troponins and creatine kinase as biomarkers of cardiac injury

02/05/13 Troponins and creatine kinase as biomarkers of cardiac injury

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AuthorsAllan S Jaffe, MDDavid A Morrow, MD, MPH

Section EditorJuan Carlos Kaski, MD, DM, DSc,FRCP, FESC, FACC, FAHA

Deputy EditorGordon M Saperia, MD, FACC

Troponins and creatine kinase as biomarkers of cardiac injury

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Mar 2013. | This topic last updated: sep 18, 2012.

INTRODUCTION — Cardiac injury is defined as the disruption of normal cardiac myocyte membrane integrityresulting in the loss into the extracellular space (including blood) of intracellular constituents including detectablelevels of a variety of biologically active cytosolic and structural proteins such as troponin, creatine kinase,myoglobin, hearttype fatty acid binding protein, and lactate dehydrogenase. Injury is usually considered irreversible(cell death), but definitive proof that cell death is an inevitable consequence of the process is not available. (See'Ischemia and enzyme elevations' below.)

Causes of cardiac injury include trauma, toxins, and viral infection, but ischemia or infarction consequent to animbalance between the supply and demand of oxygen (and nutrients) is the most common cause.

When a sufficient number of myocytes have died (myocyte necrosis) or lost function, acute clinical disease isapparent; examples include myocardial infarction (MI) or myocarditis. (See "Criteria for the diagnosis of acutemyocardial infarction" and "Clinical manifestations and diagnosis of myocarditis in adults".)

The biochemical characteristics and utility of troponins and creatine kinase MB fraction (CKMB) for the diagnosisof cardiac injury and acute myocardial infarction (MI) will be reviewed here. Other biomarkers of cardiac injury anddisease states, other than an AMI, in which elevation of biomarkers are seen are discussed separately. (See"Biomarkers of cardiac injury other than troponins and creatine kinase" and "Elevated cardiac troponinconcentration in the absence of an acute coronary syndrome".)

ISCHEMIA AND ENZYME ELEVATIONS — There is considerable debate about whether biomarkers such astroponins or CKMB are released with reversible as well as irreversible injury. If this phenomenon occurs, it shouldbe seen with all cardiac biomarkers, and it would not be possible biochemically to distinguish reversible fromirreversible injury [1].

Those in favor of the hypothesis that cardiac biomarker elevations occur with reversible injury suggest that theminor elevations seen after triathlons and/or marathons in some individuals and with severe pulmonary embolismreflect reversible injury since they tend to be transient and do not have the persistence seen with an acute MI [24].The development of more highly sensitive assays may allow for a better evaluation of this issue in the future sinceincreases from normal values may persist but not be detected without highly sensitive assays. (See "Elevatedcardiac troponin concentration in the absence of an acute coronary syndrome", section on 'Myocardial strain'.)

Older studies (using lesssensitive tests) that evaluated patients with ischemia during stress testing did not showelevations in troponins or other biomarkers and thus did not support the hypothesis [5]. However, a report from thePROMPTTIMI 35 study, which evaluated troponin release after stress testing using an ultrasensitiveprecommercial troponin (I) assay, does support the above hypothesis [6]. In this study of 120 patients referred for

evaluation of possible myocardial ischemia, significant changes in circulating troponin were detected only in the 70patients with transient stresstest induced myocardial ischemia documented on myocardial perfusion imaging. Theconsistency of the results was impressive, but the magnitude of the changes was small (mean = 0.002 mcg/L),meaning this approach cannot be used in individual patients without extremely high precision assays. Whether theincreases reflect release due to ischemia or minor amounts of damage is unclear. A similar study using anotherhigh sensitivity precommercial assay for cTnT could not replicate these findings [7].

A study using pacing and coronary sinus sampling with an hscTnT assay also found elevations both in thecoronary sinus and systemically with and without elevations in lactate in the coronary sinus [8]. These findingscould be interpreted as suggesting that cTn is released with cardiac stress and thus due to reversible injury.Alternatively, elevations could represent irreversible myocyte injury since it is now clear that reparativemechanisms exist within the heart. However, from the clinical perspective, this issue might be less critical.Elevations of cTn in most situations, save short term after extreme exertion, are associated with adverseconsequences regardless of their mechanism of release.

TROPONINS — Cardiac troponin I (cTnI) and T (cTnT) are cardiac regulatory proteins that control the calciummediated interaction of actin and myosin [9]. Both have cytosolic or early releasable and structural pools, with mostexisting in the structural pool [10,11]. (See "Excitationcontraction coupling in myocardium", section on 'Role oftropomyosin and troponins'.)

These proteins are products of specific genes and therefore have the potential to be unique for the heart. Studiesperformed with cTnI have failed to find any cTnI outside of the heart at any stage of neonatal development [12,13].In contrast, cTnT is expressed to a minor extent in skeletal muscle. However, the present cTnT assay was notthought to detect these forms [14]. Data indicate that there are at least some patients with skeletal muscle diseasewho have proteins that are detected by the antibodies in the cTnT and hscTnT assay. This implies that skeletalmuscle can, in some patients, be the source for elevations of cTnT detected in the blood [15]. Defining thefrequency of this phenomenon will require additional study. Thus, in most clinical settings, its specificity should becomparable to that of cTnI.

It is thought that early troponin release during MI comes from what has been termed the cytosolic pool, which is ofa magnitude that is similar to the amount of CKMB in that pool. In reality, a better name for this pool might be theearly releasable pool, since its cellular localization is not proven. Subsequent release is prolonged with degradationof the actin and myosin filaments in the area of damage.

Variations in assays — Although cTnI and cTnT are specific markers for myocardial damage, there are variationsin the sensitivity and specificity of various immunoassays [16,17]. This is related to a lack of standardization, thepresence of modified cTnI and cTnT in the serum, and variations in antibody crossreactivities to the variousdetectable forms of cTnI that result from its degradation [14,1822]. Pointofcare tests are usually less sensitivethan laboratorybased tests [1,23]. Newer assays, labeled 'high sensitivity' or ‘highly sensitive’ assays are beingdeveloped. However, there has been substantial confusion in the literature concerning what assays should bedefined as ‘high sensitivity’. (See 'High sensitivity assays' below.) In the absence of such a specific designation,the assays referred to are contemporary assays and not hscTn assays.

Many groups have called for standardization of assays and prospective criteria for their analytic characterization[1,2326]. The joint 2012 European Society of Cardiology/American College of Cardiology Foundation/AmericanHeart Association/World Health Federation definition of myocardial infarction endorses the use of troponin as themarker of choice overall and for each subcategory of AMI. It also states that laboratories should utilize a cutoff

value of the 99th percentile of a normal reference population to define the presence of cardiac injury. Ideally thisvalue should be measurable with a coefficient of variation (CV) of 10 percent or less [23]. However, the guidelines

do not suggest raising the value above the 99th percentile value if this metric is not met and levels of imprecisionbetween 10 and 20 percent do not make an assay unusable [27]. Since cTnT and cTnI levels are undetectable in

most normal subjects, the 99th percentile is very low (eg, 0.01 to 0.5 mcg/L). However, most assays are impreciseat this low level [16]. This limitation diminishes the sensitivity of the assays to detect changes with serial samplesbut does not significantly increase the rate of analytical false positive results [28]. Several contemporary (sensitive)

assays are now close to or at that level of precision at the 99th percentile value. Most contemporary (sensitive)assays are still not capable of measuring cTn in most normal subjects and thus determining a true 99 percent value[29].

