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Elevated cardiac troponin concentration in the absence of an acute coronary syndrome

Elevated cardiac troponin concentration in the absence of an acute coronary syndrome
Literature review current through: Aug 2023.
This topic last updated: Apr 05, 2022.

INTRODUCTION — Cardiac troponin (cTn) is the standard blood-based test to confirm the diagnosis of acute myocardial infarction. (See "Diagnosis of acute myocardial infarction", section on 'Definitions'.)

However, troponin is not specific for acute thrombotic occlusion of a coronary artery, the most common precursor to acute myocardial infarction. Increased blood concentrations of cTn can also be seen in a variety of other diseases, such as sepsis, atrial fibrillation, heart failure, pulmonary embolism, myocarditis, myocardial contusion, and renal failure. In addition, stable chronic elevation of cardiac troponin may be detectable with high-sensitivity assays in patients with underlying structural (muscle) heart disease. Analytical false positives or false negatives are rare.

Potential causes of troponin elevation unrelated to coronary thrombosis will be reviewed here. Other related topics include:

(See "Troponin testing: Clinical use".)

(See "Troponin testing: Analytical considerations".)

(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'.)

CARDIAC TROPONINS — Cardiac troponins (cTn) are regulatory proteins that control the calcium-mediated interaction of actin and myosin. The troponin complex consists of three subunits: troponin T (cTnT), troponin I (cTnI), and troponin C. (See "Excitation-contraction coupling in myocardium", section on 'Role of tropomyosin and troponins'.)

The skeletal and cardiac isoforms of cTnT and cTnI are distinct, and skeletal isoforms are not detected by the monoclonal antibody-based assays currently in use, except for cTnT in some circumstances of significant skeletal muscle disease [1]. This high specificity for cardiac isoforms is the basis for the clinical utility of cTnT and cTnI assays.

The diagnosis of myocardial infarction requires that cTn must be above the 99th percentile upper reference limit for the assay being used and that there is clinical evidence of myocardial ischemia. The 99th percentile reference limit has also been shown to differ between men and women when measured with high-sensitivity assays for cardiac troponin [2]. (See "Troponin testing: Analytical considerations".)

CELLULAR MECHANISMS — With prolonged ischemia, myocytes are irreversibly damaged (necrosis). The cell membrane degrades, followed by the gradual release of myofibril-bound cytosolic complexes [3]. Data suggest that brief periods of ischemia, sudden increases in preload, and physiological challenges like tachycardia and catecholamines can lead to the release of cTn [4,5]. In the first two situations, cTn release has been attributed to apoptosis.

However, it is possible that cardiac troponins can also be released into the circulation without cell death:

Increased myocyte membrane permeability – It is thought that myocardial depressive factors (released in the setting of sepsis and other inflammatory states) cause degradation of free troponin to lower-molecular-weight fragments [6]. With increased membrane permeability, those smaller troponin fragments could be released into the systemic circulation. In this setting, troponin may be elevated, although myocyte cell death may not have occurred. This hypothesis is also supported by the clinical observation that myocardial depression during sepsis is a fully reversible process in most surviving patients [7].

Normal turnover of myocardial cells – Cell turnover could lead to release of cTn degradation products through the formation and release of membranous blebs [8], although this has not yet been shown.

DEMAND ISCHEMIA — The concept of "demand ischemia" refers to a mismatch between myocardial oxygen demand and supply. The term was originally applied to patients with evidence of ischemia but no critical epicardial coronary heart disease (CHD). Although the same pathophysiologic principle may be valid in patients with significant CHD, it is often more difficult to identify the predominant mechanism of ischemia in such patients. The 2018 Joint European Society of Cardiology/American College of Cardiology/American Heart Association/World Health Federation task force for the Fourth Universal Definition of Myocardial Infarction (MI) refers to a Type 2 MI when the event is secondary to ischemia due to either an increased oxygen demand or a decreased supply in the absence of an acute primary coronary thrombotic event [9].

