT, without significant change on serial measurements.13 The positive predictive value (PPV) and negative predictive value (NPV) of cTnI and cTnT elevations improved substantially from initial presentation to 12 h after presentation.13 Consequently, cTn has the greatest benefit in identifying AMI at least six hours after presentation.13

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Table I. Strength of evidence for individual biomarkers for diagnosis and prognosis in AMI Biomarker

Diagnostic capability

Prognostic capability

cTn hs-Tn CK-MB Myoglobin BNP NT-proBNP Copeptin IMA H-FABP MPO CRP Choline PlGF sCD40L GDF-15

111 111 11 11 1 1 1 11 11 1 0 0 0 0 0

111 111 1 1 111 111 1 1 11 1 11 1 1 1 1

A subsequent meta-analysis confirmed that serial biomarker testing with cTn substantially improves the sensitivity for diagnosis of AMI while retaining high specificity.14 However, cTn has poor sensitivity to diagnose ischemia in the absence of infarction.14 CK-MB

CK-MB is 1 of 3 major creatine kinase isoenzymes, and although it can be found in skeletal muscle and the brain, its presence in high concentration is unique to myocardium.15 The release of CK-MB occurs rapidly after myocardial necrosis; it is not released in ischemia alone (Fig 1).16,17 Serial CK-MB measurements were the gold standard for the diagnosis of MI for many years and, when measured by mass assays, have a modest sensitivity and specificity for evaluating patients with ACS.18 The ability of plasma CK-MB to rise quickly after the onset of cell death is particularly useful in diagnosing MI and reinfarction. In a multicenter study of patients with MI, the values of CK-MB subforms were elevated in 21% and 46% of patients at 2 and 4 h, respectively, after the onset of chest pain, compared with 10% and 37% for cTnT.19 However, in another single-center study, the sensitivity at 3 h for CK-MB elevation was 47%, whereas that for cTnT was 20%.20 Large studies of patients presenting to the ED from 4 to 6 h after the onset of chest pain have shown a PPV of 42% to 82% and a NPV of 85% to 89% for ACS.20,21 However, CK-MB is less sensitive than cTn, increases more slowly than high-sensitivity assays, and is expressed sufficiently in skeletal muscle to impair specificity.15 Although CK-MB should not be used as a stand-alone diagnostic cardiac marker,22 it can be used in conjunction with cTn. A study of more than 1000 patients pre-

senting to the ED within 24 h of symptom onset found a PPV of 100% and an NPV of 95% for AMI with the combined use of cTn and CK-MB.23 MYOGLOBIN

Myoglobin is a small cytoplasmic heme protein found in all muscles. Myoglobin increases within 1 to 3 h in the setting of myocardial necrosis, usually peaks within 6 to 9 h, and may become normal in ,24 h (Fig 1).24 Of the conventional biomarkers currently in use, myoglobin is the earliest marker to rise after AMI (,2 h from the onset of chest pain) because of its relatively small size and high cytoplasmic content.25 Myoglobin has limited specificity for myocardial necrosis in patients who have renal insufficiency and skeletal muscle trauma.26 In addition, the rapid increase and normalization of myoglobin after AMI may lead to normal values for patients who present .24 h after symptom onset.27 A single myoglobin measurement at presentation has been shown to have a sensitivity of 70% and a NPV of 97.4% for predicting AMI among patients with suspected ACS.25 Because of the poor initial sensitivity of cTn for AMI, myoglobin should be used in conjunction with cTn for the early detection of AMI. One large study of ED patients evaluated for possible ACS found a combined sensitivity of myoglobin and cTnI of 94% when measured together in a serial fashion over 9 h, even though initial sensitivities were only 60% and 52%, respectively.28 Myoglobin, when compared with CK-MB, cTnI, or cTnT, may offer the best overall diagnostic performance in screening for AMI within 2 h of ED presentation.13 HIGH-SENSITIVITY TROPONIN