Since all assays are unique, one cannot extrapolate a value from one assay to another. It is important for clinicians

to be familiar with the 99th percentile value and the level of 10 percent CV for the assay used in their clinicalpractice and to be aware that these reference limits do not apply to results from other clinical providers unless theyare using the same assay. Many experts are urging that whole numbers be reported to avoid confusion since asassays become more sensitive, the number of zeros increases and the possibility of an error with one being left outor being misinterpreted is substantial.

Normal range — Young, healthy individuals without pathologic myocardial cell stress or damage are expected tohave little or no measurable troponin in their blood with any assay and with most assays presently in use this is thecase. As troponin assays become more sensitive, however, it appears that healthy individuals do have tiny butdetectable levels of troponin. Thus, defining the normal range is made difficult by our incomplete understanding ofwhat a “normal” troponin really is.

With contemporary assays, individuals with increased values above the 99th percentile URL are at increased

cardiovascular risk. Some values even slightly below the 99th percentile value seem to suggest risk, butcontemporary assays are not capable of defining these values very well due to marked imprecision. (See'Elevations in the general population' below.)

This issue has been addressed in studies that have compared younger to older individuals with values in thenormal range; the mean for the two groups differed [30]. To determine if this was a normal finding related to age orrelated to a comorbidity, they examined a cohort of older patients during longterm followup. Patients with valuesbetween the values of the younger and older group had an increased frequency of adverse events. Mortality wasincreased by 50 percent in those without a history of cardiovascular disease and by more than twofold in those withsuch a history. The importance of values in this range has been confirmed in two acute studies, one in chest painpatients and one in ED patients [31,32].

It has also been shown that having a detectable level of troponin defines a group of stable patients likely to haveeither significant coronary artery disease or elevated filling pressures [33].

Elevations in the general population — A report of 3557 participants in the populationbased Dallas Heart Studyevaluated the prevalence of cTnT elevations in the general population using contemporary (sensitive) assays [34].Values ≥0.01 ng/mL (mcg/L), which was the lower limit of detection, were seen in 0.7 percent. Four major predictorsof detectable cTnT were diabetes mellitus, left ventricular hypertrophy, chronic kidney disease, and heart failure.

These values are of prognostic importance. In a study of 957 healthy elderly patients in which 4 percent were foundto have elevated detectable level of cTnT (≥0.01 ng/mL), there was an approximate twofold increase incardiovascular mortality in this group, confirming the importance of these elevations clinically [35]. In a study of

989 individuals with putatively stable CAD [36], 6.2 percent had elevations of cTnT above the 99th percentile value.Of these patients, 58.6 percent had a cardiovascular event during followup, compared to 22.5 percent in the groupwithout elevations. However, this prognostic relationship was not found to be independent when echo parametersand a natriuretic peptide were added to the model.

Diagnosis of primary MI — The diagnosis of an acute myocardial infarction (AMI) has traditionally relied upon the

combination of chest pain, electrocardiographic (ECG) manifestations, and elevations in serum or plasmabiomarkers of cardiac injury, or pathologic findings. (See "Criteria for the diagnosis of acute myocardial infarction",section on 'Definitions'.)

Chest symptoms are frequently atypical or absent and ECG abnormalities may be nonspecific or absent. As aresult, the diagnosis of an AMI has increasingly depended upon evaluation of the rise and/or fall of bloodbiomarkers. Troponins are preferred to CKMB due to their greater specificity and sensitivity [23,37,38]. (See 'Whytroponin is preferred' below.)

The criteria used to define MI differ somewhat depending on the particular clinical circumstance of the patient:those suspected of an AMI based on their presentation; those undergoing revascularization with either coronaryartery bypass graft surgery or percutaneous intervention; or those who have sustained sudden unexpected cardiacdeath.

Several points are important for the understanding of how to use these criteria to diagnose an AMI in differentclinical settings:

The 99th percentile of the normal range of values should be the cutoff value for both troponin and CKMB.With contemporary assays, these values are still far from the normal range.

A rise and/or fall should be observed. The ability to define how much of a change is significant requires afixed period of time (usually six hours) and information concerning the variability of the measurements. Ingeneral, measurements are considered to be different if the values are more than three standard deviationsof the variability around them. We believe that laboratories should report when significant changes haveoccurred over a fixed time period since the appropriate metrics will vary depending on the assay being used.Some assays seem to perform reasonably with a 20 percent change [39], some with a 30 percent change[40], and some with the need for even greater change.

These criteria will identify more patients with AMI than previous criteria as troponin assays continue to becomemore sensitive. Consistent use of the same criteria is urged to improve the consistency of diagnosis.

Cardiac troponin concentrations usually begin to rise two to three hours after the onset of AMI. By two to threehours after presentation, up to 80 percent of patients with AMI will have troponin elevations [39]. "Rapidly appearingmarkers," such as myoglobin and CK isoforms, appear to provide little additional information when used togetherwith a sensitive assay for troponin [41]. Recent cocaine use, which can elevate CKMB, does not increase cTnIunless myocardial damage is present [42].

Unfortunately, there has been considerable reluctance to use the 99th percentile URL value clinically because ofelevations that were challenging for clinicians to explain. Recent studies have again confirmed the early diagnostic

and therapeutic value of using the 99th percentile URL for cTn. In two diagnostic studies [43,44] that compared the

results of newer, more sensitive assays (using the 99th percentile value) to those of less or equally sensitiveassays being used in the community for which cutoff values higher than the 99 percent value were being used.

The strategy of using these contemporary assays at the recommended cutoff value detected many more patientsearlier than if one used the same assays with higher cutoff values or less sensitive assays. In these studies, morethan 90 percent of patients had elevated values in their first sample. This finding reflects in part the fact that manypatients with nonST elevation MI (NSTEMI) present late after the onset of pain, but the findings were similar inthose whose putative onset was early (within three or four hours). Some of the additional reasons for such a highinitial percentage are discussed below. Since most of the assays used in these studies are already in use, the

major finding of these reports was to reaffirm the need to use the 99th percentile value for rapid diagnosis and to

optimally identify patients with AMI who present with chest discomfort. These studies also reinforced the lack ofbenefit of socalled early rising markers [44].