Myocardial oxygen supply is reduced (and serum troponins may be increased) in a number of clinical settings: sepsis, septic shock, and the systemic inflammatory response syndrome [10,11]; hypotension or hypovolemia [12]; noncardiac critically ill patients presented to the emergency department [13]; and atrial fibrillation or other tachyarrhythmias [14,15]. (See 'Non-MI causes of an elevated troponin' below.)

In these settings, increased myocardial demand can be due to:

Tachycardia

Changes in cardiac loading conditions

Increases in cardiac output to accommodate increased systemic oxygen consumption

Myocardial depression

Simultaneously, myocardial oxygen delivery may be reduced due to the following:

Reduced coronary perfusion due to both tachycardia, which reduces diastolic time, during which coronary flow occurs, and reduced perfusion pressure in the setting of hypotension and increased cardiac filling pressures.

Decreased oxygen delivery to the heart.

Ultimately, these forces combine to create mismatch in myocardial oxygen supply and demand, resulting in ischemia and the release of troponin into the systemic circulation. However, this does not imply that all elevations in these individuals are due to supply-demand imbalance. In many patients, there are direct effects related to catecholamines or in sepsis to heat shock proteins and tissue necrosis factor. Such increases in cardiac troponin are deemed as myocardial injury rather than Type 2 myocardial infarction [16]. Thus, it should not be assumed that all elevations where one sees hemodynamic perturbations are due solely to supply-demand imbalance [17].

OUR APPROACH — We agree with the 2018 Joint European Society of Cardiology/American College of Cardiology/American Heart Association/World Health Federation task force for the Fourth Universal Definition of Myocardial Infarction (MI) document, which recommends that an elevated value of cardiac troponin, in the absence of clinical evidence of ischemia, should prompt a search for other causes of myocardial necrosis [16].

Some causes require immediate medical attention: myocarditis, pulmonary embolism, heart failure, sepsis, or renal failure.

While an elevated troponin is generally associated with a worse prognosis, there is insufficient evidence at present to conclude that screening the general population (with troponin) is a useful practice.

ELEVATION IN THE GENERAL POPULATION — It is now clear with high sensitivity cardiac troponin (hs-cTn) assays that most individuals have small amounts of measurable cTn in their blood and that even values within the normal range are of prognostic importance [18] (see 'Prognosis' below). The precise mechanisms of release of these minor amounts of protein are not definitively established, but proposed causes are listed above [19,20]. (See 'Cellular mechanisms' above.)

Most conventional (sensitive, but not hs) assays detect cTn in very few normal subjects, whereas some hs assays detect cTn in nearly 100 percent depending on the population [21-28]. Thus, detectable values with an hs assay should not automatically be considered abnormal. Such measurable values are generally stable within a range of expected biological variability. In addition, there is release of cTn after extreme exercise, after rapid atrial pacing in patients with coronary artery disease, in response to catecholamines and even small amounts during stress testing. Mechanisms other than necrosis may be involved [4,29,30]. With the exception of extreme exercise, these elevations are usually diminutive.

With hs assays, most individuals will have detectable values and those that are higher are at greater risk whether they have known cardiovascular disease (CVD) such as heart failure or no appreciable CVD. It is likely that these individuals release increased amounts of cTn compared with others because of comorbidities. Because cTn, and especially hs-cTn, is so sensitive, it may pick up subtle abnormalities in many individuals who are unaware of any cardiovascular comorbidities. This concept is supported by data that using more extensive screening to eliminate comorbidities that can be detected by biomarkers such as NTproBNP, HBA1C, and eGFR, and even imaging, progressively lower the upper value of a normal reference range [31-33].

In addition, some individuals with known structural heart disease may manifest chronic (stable) elevations above the 99th percentile upper reference limit (URL) in the absence of any acute process. Acute myocardial injury can be discriminated from chronically elevated values by a significant change over serial measurements.

Patients at high cardiovascular disease risk — Individuals in the general population with troponin elevations above the 99th percentile often have detectable CVD comorbidities, and, as such, may be at higher risk of first cardiovascular events. With hs assays, even lower values may be predictive of risk.