The determination of an optimum cutoff concentration of any biomarker, including cTn, is critically important. Generally, a cutoff concentration for cTn representing 99% of the healthy population has been recommended29 to reduce the frequency of false positive results. Biomarkers should also be measurable with sufficient analytical precision and defined as a coefficient of variation (CV) ,10%.3 With conventional cTn assays, the recommended level of precision is often unachievable at a level representing the 99th percentile but rather at levels from 1.5 to 9 times higher.30 Challenges with poor cTn sensitivity early in clinical presentation have inspired the development of a new generation of highly sensitive assays, with a 10- to 100-fold lower limit of detection.29 These hs-Tn assays have allowed the diagnostic cutoff to be lowered to the level of the 99th percentile or lower while maintaining precision at a CV ,10%.29 However, recent recommendations

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have suggested a more lenient precision goal of ,20% CV.31,32 Several large multicenter studies of ED patients with suspected AMI have analyzed the diagnostic performance hs-Tn assays. In 2 landmark studies, 4 hs-Tn assays (hs-TnI, Abbott Laboratories, Abbot Park, Ill; hs-TnT and hs-TnI, Roche Diagnostics, Inc, Indianapolis, Ind; hs-TnI, Siemens Corporation, Washington, DC) were compared with a standard cTnT assay (Roche Diagnostics).33,34 Each assay showed excellent diagnostic performance for a diagnosis of AMI with an area under the receiver operating characteristic curve (ROC AUC) ranging from 0.95 to 0.96, compared with 0.90 for the standard assay in the study by Reichlin et al33 and 0.85 in the study by Keller et al.34 Even within 3 h of the onset of chest pain, hs-Tn assays performed excellently with a ROC AUC ranging from 0.92 to 0.94 compared with the standard cTnT assay at 0.76.33 Recent studies have confirmed superior performance of the new assays. Weber et al29 found that a single baseline measurement using a hs-TnT assay yielded a sensitivity of 96% and specificity of 61% for AMI, whereas the cTnT assay yielded a sensitivity of 82% and a specificity of 90%. NPV increased from 54% to 80% using the hsTnT assay, together with a decrease in PPV from 97% to 91%.29 Among patients with a negative cTnT, positive hs-TnT yielded a 82% sensitivity and 68% specificity, with a ROC AUC of 0.81,29 which suggests that the new assays increase the number of non-ST elevation MI (NSTEMI) diagnoses and enables earlier detection of evolving NSTEMI.35 The time to diagnosis has also been shown to be significantly shorter using hs-TnT compared with cTnT in patients with an initially negative cTnT concentration.36 With conventional cTn, poor sensitivity of baseline measurements necessitates the use of serial measurements to improve diagnostic performance. The use of serial sampling has also been shown using hs-Tn, although the data are less clear because of the superior performance on baseline measurements. One study showed improved sensitivity (from 69% to 94%), specificity (from 78% to 81%), and ROC AUC (from 0.82 to 0.96) with measurements of hs-TnI at baseline and after 6 h compared with single baseline measurements.37 A change in hs-TnI concentration of more than 30% between the 2 measurements had a sensitivity of 75% and a specificity of 91%.37 Another study using an hsTnT assay found that the sensitivity for NSTEMI increased gradually from 61.5% on presentation to 100% at 3 h, without a significant change in specificity.35 These authors found also that doubling the hs-TnT concentration within 3 h in the presence of a second elevated level was associated with a PPV of 100% and a NPV of 88% for NSTEMI.35 However, other data suggested that

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serial measurements using hs-Tn may not be helpful. In 1 study, the diagnostic accuracy of serial hs-TnI levels at 3 and 6 h after presentation was found to be no better than baseline samples.34 This finding held true almost regardless of the time of chest pain onset with respect to presentation, with diagnostic accuracy of 88% for patients who presented within 6 h after onset of chest pain, 95% from 6 to 12 h, and 100% for patient who presented more than 12 h after the onset of symptoms.34 Another study confirmed these findings, showing a minimal increase in the ROC AUC from 0.94 to 0.96 at baseline to 0.98 after 3 h, and no additional diagnostic information at the 1- and 2-h time points.33 The differences in conclusions from these studies may lie in the differences in the time from the onset of symptoms to emergency room presentation. In summary, it remains controversial as to whether single measurements of hs-Tn assays may be as effective in some studies as serial measurements in diagnostic performance. Nevertheless, serial data are important to establish a trajectory of cTn elevation in the absence of high clinical suspicion for ACS. If a low-positive initial hs-Tn is detected, then serial measurements can delineate whether this elevation may be chronic because of other conditions that lead to cTn elevation. INTERPRETATION OF TROPONIN ELEVATION