It should be noted that in these studies the pretest probability of disease even using the less sensitive localapproach was 36 to 46 percent in these European studies, which is much higher than usual, especially inemergency departments in the United States. This will make all assays appear to perform better. In addition, thesestudies used a less sensitive standard as their gold standard, again inflating the accuracy of their approach. Hadthe more accurate assays been used to probe the percentage of early diagnoses, the number would have beenlower. Finally, for the most part they considered any elevation indicative of a positive diagnosis rather than lookingfor a rise and/or fall in values and with the exception of one analysis, alternative diagnoses for the elevated troponinvalues were not explored [45]. These approaches enhance the sensitivity of the approach and obfuscate what couldbe an important issue with it: the idea that with greater sensitivity, a greater percentage of elevations are likely tobe chronic and due to other cardiac comorbidities and not acute ischemic heart disease [45].

The therapeutic importance of using sensitive thresholds in the evaluation of patients with ACS was highlighted in astudy of patients with suspected acute coronary syndrome (ACS). The management and outcomes of 1038individuals evaluated with a sensitive troponin I assay in 2008 using a high cutoff value were compared to 1054individuals evaluated with the same assay in 2009 using the 10 percent coefficient of variation (CV) cutoff [46].Managing physicians used differing thresholds for the detection of myocardial necrosis in the two groups: 0.20ng/mL in the former and 0.05 ng/mL in the latter. Each group was stratified into three subgroups (<0.05, 0.05 to0.19, and ≥0.20 ng/mL). The primary outcome was the combination of recurrent myocardial infarction and death atone year. The following results were obtained:

The rates of the use of secondary preventative interventions, such as statins and dual antiplatelet therapy atdischarge, in the subgroup of patients with plasma troponin concentrations of 0.05 to 0.19 ng/mL improvedsignificantly comparing the 2008 to 2009 cohorts, while the use of these interventions did not changesignificantly in the other subgroups.

In 2008, the primary outcome occurred in 39 percent of patients with plasma troponin concentrations of 0.05to 0.19 ng/mL compared with 7 and 24 percent of those with troponin concentrations of <0.05 ng/mL or ≥0.20ng/mL, respectively.

In 2009, the primary outcome occurred significantly less frequently (21 percent) in patients with plasmatroponin concentrations of 0.05 to 0.19 ng/mL, while there was no significant change in the other twosubgroups between the two years.

As acknowledged by the authors, these results might have been still better had the 99th percentile URL value beenused [47].

Because of the delay in biomarker elevations, reperfusion therapy in patients who have a suspected acute STelevation MI should not await the results of cardiac biomarkers. This approach was recommended by the 2004ACC/AHA task force, and was not changed in the 2007 ACC/AHA focused update [38,48]. (See "Selecting areperfusion strategy for acute ST elevation myocardial infarction".)

In patients without diagnostic ST segment elevation, rapid intervention is less critical. Serial biomarker testing canbe performed after four to six or more hours if the initial values are indeterminate, the ECG remains nondiagnostic,and clinical suspicion remains high. (See "Coronary arteriography and revascularization for unstable angina or nonST elevation acute myocardial infarction" and "Initial evaluation and management of suspected acute coronarysyndrome in the emergency department".)

Among patients who present with chest pain without ischemic changes on the ECG, an elevated troponin is

associated with significant increases in the incidence of both coronary artery disease in the subset of patients whounderwent angiography (90 versus 23 percent in the absence of troponin elevations) and adverse cardiac events

over the next year (33 versus 13 percent) [49]. This study used a cutoff higher than the 99th percentile. It is likelythat the differences would have been greater had the recommended cutoff been used. However, it should also beappreciated that any cardiac injury can induce elevations of troponin. It is also clear that with the use of reasonableassays for cTn, aborted AMI (those without any elevations in biomarkers) no longer exist. However, the smaller theamount of damage, the better the prognosis [50].

There are multiple potential proximal causes of MI. These are discussed separately. (See "Criteria for the diagnosisof acute myocardial infarction", section on 'Acute MI'.)

It is now clear from several series that patients with AMI need not always have fixed coronary artery disease. Thisassumption has been responsible for concerns that cTn values are “falsely positive.” Up to 30 percent of patientswith unstable coronary artery disease may not have a culprit lesion but often respond to acetylcholine withrecapitulation of their chest discomfort [51]. These patients have an excellent longterm prognosis [52]. Included inthis group most likely are the patients reported in several series who have elevated cTn values, normal coronaryarteries but magnetic resonance imaging evidence of AMI with delayed subendocardial hyperenhancement. Ofinterest, most of these patients are women [5355]. These patients would be designated as type 2 AMIs by theglobal task force definition of AMI [23]. (See "Criteria for the diagnosis of acute myocardial infarction" and "Criteriafor the diagnosis of acute myocardial infarction", section on 'Acute MI'.)

In addition, patients with fixed coronary artery disease and supplydemand abnormalities, such as postoperativepatients, fit into this category [56]. It is thought that these patients include mostly socalled type 2 AMIs such asthose identified above and thus are less in need of aggressive intervention than others. Unfortunately, thesedistinctions are impossible to make based on the cTn data and thus must be made clinically.

Late diagnosis and reinfarction — Elevations in cTnT and cTnI after an AMI persist for up to 10 days, thuspermitting late diagnosis [57,58].

Troponins can also be used for detecting reinfarction. This was illustrated in a series of nine patients in whom reelevations in cTnI were prompt and permitted the diagnosis of reinfarction [59]. As a result, CKMB is no longerrequired even though it returns to baseline levels earlier.

According to the 2012 Joint European Society of Cardiology/American College of Cardiology Foundation/AmericanHeart Association/World Health Federation Task Force for the Universal definition of Myocardial Infarction,reinfarction is used for an acute Mi that occurs within 28 days of an incident or recurrent MI. If reinfarction issuspected, an immediate measurement of cardiac troponin should be made [60]. A second sample is obtainedthree to six hours later and recurrent infarction is present if there is a ≥20 percent increase in the second sample.

Differential diagnosis — The diagnosis most apt to mimic AMI both in terms of clinical presentation and cTnresults is acute myocarditis. Both syndromes can present with ST segment elevation and substantial elevations incTn [61]. In a series of 60 patients who presented with possible AMI but had normal coronary arteries, 30 had MRIfeatures of acute myocarditis [62]. Thus, this should be a consideration in patients who present in this manner andhave normal coronary arteries. One possible indication for CMR would be to determine the source of myocardialdamage in a patient with elevated troponin levels but without obstructive coronary disease at invasive coronaryangiography. (See "Clinical utility of cardiovascular magnetic resonance imaging".)

Apical ballooning should also be considered, but in general, elevations of cTn are more modest in this condition.(See "Stressinduced (takotsubo) cardiomyopathy", section on 'Clinical presentation'.)

Both cTnI and cTnT provide improved specificity compared to the other marker proteins for the detection ofmyocardial injury, but elevations do not necessarily imply that the cause is ischemic heart disease. Troponin

elevations occur in a variety of clinical conditions, including disorders that are in the differential diagnosis of acuteinfarction such as a moderate to severe pulmonary embolism with acute right heart overload, heart failure, andmyocarditis. The troponin elevations are more often modest in these disorders and, among patients with pulmonaryembolism, usually resolve within 40 hours in contrast to the more prolonged elevation with acute myocardial injury[4]. These issues are discussed in detail separately. (See "Elevated cardiac troponin concentration in the absenceof an acute coronary syndrome" and "Diagnosis of acute pulmonary embolism", section on 'Troponin' and "Clinicalmanifestations and diagnosis of myocarditis in adults".)

