Troponin testing: Clinical use

INTRODUCTION — Cardiac troponin I and T are specific and sensitive biomarkers of myocardial injury. They are the preferred serologic tests for the evaluation of patients with suspected acute myocardial infarction. (See "Use of creatine kinase to detect myocardial injury", section on 'Why troponin is preferred'.)

This topic is intended to help the reader understand the role of troponin testing in the evaluation of patients with suspected acute myocardial infarction but will also discuss troponin testing after myocardial infarction. (See "Evaluation of emergency department patients with chest pain at low or intermediate risk for acute coronary syndrome", section on 'Initial evaluation'.).

Other relevant topics include:

●(See "Troponin testing: Analytical considerations".)

●(See "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome".)

●(See "Cardiac troponins in patients with kidney disease".)

●(See "Periprocedural myonecrosis following percutaneous coronary intervention".)

●(See "Diagnosis of acute myocardial infarction".)

●(See "COVID-19: Evaluation and management of cardiac disease in adults" and "COVID-19: Myocardial infarction and other coronary artery disease issues".)

SENSITIVE COMPARED WITH HIGH SENSITIVITY TESTS — Troponin assays with varying sensitivities are available. "Sensitive" or "contemporary" assays have been in use for a number of years. "Highly sensitive" or "high-sensitivity" troponin tests are available for clinical use throughout the world and are preferred to sensitive assays.

Measurement of cardiac troponin I and T can be performed using sensitive or highly sensitive tests. We prefer high sensitivity troponin assays, when available, as recommended by the Fourth Universal Definition of Myocardial Infarction [1]. A high sensitivity troponin assay was first approved for use in the United States in 2017. There are at least five companies that make high-sensitivity assays. (See "Troponin testing: Analytical considerations".)

The analytical performance metrics for these assays can be found on the International Federation of Clinical Chemistry and Laboratory Medicine website [2,3].

DIAGNOSIS OF ACUTE MI — Acute myocardial infarction (MI) is defined as a clinical event consequent to the death of cardiac myocytes (myocardial necrosis) that is caused by ischemia. (See "Diagnosis of acute myocardial infarction", section on 'Definitions'.).

The diagnosis of acute MI requires both evidence of acute myocardial injury (myocyte death) and clinical evidence of ischemia (eg, chest pain or an abnormal electrocardiogram). Troponin is the preferred blood-based test in the diagnostic evaluation of patients suspected of acute MI, and an elevated value is required in most cases.

Acute myocardial injury is defined biochemically as:

●A troponin must be above the 99^th percentile of the upper reference limit (URL) for the normal range of the assay being used.

●A rise and/or fall of the troponin value should be observed. Cardiac troponin concentrations usually begin to rise two to three hours after the onset of acute MI [4,5], but this may vary depending on the underlying mechanism of the MI. Other causes for acute myocardial injury can also have highly variable (ie, rising and falling) patterns.

Patients who present late after the onset of acute myocardial injury, including those with acute MI, may be on the downslope of the time-concentration curve and thus it may be difficult to appreciate a changing pattern over a short period of time [6].

The broad, clinical discussion of the integration of troponin testing into the evaluation of patients with possible acute MI is found elsewhere. (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department", section on 'Cardiac biomarkers and other laboratory testing' and "Evaluation of emergency department patients with chest pain at low or intermediate risk for acute coronary syndrome", section on 'Initial evaluation'.)

Caveats — Accurate and timely diagnosis of acute (thrombotic) MI is important, as effective management includes specific antithrombotic medications and possible percutaneous coronary intervention. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".)

However, some patients who meet the diagnostic criteria for acute myocardial injury based on the finding of an elevated troponin do not have acute coronary artery obstruction (usually a thrombotic event) as the immediate cause. To the extent possible, identifying these patients is important since their management potentially differs from those with an acute thrombotic event.

There are at least three potential reasons why a patient with clinically suspected acute (thrombotic) MI may be misdiagnosed: test-related issues, myocardial injury not related to coronary artery atherothrombosis, and acute myocardial injury not related to the coronary circulation. These three issues are discussed directly below.