Although cTn classically indicates myocyte necrosis, its release does not offer any information about the underlying cause of necrosis.3 Furthermore, several cellular processes other than necrosis can induce cTn release. These include apoptosis38; cellular release of cTn degradation products, which is achievable after 15 min mild ischemia39; increased cell wall permeability, which may occur because of stretch or ischemia40; and the release of membranous blebs, which has not yet been demonstrated in humans.38,41 Consequently, a multitude of nonthrombotic and even nonischemic causes of cTn elevation have been described. The nonischemic causes include direct myocardial injury from trauma or electrical cardioversion, myocardial wall stretch, exposure to toxins, local infection or inflammation as in myocarditis, infiltrative disorders, and sepsis.6 Renal failure, which is discussed in more detail subsequently, and neurologic injury can also cause cTn elevation, the latter through more complex mechanisms.6,42 Ischemic but nonthrombotic causes of elevation include the supply and demand imbalances in coronary blood flow observed with tachycardia, hypotension, or anemia.6 In heart failure, cTn elevation can be observed in part because of this mechanism, leading to subendocardial ischemia.32 although it has been hypothesized that coronary endothelial dysfunction43 as well as

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myocardial injury from wall stretch32 contribute as well. cTn release has also been observed in circumstances of physiologic stress in the apparent absence of myocardial necrosis. For example, after a marathon, up to 45% of runners show elevated cTnT levels, which increases to a rate of 86% using an hs-TnT assay.44 Although the underlying mechanism of this finding is unclear, it is unlikely to be related to myocardial necrosis, as no delayed enhancement suggestive of myocardial damage has been detected in cardiac magnetic resonance imaging of these patients.45 Even physiologic levels of cTn can be detected presumably because of the normal myocyte turnover.38,46 In the Dallas Heart Study of asymptomatic healthy adults, the prevalence of detectable cTnT ($0.003 ng/mL) was found to be 25.0% with the highly sensitive assay and 0.7% with the standard assay.34,47,48 In other studies, the prevalence of true elevations of hs-TnT ($0.01 ng/mL) was 4% among elderly individuals both with and without heart disease.49 Several characteristics of the particular cTn assay used must be considered carefully in the interpretation of the results. Hemolysis can cause falsely negative cTnT and falsely elevated cTnI.32,50 Furthermore, false-positive results can result also from assay interference with heterophilic antibodies,51 although antibodies are now added to most assays to reduce the incidence of this interference.51 Another important consideration is the biologic and analytical variability of the cTn assay. With the new hs-Tn assays, this variability can be significant at low levels, both within the normal reference range and slightly above it.32,52 The short-term variability (ie, hour-to-hour changes) of 1 hs-TnI assay has been estimated in the range of 32% to 46%, but it is more prominent at low levels within the normal reference range as well as slight elevations.52 With use of conventional cTn assays and at higher concentrations of hs-Tn assays, biologic variability becomes less significant. Consequently, following the serial changes in hs-Tn in individual patients may be of greater value than the use of populationbased reference ranges.52 The advent of hs-Tn has raised concern about the interpretation of elevated levels in the setting of suspected ACS, particularly to what extent elevations are observed in the presence of ischemia without infarction (Fig 1). A recent study showed that hs-TnT concentrations in coronary sinus blood increased after a short duration of atrial pacing and were higher in patients with coronary artery disease (CAD) and with coronary sinus lactate elevation to suggest ischemia.53 However, hsTnT levels were elevated even in patients without angiographic evidence of CAD or lactate elevation.53 These findings suggest that an increase in hs-TnT