Troponin elevations are also indicative of myocardial injury in patients who are critically ill and are associated withan adverse prognosis [63]. (See "Elevated cardiac troponin concentration in the absence of an acute coronarysyndrome", section on 'Critical illness'.)

Troponin release can be induced by trauma, as occurs during cardiopulmonary resuscitation, electricalcardioversion, or implantable cardioverter defibrillator (ICD) firings. In one study of 38 patients undergoing electivecardioversion using a median cumulative energy of 300 J, for example, three patients had minimal elevations ofcTnI (0.8 to 1.5 mcg/L) suggestive of subtle myocardial injury [64]. Substantial troponin elevations suggest thepresence of myocardial injury from causes unrelated to direct current cardioversion. (See "Basic principles andtechnique of cardioversion and defibrillation" and "General principles of the implantable cardioverterdefibrillator".)

Infarct size — Many clinicians use peak values of biomarkers to provide a rough estimate of infarct size. Recentdata using both scintigraphy [65,66] and MRI [67] suggest that peak cTnT values or the 72 to 96 hour valuescorrelate with infarct size determined from imaging approaches. The slope of the relationship is different if one usesthe 24hour, 48hour, or peak value versus the 72 to 96 hour value [68] and, as with CKMB, the correlation is lessrobust with NSTEMI than with STEMI. In addition, the slope of the relationship is different with and withoutreperfusion. Nonetheless, correlation ranges are good (from 0.8 to 0.93) in these studies and are better than thecorrelations reported for CKMB. Similar data are available for cTnI as well [69].

Prognosis after MI — The prognostic value of elevated troponins has been demonstrated in patients with STsegment elevation MI (STEMI) and nonST elevation MI (NSTEMI). Both cTnI and cTnT appear to be equivalent forthis purpose and any detectable elevation at the time of presentation is of significance (figure 1) [7072]. The

optimal cutoff value is the 99th percentile [73].

ST elevation MI — The range of findings in acute STEMI is illustrated by the following observations:

The GUSTOIII trial evaluated 12,666 patients with an STEMI who received fibrinolytic therapy [74]. Anelevated cTnT at the time of presentation was an independent predictor of mortality at 30 days in amultivariate regression analysis (15.7 versus 6.2 percent for a negative cTnT). This is likely at least in partbecause patients with elevated values present later.

The admission troponin concentration has prognostic value in patients with an STEMI who undergo earlyPCI. This was illustrated in a report of 140 patients undergoing PCI usually with stenting. Those withadmission cTnT ≥0.1 mcg/L were more likely to have persistently reduced blood flow in the infarctrelatedartery (TIMI flow grade less than 3) after the procedure (25 versus 8 percent for negative cTnT), a higherincidence of noreflow, and a higher mortality at both 30 days and nine months (12.5 versus 4 and 14 versus4 percent, respectively) [75]. This is likely at least in part because patients with elevated values presentlater.

A pooled analysis of 21 studies involving 18,982 patients with an acute coronary syndrome found that anelevated serum cTnI or cTnT was associated with an increased risk of cardiac death or reinfarction at 30days (odds ratio 3.44, 95% CI 2.944.03) [76]. Elevated troponins on admission were also predictive of longterm outcome (five months to three years) in those with a STEMI (OR 3.11).

NonST elevation MI — An elevation in troponin is associated with an adverse early and longterm prognosis inmen and women with a nonST elevation acute coronary syndrome (NSTEMI) [71,7685]:

In a metaanalysis of seven clinical trials and nineteen cohort studies of patients with NSTEMI, 5360patients had a cTnT measurement and 6603 had a cTnI measurement [71]. The mortality rate was higher forpatients with either an elevated cTnT (6.0 versus 1.5 percent at 28 weeks) or an elevated cTnI (5.5 versus1.7 percent at 10 weeks).

Similar findings were noted in a second metaanalysis of 21 studies: 3579 patients with NSTEMI had 30dayfollowup, and 2227 had longterm followup (five months to three years) [76]. Patients with an elevated cTnTor cTnI had a significantly higher cardiac mortality rate in both the short term (5.9 versus 1.3 percent) andlong term (10.1 versus 4.0 percent).

A number of factors may contribute to the increase in mortality. In the noninvasive arm in the FRISCII trial, anyelevation in cTnT was associated with an increased likelihood of severe three vessel disease, an unstable plaquewith thrombus and downstream microembolization, impairment of coronary flow, and reinfarction [82]. A morepronounced troponin elevation was associated with a greater likelihood of persistent occlusion of the culprit vesseland a reduced left ventricular ejection fraction.

Probably because of the higher risk, patients with an ACS and elevated troponins benefit more from an earlyinvasive therapy than those who do not have elevated troponins [8688] and from the use of GP IIb/IIIa inhibitors[72] and low molecular weight heparin [77], perhaps because troponin elevations are associated with complexlesion characteristics and thrombus formation [82,89]. (See "Trials of conservative versus early invasive therapy inunstable angina and nonST elevation myocardial infarction", section on 'Gradation of risk' and "Antiplatelet agentsin acute nonST elevation acute coronary syndromes", section on 'Serum troponins'.)

Degree of troponin elevation — The degree of elevation of cTnI or cTnT also has significant prognostic value[7880,84,90,91]. This effect has been illustrated in a number of major trials:

In the GUSTO IV ACS trial, over 7000 patients who did not undergo early revascularization were stratified byquartiles of cTnT (≤0.01, 0.01 to 0.12, 0.12 to 0.47, and >0.47) and by quartiles of CRP [90]. The 30daymortality rate increased from 1.1 to 7.4 percent from the first to fourth quartiles of cTnT. There was also asignificant increase in the 30day rate of MI from the first to second quartiles of cTnT (2.5 versus 6.7percent), but no further increase between the upper three quartiles. CRP and troponin T had independent andcomplementary prognostic significance; the mortality rate at 30 days ranged from 0.3 to 9.1 percent forpatients in the lowest to highest quartile of both markers.

A similar correlation of the degree of troponin elevation with mortality was seen in the TIMI IIIB trial (figure2), the GUSTO IIa trial (figure 3), and the FRISC study (figure 4) [7880,84]. The correlation with inhospitaland longterm mortality has also been noted in patients treated with an early invasive strategy [92].

Optimal use for prognosis requires more than an initial sample. The GUSTO IIa trial obtained baseline, peak, andlate (8 and 16 hour) cTnT measurements in 734 patients with an acute coronary syndrome. Mortality at 30 dayswas 10 percent in those with an elevated cTnT (>0.1 mcg/L) at baseline, 5 percent with a late elevation of cTnT,and 0 percent in patients who never developed a positive test [93]. After adjustment for baseline characteristics,any elevated cTnT value predicted 30day and oneyear mortality, and the 8 and 16 hour values added strength tothe baseline value (figure 5).