The issue of whether elevated troponin can predict cardiovascular events in patients without known CVD but at high risk was evaluated in 3318 men in the primary prevention West of Scotland Coronary Prevention Study [34]. Baseline hs troponin, which was within the normal range (less than the 99th percentile URL) for the vast majority of patients, was an independent predictor of coronary heart disease death, or first myocardial infarction (hazard ratio 2.3, 95% CI 1.4-3.7) over five years for the highest versus the lowest quartile of troponin. In addition, among individuals treated with statin therapy, the greatest absolute benefit was seen in those whose troponin values declined significantly compared with those whose troponin did not. Studies designed to further evaluate this approach to the role of troponin testing in patients being considered for statin therapy or in those started on statin therapy are ongoing [35].

Measurement of troponin has prognostic value in patients presenting with chest pain [36,37]. This ability was evaluated in a substudy of the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) study, which compared coronary computed tomographic angiography with functional testing [38] (see "Selecting the optimal cardiac stress test", section on 'CCTA'). Among 4021 individuals with available blood samples, higher concentrations of cTnI with a high-sensitivity troponin I assay were associated with greater event probabilities for death, acute MI, or hospitalization for unstable angina by one year in multivariate analyses. The small number of events and the small between-group differences will limit the ability to apply these results to individual patients in clinical practice.

Patients with chronic coronary syndrome — Measurement of troponin may be of value in patients with chronic coronary syndrome, also referred to as stable ischemic heart disease (SIHD) [27,39]. Potential uses include chronic screening [40], during stress testing [41,42], for prognosis [43], and in patients with heart failure [26]. (See "Chronic coronary syndrome: Overview of care" and 'Prognosis' below and "Troponin testing: Clinical use", section on 'Chronic coronary syndrome'.)

Some studies have suggested greater absolute benefit of effective secondary preventive therapies in high-risk patients identified by cTn [44,45].

NON-MI CAUSES OF AN ELEVATED TROPONIN — Most individuals in the general population have detectable troponin in the blood (see 'Elevation in the general population' above). However, many of these individuals do not have a diagnosis that needs evaluation or treatment since there are explanations for how this might occur (see 'Cellular mechanisms' above). Thus, there is uncertainty as to which individuals with an elevated troponin need additional testing. Consideration should be given to screening for structural heart disease on a case-by-case basis.

Troponin elevations have been reported in a variety of clinical scenarios (other than an acute thrombotic occlusion of the coronary artery), which is the most common cause of an elevated troponin (table 1). These clinical scenarios are often acute medical problems or serious chronic illnesses. There are three major categories: myocardial damage related to supply-demand mismatch, myocardial damage related to non-ischemic causes (eg, myocarditis or direct trauma), and myocardial injury that is multifactorial or of indeterminate cause [46]. (See 'Cellular mechanisms' above.)

Below is a list of some of the causes for the elevation of troponin. In some circumstances, these potential categories of causes may be overlapping or impossible to discriminate completely from each other, such as in the case of patients with stable ischemic heart disease who become severely ill, tachycardic, and hypotensive with sepsis, or patients with severe heart failure and significantly elevated left ventricular end-diastolic pressure [46,47].

Tachy- or bradyarrhythmias, or heart block.

Critically ill patients, especially with diabetes, respiratory failure, or sepsis.

Hypertrophic cardiomyopathy.

Coronary vasospasm.

Acute neurological disease, including stroke or subarachnoid hemorrhage.

Rhabdomyolysis with cardiac injury.

Congestive heart failure (acute and chronic).

Pulmonary embolism, severe pulmonary hypertension.

Renal failure.

Aortic dissection.

Aortic valve disease.

Apical ballooning syndrome: Takotsubo cardiomyopathy.

Infiltrative diseases (ie, amyloidosis, hemochromatosis, sarcoidosis, and scleroderma).

Inflammatory diseases (ie, myocarditis or myocardial extension of endo-/pericarditis, Kawasaki disease).

Drug toxicity or toxins (ie, adriamycin, 5-flurouracil, herceptin, snake venom).

Burns, especially if affecting >25 percent of body surface area.