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may be observed in myocardial ischemia alone rather than solely necrosis, and concerns are raised over the specificity of hs-TnT assays for infarction, although the study did not definitively rule out the possibility of microscopic areas of necrosis. Other similar studies have had mixed results. Some have failed to show hsTnT elevation after pharmacologically induced ischemia,54 and others have detected it in the absence of infarction.55 In the clinical setting, hs-Tn levels are increased commonly in patients with retrospectively confirmed diagnoses of unstable angina (UA). In one small study, 82% of patients classified as UA with negative TnI had positive hsTnI, suggesting that most patients with active ischemia had low-level troponin elevation or that these patients were misclassified.56 Large multicenter studies described previously have also found that for a diagnosis of unstable angina, hsTn elevations have low to moderate diagnostic accuracy, with ROC AUCs ranging from 0.56 to 0.76 and NPVs of 74% to 85%.33,34 One possible explanation for these findings is that cTn is released on a continuum, rather than a threshold, from ischemia to infarction.53 However, what remains unclear is whether these elevations are representative of ischemia alone or micronecrosis. Troponin in renal failure. Among patients with endstage renal disease, the prevalence of elevated cTn can be as high as 53%.11 No single, universally accepted rationale for this phenomenon exists, but possible factors include impaired renal clearance of cTn degradation products and diffuse myocardial injury.32 Usually, these patients have persistent elevations, making it imperative to study serial measurements in these patients to assess for change from baseline in combination with other clinical evidence of myocardial injury.32 Nevertheless, in hemodialysis patients without ACS symptoms, a positive cTnT can predict all-cause mortality.57 In contrast to cTnT, cTnI is unlikely to be elevated falsely in this patient population. Among chronic kidney disease and hemodialysis patients without ACS symptoms, elevated cTnI may have specificity as high as 97% and 96%, respectively, for ACS.57 PROGNOSTIC PERFORMANCE OF CONVENTIONAL AND HIGH-SENSITIVITY TROPONIN

In addition to providing diagnostic information, cTn offers powerful prognostic information in ACS. Early trials of conventional cTn elevation in patients with suspected ACS showed higher mortality among those with elevated cTnI and cTnT on admission, even after adjustment for ECG findings and comorbidities.28,58,59 The elevation of hs-Tn also predicts adverse outcomes at 1 and 6 months,29,34,60 and the prognostic performance

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of high-sensitivity assays may be superior to conventional assays.29 In addition, the use of serial hs-TnI measurements with a change of at least 30% also improves risk stratification for cardiac events and death when added to single-baseline measurements.37 Finally, even among patients with suspected ACS who do not have significant angiographic CAD, elevated conventional cTn is associated with a higher risk for death or reinfarction at 6 months.60 cTn can also provide prognostic information in patients with STEMI. Among patients treated with PCI, infarct size has been shown to correlate with peak cTnT.61 Furthermore, peak cTnT is an independent predictor of major adverse cardiac events and heart failure at 3-month follow-up.61 A single cTnT measurement after STEMI has been shown to carry equivalent prognostic information compared with serial samples.62 cTn levels can be used to direct clinical management as well. In the TACTICS-TIMI II trial, significant reductions in death, MI, and rehospitalization for ACS were found using an early invasive strategy of angiography with or without revascularization within 48 h compared with a conservative strategy of medical management only among patients with ACS with a cTnI level of 0.1 ng/mL or more.63 The benefit of more aggressive management was evident even among patients with low-level (0.1–0.4 ng/mL) cTnI elevation.63 Similarly, the use of a lower diagnostic threshold of hs-TnI levels in another study led to a reduction in the risk of adverse outcomes in those patients with an intermediate troponin range.64 As described, cTn elevation can occur in exacerbations of heart failure. An elevation in this setting is prognostic of short-term risk of death, worsening heart failure, and new or recurrent MI.65 hs-TnT also shows prognostic value in patients with heart failure.66 In the Prevention of Events with Angiotensin-Converting Enzyme Inhibition trial, hs-TnT was detected in 97.7% of patients who had stable CAD and normal systolic function, and the levels were associated with risk factors including diabetes and C-reactive protein (CRP).67 However, no relationship with MI was observed.67 cTn can offer prognostic information even if detected in asymptomatic adults. Several cardiovascular risk factors as well as left ventricular hypertrophy, left ventricular systolic dysfunction, and chronic kidney disease have been shown to correlate with hs-TnT levels.68 Furthermore, detectable hs-TnT levels within the normal reference range have been associated independently with mortality in asymptomatic adults even after an adjustment for multiple cardiac risk factors,47,49 and therefore these levels may be able to identify high-risk subjects in the primary prevention of CAD.68