Patients with marked troponin elevations (eg, highest tertile) have presented later, have visible thrombus onangiography and a lower rate of TIMI 3 flow, depressed left ventricular function, and abnormal Q waves on the ECGcompared to those in the second tertile [82,94]. These patients are less likely to have recurrent MI at one year than

those in the lower tertiles, perhaps because they were more likely to have total coronary occlusion and completedinfarctions.

High sensitivity assays — There are several high sensitivity (hs) assays that have been or are being developed[95103]. A proposed optimal criterion for calling an assay hs is the number of normal subjects it is capable ofdetecting [104]. Most contemporary (sensitive, but not high sensitive) assays detect very few normal subjects,whereas some of these hs assays detect nearly 100 percent depending on the population [95102]. Part of theproblem in this area is that companies do studies under ideal circumstances. For example, the hscTnT assay wasreported to detect roughly 80 percent of normal subjects [99]. However, in a study of based on a populationincluding abnormals where one might anticipate fewer undetectable values [105], only 25 percent of the populationhad detectable values. This likely reflects differences in populations, the age of the samples, and the specificequipment used for the analysis [106].

Analytical considerations — Only the hscTnT assay has been released for use and it has not yet been

approved for use in the US. Its analytical characteristics include a 99th percentile value of 13.5 ng/L (0.0135 ug/L)and a 10 percent CV value of 13.0 ng/L [99]. Thus, a value above 14 ng/L (0.014 ug/L) is considered abnormal. Inat least two studies, however, the performance of this assay has not been superior to conventional assays used at

the 99th percentile URL [43,107].

It should be noted that hs assays are potentially far more prone than sensitive assays to analytical problemsbecause small differences can be of such importance. For example, even mild degrees of hemolysis reducehscTnT values [108] and differences in the type of sample (heparin compared to serum or EDTA) can also make adifference [29]. In addition, with the hscTnT assay, it should be noted that the potential for elevations due toskeletal muscle disease will be greater with this hs assay than with the present generation assay [15]. Finally, with

two of the hs assays [99,109] but not a third [98], men and women have different 99th percentile values

Clinical considerations — Newer assays are as much as 10 times more sensitive than most socalled‘sensitive’ assays and they have partially clarified some of the issues raised regarding ‘normal range’ (see 'Normalrange' above). With these assays, most individuals, even those without apparent myocardial disease (“normals”),have detectable values for cTn [95,96,99]. The etiology of these minor amounts of protein is unclear and this is anarea under active investigation [8,110].

Using these highly sensitive assays, values that are elevated above the 99th percentile URL define a highriskgroup regardless of the type of underlying cardiovascular disease. Even within the normal range of these highlysensitive assays, it appears that the higher the value, the greater the risk [100,105,111113]. This suggests thateach individual has his/her own normal baseline and that elevations above that baseline occur as cardiac diseaseensues and thus defines increased risk.

These newer assays have tremendous potential for clinical medicine. For instance, they are likely to increase therapidity and accuracy of diagnosis of acute coronary syndromes [96,97,101,102,114] or to identify patients at highrisk of events with cardiovascular disease [111].

The potential benefit from the use of highly sensitive assays was evaluated in a study of 413 patients whopresented to emergency departments in Germany with symptoms suggestive of an acute coronary syndrome andwere ultimately diagnosed with acute myocardial infarction using the recommended universal definition (evidence ofmyocardial necrosis in a clinical setting consistent with myocardial ischemia and clinical manifestations ofischemia, including symptoms, characteristic changes in the electrocardiogram, or imaging evidence of ischemia orinfarction) [114]. (See "Criteria for the diagnosis of acute myocardial infarction", section on 'Acute MI'.)

In this study, the diagnosis of myocardial necrosis was established by at least one troponin measurement abovethe 10 percent imprecision cutoff of the hospitalspecific troponin assay, together with an increasing and/or

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decreasing pattern of at least 20 percent within six hours after admission. The diagnostic performance of twoprotocolspecified troponin assays (different from the hospitalspecific assays) was evaluated. These two assayswere measured on admission and after three and six hours. One of these assays was a novel hsTnI (level of

detection = 3.4 pg/mL; 99th percentile URL = 24 pg/mL; diagnostic threshold for MI = 30 pg/mL). The other is a

standard available assay from Abbott (the level of detection = 10 pg/mL; 99th percentile URL = 280 pg/mLdiagnostic threshold for MI = 300 pg/mL). The following findings were noted:

The area under the receiver operating characteristic (ROC) curves was high for both tests on admission(0.96 and 0.92, respectively). The ROC curves were similar except at the lower concentrations of troponin I,which were detectable only with the highly sensitive assay. This difference was most apparent when theonset of chest pain was less than two hours.

At admission, hsTnI had a sensitivity of 82.3 percent and a negative predictive value of 94.7 percent (forruling out MI). Comparable values for cTnI were 79.4 and 94.0 percent.

At three hours, the sensitivity was 98.2 and the negative predictive value was 99.4 percent for both assays.

Combining the 99th percentile cutoff at admission with the serial change in troponin concentration withinthree hours, the positive predictive value (for ruling in MI) for hsTnI increased from 75.1 to 95.8 and for cTnIfrom 80.9 to 96.1 percent.

Optimal specificity for the diagnosis of AMI was achieved using a percentage change of 250 percent but atthe cost of a substantial reduction in sensitivity. A 50 percent change optimized the diagnosis of AMI in latepresenters at a similar cost.

These data indicate that hs assays will facilitate the diagnosis of presently defined AMIs, but important issuesremain unresolved, including:

The gold standard applied in this and other studies is based on older, less sensitive assays. Performancecharacteristics comparing hs assays are unknown and will likely influence the optimal delta change value.

The hs assay used in the study and others have sexbased differences in the 99th percentile. It remainsuncertain whether sexspecific cut points need to be established for hs assays.

Optimal thresholds for change values are not yet defined:

a) There is a clear tradeoff between sensitivity and specificity that clinicians must recognize.

b) There are differences among the hs assays studied and this precludes establishing consistent criteriafor use with all assays.

Furthermore, they may be of value in patients with stable disease [101,112] and eventually for more chronicscreening [29], including during stress testing [6,7] and in patients with heart failure [100]. For example, in a studyof 3546 of participants in the Dallas heart study who were evaluated using a highly sensitive assay hscTnT assay,

the lower limit of detection was 0.005 ng/mL and the 99th percentile value in these apparently healthy individuals

was ≥0.014 ng/mL. Troponin was detectable in 25.0 percent, and 2.0 percent had elevations above the 99th

percentile [105]. Among those with elevations above the 99th percentile, the vast majority had detectablecardiovascular comorbidities.