Test-related issues — As is true for most other diagnostic tests, the positive and negative predictive values of a given troponin test result are influenced by the prevalence of the disease in the population in which the test is being used.

Several protocols to include or exclude ("rule out") the diagnosis of acute MI have been suggested for the screening of patients in an emergency department [7,8] (see "Evaluation of emergency department patients with chest pain at low or intermediate risk for acute coronary syndrome", section on 'Troponin testing'). Since an elevated troponin is essential for the diagnosis of acute MI, two normal troponins (if appropriately timed) can, in theory, exclude MI in most cases, assuming the criteria are sufficiently robust. However, many of these protocols rule in acute myocardial injury based on an elevated high sensitivity troponin and/or a significant change in values. However, acute myocardial injury is not synonymous with a diagnosis of acute MI. These approaches developed in chest pain patients have a specificity in populations presenting with chest discomfort of between 60 to 70 percent [9,10] (see 'Differential diagnosis' below). These protocols should not be applied to an all-comers population that might include patients with end stage renal disease, many more elderly patients, and many more critically ill patients. Thus, if these cut-offs are used in the emergency department, it should be clear they cannot be used in all patients and likely will not be applicable for use in the hospital in general. Other approaches in an all-comers populations have been suggested but have not been validated [11].

For most high-sensitivity cardiac troponin (hs-cTn) assays, the 99^th percentile URL values are higher in men than in women. In some studies, this has made a difference in diagnostic efficacy [12,13]. However, in some studies, it has not shown benefit [14] and in some even reduction in sensitivity for the detection of acute MI in men. We agree with the recommendation for sex-specific cut-off values in the United States [15]. Europe has not adopted this recommendation. The Fourth Universal Definition of Myocardial Infarctions endorsed the concept but noted that it might not be necessary for all hs-cTn assays [1].

It should be appreciated that there will be a significant increase in the number of elevated results seen with hs-cTn assays that reflect conditions other than those related to acute atherothrombotic coronary artery disease. There will be more events detected in women [12], and more events in those with minimal coronary disease and without overt culprit lesions [7,16,17]; such patients presumably require different therapies than those with acute atherothrombotic MI.

Type I versus type II MI — Most patients who are found to meet criteria for acute MI (see 'Diagnosis of acute MI' above) will have acute obstructive atherosclerotic coronary artery stenoses with acute thrombosis as the underlying pathology. However, some patients (up to 28 percent in one series) will not have significant epicardial coronary artery disease when coronary angiography is performed [18]. Many of these patients are defined as having a Type 2 MI, which is defined as an MI consequent to increased oxygen demand or decreased supply (eg, coronary endothelial dysfunction, coronary artery spasm, coronary artery embolus, tachy-/bradyarrhythmias, anemia, respiratory failure, hypertension, or hypotension) [19]. Many of these patients can also have coronary artery disease that will modulate the ischemic threshold and thus the severity of any given stressor that might cause ischemia [1]. (See "Diagnosis of acute myocardial infarction", section on 'Definitions'.)

With the use of previous non-high sensitivity assays, patients with acute ischemia and an elevated troponin value benefited from diagnostic coronary angiography and possible percutaneous coronary intervention. This is not nearly as clear with hs-cTn assays since the increased sensitivity of these assays means that larger numbers of patients with type 2 acute MI will be detected; these patients may not benefit from an invasive approach [20].

It may be useful for clinicians to be aware of how the values with prior standard assays compare with high sensitivity ones. Since the advocacy for an invasive strategy was based on elevations of the standard assays, results above the value with the hs-cTn assay that comport to the prior value may be helpful to clinician. These values have been termed "anchor values" by some [11]. For example, a value of 30 ng/L with the fifth generation hs-cTnT assay comports to a value of 0.01 ng/mL with the fourth generation assay and a value of 52 ng/L to a value of 0.03 ng/mL. For some hs-cTnI assays, the 99^th percentile URLs will remain the same. For others, the appropriate conversions will need to be developed.