Exertion.

Transplant vasculopathy.

Cardiac contusion or other trauma including surgery, ablation, pacing, implantable cardioverter-defibrillator shocks, cardioversion, endomyocardial biopsy, cardiac surgery, following interventional closure of atrial septal defects.

In one series of 21 patients with elevated troponin levels and a normal coronary angiogram, the following etiologies for troponin elevations were suggested [14]:

Tachycardia – 28 percent

Pericarditis – 10 percent

Heart failure – 5 percent

Strenuous exercise – 10 percent

No clear precipitating event – 47 percent

Coronavirus disease 2019 (COVID-19) — Elevated troponin in patients with or suspected of COVID-19 infection is discussed separately. (See "COVID-19: Evaluation and management of cardiac disease in adults".)

Critical illness — Troponin elevations are common in patients with critical illness and are associated with a worse prognosis [10-13,48]. (See 'Prognosis' below.)

The incidence and significance of demand ischemia in sepsis and systemic inflammatory response syndrome (SIRS) were illustrated in a report of 20 patients treated in a medical intensive care unit (ICU) [10]:

Seventeen patients (85 percent) had elevated cTnI levels.

Ten of these 17 patients had no evidence of significant coronary heart disease (CHD).

Five patients with an elevated cTnI died, all of whom had autopsies, and the coronary arteries were normal in four of these cases.

The potential causes and prognostic implications of demand ischemia were further described in a report of 58 patients, the majority of whom were admitted to an ICU for sepsis, septic shock, or SIRS [11]:

32 patients (55 percent) had elevated troponin levels.

Mortality was significantly higher in patients with troponin elevations (22 versus 5 percent).

Tumor necrosis factor-alpha, interleukin-6, and C-reactive protein levels were significantly higher in patients with elevated troponin levels.

Significant coronary artery disease was excluded in 72 percent of troponin-positive patients.

Thus, troponin elevation among patients with sepsis and SIRS is common. Affected patients often have no evidence of significant CHD. In this setting, troponin elevation is associated with a worse prognosis (see 'Prognosis' below), but it is unclear whether any cardiovascular intervention could improve outcomes. Although a causal relationship has yet to be established, inflammatory mediators in conjunction with a myocardial oxygen demand-supply mismatch are potential explanations for this phenomenon.

Troponin elevations suggestive of demand ischemia have also been described in a broader range of critically ill patients. In a review of 20 observational studies involving 3278 critically ill patients in which cTn concentrations were reported [48], the following findings were noted:

The frequency of elevated cTn was 12 to 85 percent, with a median of 43 percent.

In six studies in which adjusted analyses were performed, elevated cardiac troponin was associated with a significantly increased risk of death (odds ratio 2.5; 95% CI 1.9-3.4).

Tachycardia — Tachycardia alone has been implicated as a cause of troponin elevations in small case series. In one series of 21 patients with elevated cTnI levels and normal coronary angiograms, tachycardia was determined to be the explanation of the troponin elevation in six patients [14]. A second series described four patients with troponin elevations after episodes of supraventricular tachycardia, who had no evidence of CHD. These reports illustrate that myocardial troponin can be released as a consequence of tachycardia alone in the absence of myodepressive factors, inflammatory mediators, and CHD.

Left ventricular hypertrophy — cTn elevation has been described in the context of left ventricular hypertrophy (LVH). In a series of 74 consecutive patients without clinical evidence of active myocardial ischemia referred for routine echocardiography, 7 of 25 patients in the tertile with the greatest LV mass had an elevated cTnI. In contrast, one patient in the intermediate range, and none of the patients in the lowest tertile had an elevated troponin level [49].

It is well recognized that LVH can lead to occult subendocardial ischemia via increased oxygen demand from increased muscle mass, coupled with decreased flow reserve due to remodeled coronary microcirculation (see 'Demand ischemia' above). Similar observations have been made in the setting of aortic valve disease, in which elevated troponin level was associated with greater LV wall thickness and higher pulmonary artery systolic pressures [50].