However, the use of more sensitive assays may lead to situations in which the cause of the elevations is not

apparent [99,102]. Although these elevations are likely to be related to cardiovascular abnormalities [101], it isunclear at present how clinicians should respond to such elevations other than to exclude an acute process withthe use of serial measurements to see if a changing pattern is present [29,102,115]. In addition, subsetting patientsbefore receiving the results of testing in a Bayesian manner may help improve the ability to manage these patientsrather than allowing the lab test to override clinical judgment [102].

The prognostic implications of elevations of cTn have been evaluated in multiple studies of which the followingthree are representative:

In the 2010 report of 3546 individuals (discussed above) who were evaluated with a highly sensitive assay,elevation of cTnT was significantly associated with allcause mortality in the highest cTnT category(adjusted hazard ratio 2.8, 95% CI 1.45.2) [105]. In addition, there were differences in the normal valuesfound in men and women and as opposed to 0.7 percent of the population having an elevated value.

In a study of adults aged 65 years or older without prior heart failure (HF), high sensitivity cTnT wasmeasured at baseline (n = 4221) and two to threeyear followup (n = 2918) [113]. cTnT was detectable(≥3.00 pg/mL) in 66 percent at baseline. During a median followup of nearly 12 years, there was asignificantly increased risk of HF and cardiovascular death in those with detectable levels at baseline,compared to those without. Among individuals with initially detectable cTnT, a subsequent increase of morethan 50 percent was associated with a greater risk for HF and cardiovascular death.

These observations demonstrate that troponin elevations can be due to structural heart disease in the absence ofany acute process and thus have prognostic value. As assays become more sensitive as discussed above, thispercentage will likely increase and the need to observe a rising pattern to distinguish acute from chronic elevationswill become more important [116].

There is still considerable controversy about how to use these assays to detect acute events such as AMI. Inmany patients with AMI, large changes in cTn occur over time and the diagnosis is easy [117]. However, especiallywith hscTn assays, the number of more subtle cases will increase. These challenges revolve around a couple ofissues:

The 99th percentile URL is different for different groups. In some assays, this can be gender related and insome it is related to underlying comorbidities such as age [118] or diabetes [119]. Thus, whereas someclinicians in the past have used an abnormal value in many situations as synonymous with acute disease,such a strategy will misclassify even more patients with hscTn assays.

Because of the large number of minor elevations associated with chronic disease, whether detected orundetected, the ability to define a rising or falling pattern has become even more important. However, theoptimal criterion for a meaningful change has not yet been defined. Several approaches have beenadvocated, each of which increases specificity at the cost of reducing sensitivity. Because most studies arepredicated on the use of older cTn assays as the gold standard, cases of MI detectable only with hs assaysare not included [43,107], whereas patients who have CAD are often included as having AMI if a baselineelevation of hscTn is found even if a rise is not found. Therefore, even the approaches proposed to datemay not be optimal:

Biological variation: This approach is based on conjoint biological and analytic variability that can onlybe derived in normal subjects. This metric defines the extent to which variation alone can explain agiven rise and/or fall of values. The key metric is the reference change value (RCV). The RCV hasvaried, depending upon the assay, from 42 to 86 percent [106,120,121] and is unique not only to eachindividual assay but even with the same reagents, to differing pieces of equipment [106]. Some experts

have advocated these values be used to define when a rising and falling pattern is present [122]. Todate, there are no published clinical data supporting this approach.

Percentage change: The use of a percentage criteria can be based on biological variation or some otherderived metric. Notably, some of the percentages proposed for clinical use are much lower thanbiological change. In addition, at low values a large percentage change may be reasonable but at highervalues, it may not be nearly as successful. In addition, it is likely from the theory of biological variationthat the further a value is from the RCV, the more cases due to variability alone (true false positives) willbe included.

Absolute change: A recent paper using the hscTnT assay has suggested that the use of a value of 7 to9 ng over a one to two hour period optimizes sensitivity for detection of acute changes and thus AMI.These data require confirmation and depending on the baseline value, will often be below biologicalvariation, so will by definition likely (depending on the percent change) include some individuals whosechange is due to variability alone.

Given the limitations to each of these approaches to clinical application of hscTn assays, careful individualizationof patients based on clinical grounds is mandatory. It also should be appreciated that some patients who do notmanifest change could be late after AMI and that may only be apparent by seeing a falling in values over time.Finally, some patients with putative unstable angina will have elevated hscTn values that do not change but arelikely due to structural heart disease. This group could be confusing to clinicians. Finally, it is likely that the relativepercentage of Type 2 AMIs will increase with use of increasingly sensitive cTn assays. Such patients with Type 2(demandrelated) MI are not likely to benefit from the aggressive antithrombotic therapy that prior studies havedocumented to be of benefit in patients with predominantly Type 1 (acute atherothrombotic) nonSTEMI. Theclinical implication is that until more data are available, clinicians may need to individualize the care of thesepatients.

Based on the concerns stated above, we would suggest that additional data are needed before advocating theroutine use of high sensitive troponin assays.

CREATINE KINASE — The enzyme creatinine kinase (formerly referred to as creatinine phosphokinase) exists asisoenzymes, which are dimers of M and B chains and exist in three combinations: MM, MB, and BB [123]. Theseisoenzymes reside in the cytosol and facilitate the egress of highenergy phosphates into and out of mitochondria.Their diagnostic use has become markedly diminished over time but they are included here predominantly for thoseareas of the world where cardiac troponin assays are not yet in exclusive use.

CK basics — Creatine Kinase (CK) isoenzyme activity is distributed in many tissues, including skeletal muscle,but there is more of the CKMB fraction in the heart [124]. Most muscles have more CK per gram than heart tissue[125,126]. Thus, skeletal muscle breakdown can lead to absolute increases in CKMB in the plasma. In addition, inresponse to organ damage, including vigorous exercise [127], there is regeneration of skeletal muscle fibers and reexpression of proteins that existed during ontogeny, resulting in increased production of B chain CK protein[126,128,129]. A large percentage of the CK that is released is degraded locally or in lymph [130]. Reperfusiontruncates this process and increases the rapidity and magnitude of egress of CK into plasma [131].

Total CK measurements for the detection of cardiac damage — Elevations in total serum CK lack specificity forcardiac damage, which improves with measurement of the MB fraction. The normal range of CK also variesconsiderably; a twofold or greater increase in the CK concentration is required for diagnosis. This criterion can beproblematic in older individuals who, because of their lower muscle mass, may have low baseline serum total CKand, during MI, may have elevated serum CKMB with values of total CK that rise but remain within the normalrange [132134]. For these reasons, total CK has not been used in the diagnosis of myocardial damage for years.

CKMB fraction for diagnosis of AMI — When cardiac troponin is available, CKMB should not be used for thediagnosis of acute myocardial infarction. If it is the only assay available, it can be used but is far less sensitive and

specific. Assays for CKMB can be performed easily and rapidly.