Differential diagnosis — As discussed above, in patients with chest pain or equivalent symptoms, an electrocardiogram suggestive of myocardial ischemia, and an elevated troponin, particularly when markedly elevated, the most likely diagnosis is acute (thrombotic) MI, with obstructive coronary artery disease being the most likely cause. Other patients will have a supply-demand mismatch.

However, this constellation of findings may represent one of several other clinical entities not related to limitations of coronary blood flow. For patients with an acute or subacute clinical presentation, at least four other causes of moderately or markedly elevated of troponin have been identified other than chronic elevations such as in end stage renal disease and rare analytical causes: acute myocarditis, stress (Takotsubo) cardiomyopathy, pulmonary embolism, and trauma.

●Acute myocarditis is the diagnosis most apt to mimic acute (thrombotic) MI, both in terms of clinical presentation and troponin results, particularly when the troponin is very elevated [21]. In a series of 60 patients who presented with possible acute MI but had normal coronary arteries, 30 had magnetic resonance imaging features of acute myocarditis [22]. Thus, acute myocarditis should be a consideration in patients, especially women, who present in this manner and have normal coronary arteries [23]. One approach might be to use cardiovascular magnetic resonance imaging to determine the source of myocardial damage in a patient with elevated troponin levels but without obstructive coronary disease at invasive coronary angiography. (See "Clinical utility of cardiovascular magnetic resonance imaging".)

●Takotsubo syndrome ("stress cardiomyopathy") should also be considered, but in general, elevations of cTn are more modest in this condition. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy", section on 'Clinical manifestations'.)

●Pulmonary embolism with acute right heart overload and heart failure can have a rising and/or falling pattern of hs-cTn values and thus mimic acute MI. The troponin elevations are more often modest in these disorders and, among patients with pulmonary embolism, usually resolve within 40 hours in contrast to the more prolonged elevation with acute myocardial injury [24]. (See "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome" and "Clinical manifestations and diagnosis of myocarditis in adults", section on 'Cardiac biomarkers'.)

●Troponin release can be induced by trauma, as occurs during cardiopulmonary resuscitation, electrical cardioversion, or implantable cardioverter defibrillator firings. In one study of 38 patients undergoing elective cardioversion using a median cumulative energy of 300 Joules, for example, three patients had minimal elevations of cTnI suggestive of subtle myocardial injury [25].

There is no single threshold hs-cTn value that reliably discriminates any of these causes. The use of serial values to assess for a dynamic rise or fall in concentration, the absolute concentration, and the clinical syndrome should all be integrated by the clinician to make an assessment regarding the cause of myocardial injury.

Other causes of troponin elevation are discussed separately. (See "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome", section on 'Non-MI causes of an elevated troponin'.)

Unanticipated results — For many patients suspected of an acute MI, the troponin value(s) may be unexpected. The following are possible explanations:

●It is anticipated that the initial troponin will return elevated. Although this occurs much less often with high-sensitivity assays, it can still be that insufficient time has passed from the onset of symptoms to the time of the test to allow for the troponin to rise significantly. If this occurs after serial sampling, it may be appropriate to label these patients as having unstable angina.

●Some patients may present with an elevated hs-cTn but without a changing pattern of values. This may represent the late presentation of acute MI [26]. Alternatively, they could have the elevations due to structural heart disease and might also have unstable angina. (See "Acute coronary syndrome: Terminology and classification" and "Diagnosis of acute myocardial infarction", section on 'Definitions'.)

●It should also be appreciated that since many antibody-based troponin assays use biotinylation, the high circulating levels of biotin can interfere with the assays themselves [27,28]. With some antibody-based assays for other analytes, values can be increased by biotin interference; however, with cTn, reports available thus far suggest that values are only decreased. At times, patients may be unaware they are even taking Biotin. Biotin is cleared renally so in that situation, additional scrutiny may be necessary.