Coronary vasospasm — Myocardial ischemia caused by coronary vasospasm (Prinzmetal angina) can lead to troponin elevations. This was illustrated in a series of 93 patients with suspected myocardial ischemia in whom coronary angiography revealed no hemodynamically significant lesions [51]. Twenty-three (25 percent) had elevated levels of cTnI. Ergonovine provocation testing showed evidence of coronary vasospasm in 41 patients, and in 17 of the 23 patients with cTnI elevations. (See "Vasospastic angina".)

Acute stroke — Both elevated cTn levels and ischemic electrocardiographic changes have been described in the setting of acute stroke or intracranial hemorrhage. In one series of 149 patients with symptoms of acute stroke, 27 percent were found to have elevated serum cTnI [52].

Elevations in cTnI have also been noted in two case series of patients with subarachnoid hemorrhage [53,54]. In these reports, cTnI elevations correlated with both the severity of neurologic injury and cardiovascular abnormalities including LV dysfunction, pulmonary edema, and hypotension requiring pressors. In one of the studies, elevations in cTnI also predicted a higher likelihood of in-hospital death or severe disability at discharge, although this relationship was no longer significant at three months [54]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".)

The most likely explanation of troponin elevation and myocardial damage in this setting is an imbalance of the autonomic nervous system, with resulting excess of sympathetic activity and increased catecholamine effect on the myocardial cells [53,55].

The magnitude of troponin elevation in these reports is often less than that seen with acute MI due to coronary artery occlusion. Thus, it is not clear to what extent the LV dysfunction and hemodynamic compromise reported in these case series is due to acute myocardial injury in the setting of the stroke, or reflects new myocardial and hemodynamic stress in patients with underlying cardiovascular disease.

In addition, since follow-up echocardiograms were not routinely obtained, it is not known how many of these patients may have had improvement in LV function after recovering from the acute stroke. Reversible LV dysfunction in the setting of acute noncardiac illness is an increasingly reported phenomenon, and autonomic imbalance with catecholamine excess is proposed to play a role in both stroke-related myocardial injury and stress-induced cardiomyopathy. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".)

Atrial fibrillation — Elevated concentrations of cTn, in particular when measured with high-sensitivity (hs) assays, have been described in patients with atrial fibrillation in the absence of clinically overt heart failure or demand myocardial ischemia [56-58]. These studies have found that higher concentrations of troponin I or T are independently associated with a higher risk of stroke or systemic embolism, as well as with the risk of MI and cardiac mortality and are substantially more predictive than the CHADS2 and CHA2DS2-VASc scores [56,57]. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.)

For example, in a report from the ARISTOTLE trial comparing apixaban with warfarin in atrial fibrillation patients , an hs-TnI assay detected troponin (≥1.3 ng/L) in 98.5 percent of patients and 9.2 percent had levels ≥23 ng/L (the 99th percentile in healthy individuals) [58]. Comparing the highest with the lowest quartile of troponin, the risk of stroke or systemic embolism was significantly increased (adjusted hazard ratio 1.98, 95% CI 1.42-2.78).

The underlying mechanisms behind these risk relationships are not definitively established and are most likely multiple, including myocardial necrosis and apoptosis, myocardial stress due to tachycardia, underlying inflammatory and fibrotic processes, myocardial dysfunction due to variations in atrial and ventricular volume and pressure load, and possibly coronary microembolism.

Direct myocardial injury — Troponin elevation can occur in the setting of myocardial injury by traumatic or inflammatory processes:

The incidence and significance of cTnI elevations following blunt thoracic trauma were illustrated in a report of 333 patients, in whom serial electrocardiograms and cTnI values were followed over eight hours [59]. Elevation in cTnI occurred in 145 patients (44 percent); 44 patients (13 percent) had evidence of clinically significant blunt cardiac injury, defined by hypotension, arrhythmias, anatomic abnormalities, or depressed cardiac index, 32 of whom had cTnI elevations. Thus, a degree of direct cardiac injury, as evidenced by cTnI elevations, is common after blunt chest trauma, although only a minority of patients with troponin elevations in this setting develop significant clinical complications attributable to cardiac injury.