Most assays measure CKMB mass, which is more sensitive than activity assays. In addition, mass assays avoid,for the most part, detection of macrokinases (CK linked to IgG and dimers of mitochondrial CK) that can confounddiagnosis with activity assays. The presence of macrokinases should be considered, as one possibility, when CKMB is a very high percentage (>20 percent) of total CK [9]. However, patients with chronic skeletal muscle diseaseoften have falsely positive CKMB results when percentage criteria are used [129,135137]. The proportion of CKthat is CKMB can be as high as 50 percent with chronic skeletal muscle injury, such asdermatomyositis/polymyositis, due to increased production of B chain CK protein [126,129,135].

Specificity and sensitivity — CKMB has high specificity for cardiac tissue and was the preferred marker ofcardiac injury for many years [9]. CKMB typically begins to rise four to six hours after the onset of infarction but isnot elevated in all patients until about 12 hours [138,139].

An elevated CKMB is relatively specific for myocardial injury, particularly in patients with ischemic symptomswhen skeletal muscle damage is not present. Elevations return to baseline within 36 to 48 hours, in contrast toelevations in troponin, which can persist for as long as 10 to 14 days [140]. This means that CKMB, unliketroponins, cannot be used for the late diagnosis of an acute MI but can be used to suggest infarct extension iflevels rise again after declining. (See "Criteria for the diagnosis of acute myocardial infarction".)

Gender specific values are essential for diagnostic use [17]. CKMB typically begins to rise four to six hours afterthe onset of infarction but is not elevated in all patients until about 12 hours [138,139]. It is now clear that cTn risesfar more rapidly [41]. Elevations return to baseline within 36 to 48 hours, in contrast to elevations in troponin, whichcan persist for as long as 10 to 14 days [140]. Because CKMB can be released from skeletal muscle, itsdiagnostic use is impaired when skeletal muscle injury is present [42]. Some have suggested using a ratio of CKMB to total CK to improve specificity, but that approach markedly reduces the sensitivity.

CKMB fraction for prognosis — There is a relationship between infarct size, which can be estimated by CKMBand prognosis. Peak values are less precise, but if adequate numbers of samples are obtained, they can provide areasonable estimate. Comparisons with cTn suggest that cTn provides better estimates [6569].

CK and coronary reperfusion — The time to peak CK levels and the slope of CKMB release can be used toassess whether reperfusion has occurred after fibrinolysis and, when used in conjunction with clinical variables, canpredict whether TIMI 0 or 1 and TIMI 2 or 3 grade flow is present [57]. However, CKMB criteria cannot identify thepresence of TIMI 3 flow, which is the only level of perfusion associated with improved survival after fibrinolysis andthis approach is not necessary at all with primary PCI.

Reinfarction and late diagnosis — Since CK levels return to baseline 36 to 48 hours after infarction, resamplingcan be used to detect reinfarction, and because cTn does not normalize that rapidly, it was initially suggested thatCKMB might be of value in this area. It is now clear that cTn increases rapidly, albeit from an abnormal baseline inpatients with reinfarction. Therefore, the use of cTn has been recommended for all AMI diagnosis, includingreinfarction [23].

WHY TROPONIN IS PREFERRED

Diagnosis — Because of their increased sensitivity and specificity compared with CKMB and other markers,troponins are preferred for the diagnosis of MI. (See 'Diagnosis of primary MI' above.)

The basis for the consistent observation that troponin is more sensitive than CKMB relates to the fact that moretroponin is found in the heart per gram of myocardium and that a greater percentage depleted from the heart bycardiac injury arrives in the blood [37].

With regard to specificity, troponin elevations are almost always specific for cardiac injury, except for the infrequent

analytical false positives caused by fibrin interference and/or crossreacting antibodies [37]. As mentioned above,CKMB is not specific for cardiac injury, as a small amount is found in skeletal muscle. (See 'CK basics' above.)

It is difficult today to find any situation in which CKMB adds anything other than cost to the clinical utility of cTn ifthat marker is used properly [37].

Prognosis — A number of welldone studies have shown that troponin measurements have enhanced prognosticvalue compared to CKMB measurements in patients with a nonST elevation ACS [76,141143]. This wasillustrated in a review of almost 30,000 such patients from the multicenter CRUSADE initiative in the United States[141]. The following findings were noted:

The results were discordant in 28 percent of patients. Troponin was more sensitive, as 18 percent hadelevated troponin but normal CKMB values. In addition, 10 percent had false positive CKMB elevations, asdefined by normal troponin values.

Compared to patients who were negative for both biomarkers, inhospital mortality was not increased inpatients who were troponinnegative and CKMBpositive (ie, false positives; 3.0 versus 2.7 percent,adjusted odds ratio 1.02, 95 percent CI 0.751.38)

Compared to patients who were negative for both biomarkers, there was a nonsignificant trend towardincreased mortality in patients who were troponinpositive/CKMBnegative (4.5 versus 2.7 percent, adjustedodds ratio 1.15, 95 percent CI 0.861.54) and a significant increase in mortality in patients who were positivefor both biomarkers (5.9 versus 2.7 percent, adjusted odds ratio 1.53, 95 percent CI 1.181.98).

These differences in outcomes could not be explained by differences in therapy since the two discordant groupswere treated similarly with antithrombotic agents and percutaneous coronary intervention (PCI). Thus, an isolatedCKMB elevation has limited prognostic value in patients with a nonST elevation ACS, while an isolated troponinelevation was associated with increased risk.

Similar findings have been noted in other studies [76,142,143]. In a report of over 10,000 patients with an ACS fromthe multicenter GRACE registry, 1110 (10.4 percent) were troponinpositive/CKMBnegative and 822 (7.7 percent)were troponinnegative/CKMBpositive (false positives) [143]. Inhospital mortality was highest when both troponinand CKMB were positive (7.7 percent), intermediate in troponinpositive/CKMBnegative patients (3.9 percent),and lowest in patients in whom both markers were negative and those who were troponinnegative/CKMBpositive(1.7 and 2.3 percent, respectively).

BIOMARKERS AFTER REVASCULARIZATION

After PCI — There has been considerable controversy over the prognosis of elevated cardiac biomarkers afterpercutaneous coronary intervention (PCI). This issue is discussed in detail elsewhere. (See "Periproceduralmyocardial infarction following percutaneous coronary intervention", section on 'Prognosis'.)

After CABG — Perioperative MI after CABG is defined as increases in biomarkers greater than 10 times the 99th

percentile upper reference limit (URL) plus either new pathological Q waves or LBBB on the postoperative ECG, orangiographically documented new graft or native coronary occlusion, or imaging evidence of new loss of viablemyocardium. (See "Criteria for the diagnosis of acute myocardial infarction", section on 'After revascularization'.)

MI in this setting occurs in 4 to 5 percent of patients. (See "Early cardiac complications of coronary artery bypassgraft surgery", section on 'Perioperative MI'.)

Elevations in CKMB are much more common than Q waves, occurring in 62 to 90 percent of patients [144146].This dissociation from Q waves suggests that most of the damage that occurs during CABG is subendocardial andthus is a routine sequela of the procedure rather than a coronary artery problem [147]. Only marked CKMB

elevations (5 to 10 times the upper limit of normal) are associated with transmural infarction [147] and increasedlongterm mortality [145].