In the interim, clinicians should be aware that this effect exists. Clinicians should consider asking patients whose initial troponin value is unexpectedly normal or unexpectedly abnormal whether they may be taking biotin or a multivitamin that might contain biotin. Similar to other clinical circumstances in which a result is not expected, it is reasonable to further observe the patient and repeat the troponin.

●Laboratory errors such as those that might occur with incorrect patient identification.

AFTER MYOCARDIAL INFARCTION — Troponin can be used to evaluate infarct size, to diagnose reinfarction, and for prognosis.

Infarct size — Data using both scintigraphy [29,30] and magnetic resonance imaging [31] suggest that peak cardiac troponin T (cTnT) values or the 72- to 96-hour values correlate with infarct size determined from imaging approaches. The slope of the relationship is different if one uses the 24-hour, 48-hour, or peak value versus the 72- to 96-hour value [32], and the correlation is less robust with non-ST elevation myocardial infarction (NSTEMI) than with ST-segment elevation MI (STEMI). In addition, the slope of the relationship is different with and without reperfusion. Nonetheless, correlation ranges are good (from 0.8 to 0.93) in these studies. Similar data are available for cTnI as well [33].

Prognosis — The prognostic value of elevated troponins has been demonstrated in patients with STEMI and NSTEMI. Both cTnI and cTnT appear to be equivalent for this purpose, and any detectable elevation at the time of presentation is of significance [34-36]. The prognosis is better when the amount of damage is less [37]. Indeed, data suggest that even values below the 99^th percentile upper reference limit, especially if in the higher ranges, may be of prognostic importance [38].

Reinfarction — Troponins can also be used for detecting reinfarction, which is an acute MI that occurs within 28 days of an incident or recurrent MI [1]. If reinfarction is suspected, an immediate measurement of cardiac troponin should be made [1]. A second sample is obtained three to six hours later, and recurrent infarction is present if there is a ≥20 percent increase in the second sample.

NONCARDIAC SURGERY — Troponins are used to diagnose perioperative myocardial infarction (MI) and myocardial injury after noncardiac surgery. This issue is discussed in detail elsewhere. (See "Perioperative myocardial infarction or injury after noncardiac surgery".)

CORONARY ARTERY REVASCULARIZATION — There has been considerable controversy as to whether elevated cardiac biomarkers after percutaneous coronary intervention are associated with a worse prognosis. This issue is discussed in detail elsewhere. (See "Periprocedural myonecrosis following percutaneous coronary intervention", section on 'Prognosis'.)

Perioperative myocardial infarction (MI) after coronary artery bypass graft surgery (CABG) is defined as increases in troponin greater than 10 times the 99^th percentile upper reference limit plus either new pathological Q waves or left bundle branch block on the postoperative electrocardiogram, angiographically documented new graft or native coronary occlusion, or imaging evidence of new loss of viable myocardium. The higher the peak value or the integrated area under the curve, the worse the prognosis. It is also clear that when the baseline cardiac troponin (cTn) value is elevated, the post-surgical values will be higher. (See "Diagnosis of acute myocardial infarction", section on 'After revascularization'.)

Troponin has been studied in patients who have undergone CABG:

●The diagnostic value of troponin elevations was illustrated in a study of 590 patients in whom a cTnT concentration >3.4 mcg/L (3400 ng/L) 24 hours after CABG correlated best with a perioperative MI as defined by new Q waves on the electrocardiogram and creatine MB fraction (CK-MB) >100 international units/L within 48 hours after surgery [39] (see "Use of creatine kinase to detect myocardial injury", section on 'Why troponin is preferred'). The sensitivity and specificity, and positive and negative predictive values, were 90, 94, 41, and 99 percent, respectively.

●The prognostic value of troponin elevations was addressed in a report of 224 patients in whom cTnT and CK-MB were measured every eight hours after cardiac surgery [40]. In a multivariable analysis, serum troponin T concentrations ≥1.58 mcg/L ([1580 ng/L] which represented the upper quintile) were the strongest predictor of postoperative death or shock immediately postoperatively or at 18 to 24 hours.