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B-TYPE NATRIURETIC PEPTIDE (BNP)

In recent years, natriuretic peptides have emerged as effective biomarkers for the diagnosis of heart failure and myocardial dysfunction (Fig 1). The most relevant biomarkers in this peptide family include BNP and Nterminal pro-B-type natriuretic peptide (NT-proBNP). BNP is a cleavage product of NT-proBNP, which in turn is a cleavage product of pro-B-type natriuretic peptide, made predominantly in the ventricles.69 Natriuretic peptides work as protective hormones that counteract the physiologic abnormalities of heart injury and myocardial dysfunction. The Breathing Not Properly trial by Maisel et al70 was the first study to validate the use of BNP in the diagnosis of patients presenting to the ED with acute dyspnea, and it showed effectiveness in establishing or excluding the diagnosis of acute heart failure.70 BNP also has diagnostic and prognostic utility for MI. Among patients in the ED with suspected ACS, BNP . 30 pmol/L has been shown to be 76% specific and 71% sensitive for the diagnosis of MI, with an NPV of 96%.71 BNP is an independent predictor of short- and long-term major adverse events after MI,71,72 and when combined with left ventricular ejection fraction, it improves risk stratification substantially for mortality, heart failure, and new ischemic events.71 NT-proBNP has also been studied extensively for the diagnostic evaluation of patients with myocardial injury and acute dyspnea with similar results.73 In a recent study of patients with ACS, the NT-proBNP level 6 weeks after diagnosis was an independent predictor of risk for future adverse outcomes, and it added incremental prognostic value to established risk factors.74 Natriuretic peptide assays are inexpensive, reproducible, and accessible, which makes them effective adjuncts to physical examination, standard laboratory evaluations, and imaging studies in the diagnosis and management of ischemia. With more experience in their clinical application, natriuretic peptides should continue to play a significant role in the evaluation and management of ACS patients in the future. COPEPTIN

Copeptin is a glycosylated peptide that shares the same precursor as vasopressin. Copeptin is stable in serum and easy to measure. Normal degrees of copeptin secretion mirror vasopressin secretion in maintenance of plasma osmolality. However, in severe diseases such as shock, sepsis, stroke, or cardiovascular diseases, the nonosmotic release of AVP is portrayed by a sharp increase in plasma copeptin, which carries diagnostic and prognostic value for myocardial injury (Fig 1). The Leicester Acute Myocardial Peptide study was the first to investigate the prognostic potential of

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copeptin in patients admitted with AMI.75 Plasma copeptin was the highest on admission and reached a plateau at days 3 to 5. Persistently elevated copeptin at this later time point was associated with death and readmission for heart failure, independent of established conventional risk factors, showing that copeptin can be used as a marker of death or heart failure in patients with AMI.75 When combined with NT-proBNP, copeptin provided a more accurate prediction of adverse outcome.75 Copeptin may also have a role in the diagnosis of patients presenting to the ED with chest pain. Copeptin levels have been found to be significantly higher in patients with AMI compared with other diagnoses.76 In 1 study, the combination of cTnT and copeptin at initial presentation resulted in a ROC AUC of 0.97, which is significantly higher than 0.86 for cTnT alone.76 A negative cTnT and copeptin at presentation allowed AMI to be ruled out with an NPV of .99%.76 The preceding studies underscore the fact that in triage of patients with suspected ACS and myocardial dysfunction, copeptin can improve diagnostic performance and clinical decision making in combination with conventional markers. ISCHEMIA-MODIFIED ALBUMIN (IMA)