Elevated troponin may be a more specific and sensitive marker than CKMB of a new MI after CABG, and may bemore predictive of early complications:

The diagnostic value of troponin elevations was illustrated in a study of 590 patients in whom a cTnTconcentration >3.4 mcg/L 24 hours after CABG correlated best with a perioperative MI as defined by new Qwaves on the ECG and CKMB >100 IU/L within 48 hours after surgery [148]. The sensitivity and specificity,and positive and negative predictive values were 90 and 94 percent.

The prognostic value of troponin elevations was addressed in a report of 224 patients in whom cTnT and CKMB were measured every eight hours after cardiac surgery [146]. In a multivariable analysis, serum troponinT concentrations ≥1.58 mcg/L (which represented the upper quintile) were the strongest predictor ofpostoperative death or shock immediately postoperatively or at 18 to 24 hours. CKMB did not haveindependent shortterm prognostic importance when troponin T was measured. Longterm data were notprovided.

A recent investigation of 1365 patients supports this contention for cTnI as well. Measurements were taken2 and 24 hours after surgery. After multivariate correction, cTnI levels were predictive of both 30day andoneyear mortality and there was a gradation of risk with those with the highest values manifesting thegreatest risk [149].

However, it should be appreciated that all elevations of troponin after CABG are not indicative of a vascular event.The process of cardiopulmonary bypass itself, issues related to cardiac preservation, and mechanical injury can allcontribute. Recent CMRI data suggest that until troponin (or CKMB) values are very elevated, most of the damageis subendocardial and often apical, suggesting a nonvascular etiology [147]. Even when marked elevations occur,only 67 of 118 patients have a primary graft occlusion, emphasizing the need to consider the etiology of biomarkerelevations and not considering all elevations due to vascular events [150].

For infarction after cardiac surgical procedures, a fivefold increase from baseline in biomarkers is recommendedalong with ancillary criteria such as new Q waves.

BIOMARKERS AFTER NONCARDIAC SURGERY — Troponins are ideal for diagnosing perioperative MI afternoncardiac (mostly vascular) surgery. The same cutoff levels used to diagnose an acute MI should be used todetect perioperative injury in such patients. The discussion of the significance of a postoperative troponin elevationis found elsewhere. (See "Perioperative myocardial infarction after noncardiac surgery".)

USE IN RENAL FAILURE — Issues relating to the clinical use of cardiac troponins and CKMB in patients withrenal failure are presented in detail separately. (See "Serum cardiac enzymes in patients with renal failure".)

SUMMARY — The measurement of serum biomarkers is a key component in the diagnosis of irreversiblemyocardial cell death (as occurs with myocardial infarction) or possibly reversible cell injury. Troponins and creatinekinase (CK) MB are the two biomarkers which have the greatest utility for this purpose. They are also superior toother biomarkers for assessing prognosis. (See "Biomarkers of cardiac injury other than troponins and creatinekinase".)

The following points summarize the proper use of these biomarkers for diagnosis and prognosis of acutemyocardial infarction:

Troponin values within the normal range (using current methodologies) likely come from a mixture of trulynormal individuals with detectable values and some with comorbidities reflected by low but detectable

values. (See 'Normal range' above.)

Troponin elevations (above the 99th percentile) can be due to structural heart disease in the absence of anyacute process. (See 'Elevations in the general population' above.)

The diagnosis of an acute myocardial infarction depends on observation of a rise and/or fall of blood

biomarkers, particularly troponins, with at least one value above the 99th percentile, in addition to clinicalinformation or electrocardiographic changes. The more sensitive the assay, the more important it is todetermine a change for confirmation. This need is particularly important with highly sensitive assays. (See'High sensitivity assays' above.)

We recommend using cardiac troponins in preference to CKMB for diagnostic and prognostic purposes; it isunnecessary to obtain both values. Cardiac troponins I and T are equally useful. We do not recommend theroutine use of high sensitive assays of troponin at the present time.

The impact of a rise is serum biomarkers after PCI is discussed elsewhere. (See "Periprocedural myocardialinfarction following percutaneous coronary intervention", section on 'Prognosis'.)

For the diagnosis of myocardial infarction after coronary artery bypass graft surgery (CABG), a 10foldincrease from baseline in biomarkers along with ancillary criteria, such as new Q waves, is needed.Myocardial infarction after CABG is associated with an increase in mortality. (See 'Biomarkers afterrevascularization' above.)

There is a delay in the rise of biomarkers after an acute MI. In patients who have an acute STEMI,reperfusion therapy should not await the results of cardiac biomarkers. In patients without diagnostic STsegment elevation, serial biomarker testing is performed after four or more hours if the initial values areindeterminate, the ECG remains nondiagnostic, and clinical suspicion remains high. (See 'Diagnosis ofprimary MI' above.)

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Topic 86 Version 22.0

GRAPHICS

Cardiac troponins are predictive of outcome inunstable angina

Among patients with class IIIB unstable angina (primary acuterest angina within the preceding 48 hours), both ST segmentdepression and serum troponins have independent predictivevalue. Serum troponins can distinguish between patients at highrisk for a cardiac event at 30 days and those at low risk (20percent if troponinpositive versus less than 2 percent iftroponinnegative).TnI: troponin I; TnT: troponin T.Data from Hamm CW, Braunwald E. Circulation 2000; 102:118.

Cardiac troponin I concentration and mortality in unstableangina

Mortality rate at 42 days according to the level of cardiac troponin Imeasured at baseline in 1404 patients with unstable angina or nonQwave myocardial infarction. There was a progressive increase in riskwith higher troponin levels.Data from Antman EM, Tanasijevic MJ, Thompson B, et al. N Engl J Med 1996;335:1342.

Plasma troponin T and mortality in acute myocardialischemia

Mortality rates at 30 days related to the plasma level of cardiactroponin T measured at baseline in 801 patients presenting withsymptoms and ECG changes of acute ischemia. There is a progressiveincrease in mortality with higher troponin levels.Data from Ohman EM, Armstrong PW, Christenson RH, et al. N Engl J Med 1996;335:1333.

ST segment depression and troponins predict outcomein nonST elevation ACS

In the FRISC trial of 917 patients with a nonST elevation acutecoronary syndrome (unstable angina or nonST elevationmyocardial infarction), elevated serum troponin T, obtainedwithin 24 hours, is associated with an increased incidence ofdeath from cardiac causes at a mean followup of 37 months; itseffects are additive to the presence of ST segment depression.Data from Lindahl B, Toss H, Siegbahn A, et al. N Engl J Med 2000;343:1139.

Positive serum troponin T predicts lower survival aftermyocardial infarction

KaplanMeier estimates of survival show that a positive serumtroponin, obtained any time during the first 24 hours afteradmission for an acute coronary syndrome, predicts a highermortality at 30 days and one year.Data from Newby LK, Christenson RH, Ohman M, et al. for the GUSTO IIaInvestigators, Circulation 1998; 98:1853.

troponins and creatine kinase as biomarkers of cardiac injury

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