Implantable cardioverter-defibrillator shocks [60].

Infiltrative disorders such as amyloidosis; it has been postulated that extracellular amyloid deposition may lead to myocyte compression injury, leading to myocardial damage and troponin release [61].

High-dose chemotherapy; troponin levels have been suggested as a method for detecting cardiotoxicity and predicting the development of future LV dysfunction in this population [62].

Inflammatory disorders including acute pericarditis [63] and myocarditis [64]. (See "Clinical manifestations and diagnosis of myocarditis in adults", section on 'Cardiac biomarkers'.)

Immune response after heart transplantation. Chronically elevated troponin levels after cardiac transplantation may be associated with a poorer prognosis (see 'Prognosis' below). In a prospective cohort study of 110 consecutive patients after cardiac transplantation, troponin levels remained persistently elevated in 51 percent of patients and were associated with more fibrin deposition in the microvasculature and among myocytes, as well as a significant increase in the risk for coronary artery disease and graft failure [65].

Heart failure — Troponin elevations tend to be associated with advanced heart failure and an adverse prognosis [66]. The clinical evidence supporting this association is presented separately. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Troponins'.)

Heart failure can lead to the release of cTn principally via two related mechanisms: myocardial strain and myocyte death.

Volume and pressure overload of both the right and left ventricle can produce excessive wall tension or "myocardial strain," with resulting myofibrillar damage [50]. Support for a connection between myocardial strain and elevated troponin levels comes from several lines of evidence:

There is a close correlation between troponin levels and B-type natriuretic peptide (BNP), and BNP is itself a marker of right and LV wall strain [67].

Troponin degradation has been demonstrated with increased preload, independent of myocardial ischemia, in isolated rat hearts [8].

Increased myocardial wall stress may lead to decreased subendocardial perfusion, with resulting troponin elevation and decline in LV systolic function [66].

Troponin elevation in normal persons after ultra-endurance exercise has been described [68,69]. This may be related to an increase in myocardial strain during exercise, although catecholamine-induced vasospasm has also been invoked as an explanation [3].

In addition, in vitro experiments with myocytes established a link between myocardial wall stretch and programmed cell death, which may also contribute to troponin elevations in this setting [70]. Progressive myocyte loss is now thought to play a prominent role in the progression of cardiac dysfunction and may explain the ominous prognosis of patients with heart failure and elevated troponin levels. Several factors may contribute to myocyte death, including:

Activation of the renin-angiotensin system

Sympathetic stimulation

Inflammatory mediators

Integrin stimulation

Pulmonary disease — Troponin elevations are also described in a variety of pulmonary diseases, usually associated with significant right heart strain.

Serum troponins are elevated in 30 to 50 percent of patients with a moderate to large pulmonary embolism. The presumed mechanism is acute right heart overload, and elevated levels are associated with a significant increase in mortality. The troponin elevations usually resolve within approximately two days after pulmonary embolism in contrast to the more prolonged elevation with acute myocardial infarction. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Laboratory tests'.)

Levels of cTnT were elevated in 8 of 56 patients (14 percent) with chronic pulmonary hypertension in one series [71]. cTnT elevations were associated with the following (see "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)"):

Higher heart rates

Lower mixed venous oxygen saturation

Higher levels of B-type natriuretic peptide

Significantly lower two-year survival (29 versus 81 percent with normal cTnT levels)

Exacerbation of chronic obstructive pulmonary disease can also increase troponin levels and has been identified as an independent predictor of in-hospital mortality [72].

Chronic kidney disease — Persistent elevation of cTn is frequently observed among patients with end-stage kidney disease. This issue is discussed in detail separately. (See "Cardiac troponins in patients with kidney disease", section on 'Effect of CKD on troponin levels'.)

The cTnT elevations seen in patients with renal failure may be due to structural myocardial abnormalities and are invariably associated with pathological evidence of myocardial injury. Data also suggest an important role for renal clearance when values are low despite the fact that cTn is not detected in the urine [73]. With hs-cTn assays and especially hs-cTnT, nearly all patients with end stage renal disease will have elevations above the 99th percentile URL [74]. All of these are prognostically important [73,75]. (See "Cardiac troponins in patients with kidney disease".)