IMA is a biomarker for acute ischemia that is approved by the U.S. Food and Drug Administration. When exposed to ischemic conditions, the N-terminus of albumin is damaged, which makes it unable to bind metals and capable of being measured by an albumin cobalt-binding test.77 Because its levels in the blood increase within minutes of the onset of ischemia and return to normal within 6–12 h, IMA has been implicated in the detection of acute ischemia prior to necrosis (Fig 1).78,79 One study of patients with suspected ACS found that IMA had a better NPV for ACS of 92% than the combination of CK-MB, myoglobin, and cTnT (86%), and the use of all 4 biomarkers together resulted in an NPV of 95%.80 Similarly, a meta-analysis showed that in this patient population, the combination of a nondiagnostic EKG, negative cTn, and negative IMA led to a sensitivity of 94.4% and NPV of 97.1%.81 However, the PPV of IMA has been reported as low as 40%.80 Together, these data suggest that IMA may have the ability to help rule out a diagnosis of ACS in patients with chest pain. However, other IMA studies have yielded less favorable results. One study of ED patients with possible ACS found that in those presenting within 4 h of chest pain onset, IMA had an ROC AUC of only 0.58 to diagnose ACS.82 IMA may have limited potential as a prognostic marker as well. The sensitivity and specificity of elevated IMA for future mortality has been reported at 76% and 74%, respectively, which is of similar magni-

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tude compared with cTnT.77 However, in this particular study, cTnT was not increased significantly in those with high IMA, which suggests that IMA may not have identified patients with eventual myocardial necrosis.77 Additional research must be done in this area. Thus, whereas IMA has shown potential as an adjunct marker to troponin for ischemia in some studies, more research is required before it can be confidently used clinically. Poor specificity for cardiac ischemia and variable optimal cut-off values are primary concerns. Increased IMA levels have been observed in nonmyocardial ischemia such as that from skeletal muscle and the gastrointestinal tract. Furthermore, albumin can be modified to IMA by hypoxia, acidosis, and free radicals, all of which can occur from the oxidative tissue stress found in many other conditions.83,84 HEART-TYPE FATTY-ACID-BINDING PROTEIN

Heart-type fatty-acid-binding protein (H-FABP) is a cytosolic, low-molecular-weight protein involved in fatty acid transport and metabolism. Although it is expressed overwhelmingly in the myocardium, small quantities also can be found in the brain, kidney, and skeletal muscle.85 The small size of the protein allows it to leak out of the porous cell membranes of ischemic myocardial cells. As a result, several studies have indicated that it is a marker of myocardial ischemia even in the absence of frank necrosis (Fig 1).86 H-FABP may have utility both as a diagnostic marker of ACS as well as a prognostic marker in ACS patients and those at lower risk for CAD. One study compared H-FABP with traditional markers such as cTnI, CK-MB, and myoglobin in the early diagnosis of MI, and it was found that N-FABP had better sensitivity than the other markers studied at 0–3 h (64.3%) and at 3–6 h (85.3%) after the onset of chest pain.87 Combining HFABP with cTnI yielded better results with sensitivities increasing to 71.4% and 88.2% for those time points, respectively. This combination also resulted in NPVs of 94% at 0–3 h, 98% at 3–6 h, and 99% at 6–12 h after chest pain onset.87 In another study comparing HFABP with hs-TnT for the early diagnosis of ACS, hsTnT and H-FABP had similarly favorable ROC AUCs of 0.82 and 0.83, respectively.88 Although the overall specificity of the markers used in this study was poor, H-FABP did perform better than hs-TnT (78.2% vs 61.2%) in a population of patients with a high prevalence of STEMI.88 H-FABP also has prognostic utility in myocardial injury. Among high-risk patients with ACS, 1 large study found patients H-FABP elevation at presentation to be at 2.6-fold increased risk of serious cardiac events and death, independent of other biomarkers.89 Furthermore, higher elevations may carry