●An investigation of 1365 patients supports this contention for cTnI as well. Measurements were taken 2 and 24 hours after surgery. After multivariate correction, cTnI levels were predictive of both 30-day and one-year mortality, and there was a gradation of risk with those with the highest values manifesting the greatest risk [41].

It should be appreciated that not all elevations of troponin after CABG are indicative of an ischemic injury due to an intravascular event. The process of cardiopulmonary bypass itself, issues related to cardiac preservation, and mechanical injury can all contribute. Cardiac magnetic resonance imaging data suggest that until troponin values are very elevated, most of the damage is subendocardial and often apical, suggesting a nonvascular etiology [42]. Even when marked elevations occurred, only 67 of 118 patients had a primary graft occlusion; this emphasizes the need to consider the etiology of biomarker elevations and not assume that all elevations are due to vascular events [43].

GENERAL POPULATION — Although serum or plasma troponin is most commonly measured in patients with a suspected acute event, troponin may be elevated in the absence of an acute event. In these (general population) patients, the typical rise and fall of troponin with an ischemic event will not be seen. Information regarding troponin elevation in the general population is found elsewhere. (See "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome", section on 'Elevation in the general population'.)

CHRONIC CORONARY SYNDROME — Troponin testing with high-sensitivity troponin assays (hs-cTn) has been suggested as one way to reasonably exclude inducible myocardial ischemia on stress testing in patients with chronic coronary syndrome, also referred to as stable ischemic heart disease. We do not recommend this approach.

The concept derives in part from the data that a very low value in patients with chest pain on presentation can be used to exclude acute MI and is associated with a very good prognosis over time [44,45] (see "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department", section on 'Cardiac biomarkers and other laboratory testing' and "Evaluation of emergency department patients with chest pain at low or intermediate risk for acute coronary syndrome", section on 'Initial evaluation'). In addition, small-to-modest-sized studies of stress testing have suggested that very low hs-cTn values may well be predictive of a negative stress test [46].

A large cohort analysis published in 2020 has challenged that contention [47]. The investigators evaluated 1896 patients referred for stress testing using myocardial perfusion imaging with single-photon emission computed tomography and probed a variety of cut-off values and several assays using previously defined cut-off values shown to exclude MI based on a solitary value. The negative predictive value of a very low hs-cTn value was 66 to 70 percent. Sensitivity was in the range of 90 percent with all three assays and cut-off values. Importantly, the results of stress testing and hs-cTn were additive in regard to longer-term outcome events. This study suggests that predicting a negative result by stress testing cannot be predicated on a low hs-cTn value alone.

Information regarding troponin elevation in patients with chronic coronary syndrome is found elsewhere. (See "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome", section on 'Patients with chronic coronary syndrome'.)

CHRONIC KIDNEY DISEASE — Issues related to the clinical use of cardiac troponins in patients with renal failure are presented in detail separately. (See "Cardiac troponins in patients with kidney disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)" and "Society guideline links: ST-elevation myocardial infarction (STEMI)".)

SUMMARY

●General principles – Cardiac troponin I and T are specific and sensitive biomarkers of myocardial injury. They are the preferred blood-based tests for the evaluation of patients with suspected acute myocardial infarction (MI). Their measurement can be performed using sensitive or high sensitivity tests. We prefer high sensitivity troponin assays, when available. (See 'Introduction' above and 'Sensitive compared with high sensitivity tests' above and 'Diagnosis of acute MI' above.)

●Type I versus Type II MI – Not all patients who meet criteria for the diagnosis of acute MI have intracoronary atherothrombosis as the underling pathology. Other causes such as type II MI and non-coronary artery disease causes should be considered. (See 'Type I versus type II MI' above and 'Differential diagnosis' above.)

●Testing after noncardiac surgery or coronary artery revascularization – In addition to the evaluation of patients with suspected acute MI, troponin testing may be of value in patients who have undergone noncardiac surgery or coronary artery revascularization. (See "Perioperative myocardial infarction or injury after noncardiac surgery" and 'Coronary artery revascularization' above.)