Burns — Severe thermal injury is associated with cardiac contractile dysfunction and elevated cardiac troponin. Elevation of cTn is demonstrated among patients who have sustained >25 percent (total body surface area) of thermal injury. The rise in cTn appears to be related to the extent of burns rather than patient's age, pre-existing medical conditions, or the administration of resuscitation fluid [76]. (See "Overview of the management of the severely burned patient".)

Kawasaki disease — The association of elevated cTn and myocarditis among patients with Kawasaki disease (KD) is not clear. One group suggested that among children with Kawasaki disease, there is a significant increase in the cTn, which would indicate acute myocarditis and myocardial cell injury in the early stages of the disease [77]. On the contrary, another study did not demonstrate significant elevation in cTn among KD patients [78]. (See "Kawasaki disease: Clinical features and diagnosis" and "Kawasaki disease: Initial treatment and prognosis".)

Cardioversion — Cardioversion and defibrillation can lead to mild but significant rise in cTn levels. This rise is more pronounced among patients with relatively large LV end diastolic dimensions [79]. (See "Basic principles and technique of external electrical cardioversion and defibrillation".)

False positive tests — There are infrequent causes for analytical false positive values. (See "Troponin testing: Analytical considerations", section on 'Assay false positives and false negatives'.)

PROGNOSIS — In general, individuals with troponin elevation have a worse cardiovascular disease (CVD) prognosis than those without. This applies to individuals thought to be healthy or to those with known disease. (See 'Elevation in the general population' above.)

The best available data on the prevalence of elevated troponin in the general population and the impact on prognosis come from a 2017 study of 154,052 individuals in 28 prospective studies [80]. The following findings were noted:

High sensitivity cardiac troponin (hs-cTn) was detectable in 80 percent of individuals (cTnI: 83 percent; cTnT 70 percent).

The relative risks, comparing the top to the bottom troponin third for CVD, fatal CVD, coronary heart disease, and stroke were 1.43, 1.67, 1.59, and 1.35, respectively, all of which were statistically significant. This increase in risk was independent of conventional CVD risk factors.

In a subgroup analysis, hs-cTnT was detectable in 87.5 percent of individuals and 85 percent of individuals had values within the normal range of ≤14 ng/L. The median concentration was 7 ng/L (interquartile range of 4 to 11).

While these findings suggest that measuring cTn may be useful to screen seemingly healthy individuals for CVD risk, we do not recommend this for routine practice at present for several reasons. The first is that the values that are prognostic overlap very substantially with individuals who are not at risk. In addition, at these levels, both analytical and biological variation are substantial so that values may change a few ng/L when repeated, moving from a predictive value to one that is not. This has been elegantly shown in chest pain patients as well [81]. Finally, we do not yet understand the best response to a given elevation. This area is advancing rapidly and the data suggest that we can test treatments with a reasonable number of patients [82].

The following studies demonstrate the prognostic value of troponin in patients with stable ischemic heart disease:

cTnT concentration was measured using an hs assay in a study of 2285 patients who had both type 2 diabetes and stable ischemic heart disease from the BARI trial [43]. Of these, 99.6 percent had detectable (≥3 ng per liter troponin T concentrations) and 39.3 percent had abnormal troponin T concentrations (≥14 ng per liter, which was the upper reference limit for definite myocardial necrosis in this study). Comparing patients with abnormal troponin T concentrations at baseline with those with normal concentrations, the five-year rate of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke was significantly increased (27.1 versus 12.9 percent; adjusted hazard ratio 1.85, 95% CI 1.48-2.32). This adverse prognosis was not altered by those who received an invasive strategy as part of the BARI trial [43]. These data amplify the findings reported by others concerning the increases in hs-cTn values with diabetes [83] and the known increases and their prognostic importance in those with putatively stable coronary artery disease [36,84].