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a higher risk.90 H-FABP can also stratify risk in among lower risk patients. A single H-FABP measured 12–24 h after symptom onset among patients with negative cTn has been found to be an independent predictor of MI or death at 18 months.88 With additional studies in this cohort, the biomarker could be a strong prognostic tool for those currently classified as low risk for severe cardiac events. However, the routine adoption of H-FABP as a diagnostic or prognostic marker in ACS will require additional attention to several analytic issues including optimum cutoff value, differing concentrations between plasma and serum samples, and variations based on age and renal function.90,91 MYELOPEROXIDASE (MPO)

MPO is an inflammatory enzyme that is found abundantly in ruptured atherosclerotic plaques.92 Levels of this biomarker have been shown to correlate significantly with established markers of inflammation including interleukin-6, CRP, white blood cell count, and tumor necrosis factor alpha.93 MPO is released by macrophages and neutrophils during acute inflammation and is involved with the oxidation of lipids and destruction of the vasodilator nitric oxide.92-94 As a result of its connection to inflammation and atherosclerosis, MPO has been implicated not only as a potential biomarker in stable ischemic heart disease but also in acute myocardial injury, in which it serves as a marker of plaque instability, with increased levels indicating the activation of inflammatory cells around a vulnerable plaque (Fig 1).95 MPO has demonstrated some value as a prognostic biomarker in predicting future adverse events. Although MPO can help assess the risk of CAD in healthy individuals, the relationship between MPO and CAD is stronger in patients with established or suspected ACS. A study of ED patients complaining of chest pain found that MPO levels were significantly higher in patients who were found to have MI within 16 h of presentation compared with those who were not. MPO was an independent predictor for increased risk of MI, major adverse coronary outcomes, and need for revascularization within 30 days and 6 months after initial presentation.96 Among patients with established ACS, MPO has been shown to be an independent predictor of future MI, but not all-cause mortality, at 2 years.97 Finally, whereas MPO has strong ties to atherosclerosis, inflammation, and oxidative stress, more research needs to be done in patients with renal impairment before it can be used confidently in the ACS cohort. CRP

CRP is an acute-phase protein produced by the liver that is upregulated in conjunction with the inflammatory

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response.98 CRP activates complement through the classic pathway, and in doing so, it binds to damaged cells including those in infarcted myocardium (Fig 1).99 Recent studies have aimed at determining the role of CRP both as a diagnostic and prognostic tool for ACS. However, the evidence is conflicting and limited by the fact that CRP is a nonspecific marker of inflammation.98 Although the use of CRP as a diagnostic tool for ACS in a patient presenting with acute chest pain is generally limited by poor accuracy,100 some data suggest that a CRP level of 20 mg/dL may be indicative of subacute cardiac rupture after MI.101 As a prognostic tool, CRP may be useful in patients with ACS in which high CRP levels (10–15 mg/L) have been a strong indicator of long-term future cardiac events,102-105 although the evidence for CRP as a predictor of short-term events is conflicting.106 In another study of patients with MI treated with thrombolysis, high CRP levels (.226 mg/L) were associated with an increased risk of death within the first 6 months of the infarct event.107 Similar studies showed that this risk could be reduced with the treatment of angiotensin-converting enzyme inhibitors and amiodarone.108-110 Thus, the use of CRP as a biomarker for myocardial injury should be done in conjunction with other biomarkers for a more complete and accurate diagnosis. CHOLINE

Choline is a water-soluble essential nutrient found in the head groups of phospholipids that make up cell membranes.111 Choline is released into the blood after cleavage of phospholipids (Fig 1). It has potential use as a prognostic and diagnostic marker for ACS, ischemia, and necrosis. A recent study examining whole blood choline levels after hospital admission determined that choline is a strong predictor of cardiac arrest or death and may identify high-risk unstable angina patients who have not had an acute infarct event.112 Although choline alone has been shown to be a strong predictor, when combined with cTn, the strength of risk assessment increases greatly.112 As a biomarker for myocardial injury, choline can be beneficial for future prognosis in patients with ACS, although it should be coupled with other biomarkers such as cTn to increase the accuracy of clinical assessment. PLACENTAL GROWTH FACTOR

Placental growth factor (PlGF), like CRP, is a biomarker of vascular inflammation. It stimulates angiogenesis as well as the recruitment and proliferation of inflammatory cells, which produce collagen-degrading enzymes, and their adhesion to vascular walls.113 Consequently, this biomarker plays a role in plaque

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vulnerability, rupture, and acute cardiovascular events, and it may be useful in the risk stratification of patients with STEMI (Fig 1).114 Among patients presenting to the emergency room with suspected ACS, a combination of BNP and PlGF in 1 study was the most accurate predictor of adverse cardiac events at 1 year; together, they offered an NPV of 97% for 30-day events.115 The absence of elevations in the serial values of BNP and PlGF led to a ,1% incidence of adverse events at 1 year.115 PlGF may, therefore, be helpful in the risk stratification of patients in low- to moderate-risk categories.

SOLUBLE CD40 LIGAND (SCD40L)

sCD40L is a cellular ligand released from activated platelets and stimulated lymphocytes, and as a result it can be indicative of the activation of inflammatory and coagulant pathways (Fig 1).116,117 Early studies showed an association with elevations in this marker and adverse cardiac events in patients with suspected ACS.118,119 However, multiple preanalytic and analytic difficulties have limited clinical use of sCD40L in ACS prognosis.120 Indeed, subsequent studies have failed to show the associations found in previous studies.117,121 sCD40L does not have a current role in the risk assessment of patients with ACS.

GROWTH-DIFFERENTIATION FACTOR-15 (GDF-15)

GDF-15 is a cytokine that is expressed in the liver constantly but strongly upregulated after injury to other organs.122 Increases in GDF-15 levels have been observed specifically in myocardial and reperfusion injury.123 In vitro experiments of cardiac myocytes have suggested that GDF-15 may play a role in cardiac injury and adaptation (Fig 1),124 and GDF-15 may have both prognostic and diagnostic value for ACS. Diagnostically, serum GDF-15 levels increase after an ischemic event or reperfusion injury, although specificity is poor.124 As a prognostic tool, high levels of GDF-15 have been found to be an independent predictor for yearly mortality rate and the use of invasive strategy, and they add prognostic value to current cardiac biomarkers, including BNP, cTnT, and the thrombolysis in myocardial infarction score.125,126 A high level of GDF-15 on admission of patients with ACS has shown to be a strong predictor of recurrent MI and to identify patients that would benefit from an invasive strategy.127 High levels of GDF-15 have also predicted 1-year mortality in patients with STEMI.125 Differences in mortality rates can be observed within 30 days of baseline measurement, which may also provide an early window for intervention to prevent further events.125,127

CONCLUSION

The future of biomarkers in the detection of myocardial injury may call for a multimarker approach for diagnosis and prognosis (Table 1). Indeed, data have already accumulated to support this approach. One study using cTnT, CRP, and NT-proBNP showed that elevations in 2 or 3 of these biomarkers predicted worse outcomes than those with 1 biomarker alone.128 Early markers of ischemia such as IMA and H-FABP may identify higher risk patients and may call for more aggressive intervention or closer monitoring. However, the emerging generation of hs-Tn assays may obviate the need for these other assays, particularly myoglobin and CK-MB, as elevations may precede clear-cut myocardial necrosis. As we have begun to learn from hs-Tn assays, an adequate study of a multitude of assay considerations including biologic variability for emerging biomarkers will be necessary prior to widespread adoption into routine clinical practice. Regardless, the future undoubtedly will call for a more discerning clinician to interpret elevations in biomarkers, particularly hs-Tn, in an appropriate clinical context.

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