In a study of 3679 patients assessed with an hs-cTnT, there was a strong and graded increase in the cumulative incidence of cardiovascular death and heart failure during a median follow-up of 5.2 years [37].

In a study of 3623 individuals, hs-TnI levels were measured at baseline. During a median follow-up of 5.2 years, hs-TnI levels in the fourth compared with the three lower quartiles were associated with the incidence of cardiovascular death or heart failure after adjusting for conventional risk factors (hazard ratio 1.84, 95% CI 1.30-2.61) [36].

In a study of nearly 8000 patients, baseline hs-TnI was an independent predictor of coronary heart disease death and nonfatal myocardial infarction comparing the highest with the lowest tertile (hazard ratio 1.64, 95% CI 1.41-1.90) during a median follow-up of six years [85].

In a study of 984 patients with stable coronary heart disease who underwent stress echocardiography, 81 percent had detectable hs-cTnT compared with 6 percent using a standard troponin T assay [86]. Higher hs-cTnT levels were associated with multiple abnormalities of cardiac structure and function (eg, greater inducible ischemia and worse left ventricular ejection fraction). However, they remained independently predictive of subsequent cardiovascular events (myocardial infarction, heart failure, or cardiovascular death); each doubling in hs-cTnT was associated with a 37 percent higher rate.

The following studies illustrate potential future application of hs-cTn testing for risk-based treatment guidelines for patients at risk of or with established cardiovascular disease:

In a study of nearly 13,000 individuals in a pooled analysis of three population-based cohort studies, participants with elevated blood pressure not recommended for antihypertensive treatment were stratified based on hs-cTnT and N-terminal pro-B-type natriuretic peptide (NTproBNP). Individuals with elevated (versus nonelevated) hs-cTnT or NTproBNP had more than a twofold higher incidence of cardiovascular events (11 versus 4.6 percent, respectively), translating to a 10-year number needed to treat to prevent one event for intensive blood pressure lowering of 36 and 85, respectively [87].

In a study of 8635 patients with stable coronary heart disease with a prior myocardial infarction, patients were assigned to risk groups of either very-high-risk or lower-risk atherosclerotic cardiovascular disease (ASCVD) based on their cardiovascular history, comorbidities, and the basis of hs-cTnI level. When patients in the very-high-risk ASCVD group were risk stratified by hs-cTnI level, 614 of 6789 patients (9 percent) with an undetectable hs-cTnI level had a three-year event rate of 2.7 percent (<1 percent per year), which was less than the overall rate in the lower-risk ASCVD group. However, in the lower-risk ASCVD group, 417 of 1846 patients (22.6 percent) with an hs-cTnI level >6 ng/L had an event rate of 9.1 percent, comparable to the overall rate in the very-high-risk ASCVD group. The addition of hs-cTnI to guideline-derived ASCVD risk category improved risk classification. Overall, use of hs-cTnI appropriately reclassified 11.9 percent of patients (1 in 11 with very-high-risk ASCVD and one in four with lower-risk ASCVD), leading to different cholesterol treatment recommendations [88].

SUMMARY AND RECOMMENDATIONS

Non-MI causes of an elevated troponin – Increased blood concentrations of cTn can also be seen in a variety of non-thrombotic diseases, such as sepsis, atrial fibrillation, heart failure, pulmonary embolism, myocarditis, myocardial contusion, and renal failure (table 1). In addition, stable chronic elevation of cTn may be detectable with high-sensitivity assays in patients with underlying structural (myocardial) heart disease, including those with stable coronary artery disease. (See 'Non-MI causes of an elevated troponin' above.)

Elevated cTn in such settings may be due to myocardial ischemia and therefore confer a diagnosis of Type 2 MI or is due to mechanisms other than ischemia consistent with a diagnosis of myocardial injury .

Prognosis – Elevated cTn is associated with a worse prognosis across the spectrum, from healthy individuals to those with life-threatening disease. (See 'Prognosis' above.)

Our approach – We search for the cause of the elevated value of cTn in patients who are not diagnosed with acute myocardial infarction. (See 'Our approach' above.)

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Topic 1469 Version 38.0

References

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