INTRODUCTION
Troponin T and I isoforms are highly specific and sensitive to cardiac myocytes and, therefore, are known as cardiac troponins (cTns). The detection of cTn-T or cTn-I in the bloodstream is, therefore, a highly specific marker for cardiac damage. Troponin levels peak at 12–48 h but remain elevated for 4–10 days. The sensitivity for detecting troponin T and I approaches 100% when sampled 6–12 h after acute chest pain onset.[ 1 ] High sensitivity assays measure cTn concentrations fivefold to 100-fold lower than conventional assays and detect troponin concentrations below the 99th percentile in >50% of normal individuals.[ 2 ] Troponins are best friends for physicians; however, they are a double-edged sword if not interpreted appropriately. Misdiagnosis is harmful with regard to patient outcomes. The present review focuses on common mistakes in the interpretation of troponins in various acute clinical settings as listed in Table 1 , gray zones and recent advances in the understanding of myocardial injury .
Table 1: Common mistakes in interpretation of high sensitivity troponins
Fourth universal definition of myocardial infarction - What is new?
The diagnostic criteria for myocardial infarction (MI) according to the latest universal definition of MI are shown in Table 2 .[ 3 ] In the latest document, the emphasis is on the differentiation between MI and myocardial injury , highlighting periprocedural myocardial injury , the use of cardiovascular magnetic resonance to evaluate the mechanisms of myocardial injury , and computed tomographic coronary angiography in suspected acute coronary syndromes. Benefits of high-sensitivity cTn assays and the role of rapid rule-out protocols for the diagnosis of MI have been reiterated. Evolving diagnostic entities with varied clinical presentations such as takotsubo syndrome (TTS) and MI with Nonobstructive Coronary Arteries (MINOCA) have been characterized separately.
Table 2: 4th Universal definition of myocardial infarction *
Prognostic significance of high sensitivity troponins
High sensitivity troponins are recommended whenever available over conventional assays and have largely replaced them even in low-resource settings in our country. Elevated high sensitivity cTn is associated with significant short term and long-term adverse effects in patients presenting with chest pain to the emergency and acute coronary syndromes,[ 4 ] stable ischemic heart disease,[ 5 ] chronic heart failure (HF),[ 6 ] and even in noncardiac medical illnesses.[ 7 ] They correlate with the amount of myocardial injury precisely and thereby highly prognostic in acute coronary syndromes.
Is >99 percentile of the upper reference limit cut-off validated?
Detection of a rise and/or fall of cTn values with at least one value above the 99th percentile of upper reference limit (URL) is required for the diagnosis of myocardial injury . Shah et al . studied high sensitivity troponin values in patients with suspected acute coronary syndrome from different international centers in 42,282 patients.[ 8 ] Use of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10 360 patients with myocardial injury or infarction but was not associated with a lower subsequent incidence of MI or cardiovascular death at 1 year. They raised a pertinent question, whether the diagnostic threshold for MI based on the 99th centile derived from a normal reference population is correct? Mariathas et al . studied consecutive high sensitivity troponin I concentrations in 20,000 consecutive hospitalized patients and concluded that 1 in 20 patients had elevation of troponins according to the manufacturer recommended cut-off and in most of them, there was no clinical suspicion of acute MI.[ 9 ] Despite some uncertainty, we continue to follow the same cut-off as advocated in all the guidelines at present indicating the necessity for active research in that area.
Various manufacturers, assays, and cut-offs - The problem of too many
The absolute cut-off values depend on assay type and manufacturer and is an easy source of confusion.[ 10 ] Cut-off levels for different commonly used commercially available analyzers are shown in Table 3 . All clinicians should take in to account the assay and analyzer used following the manufacturer recommended cut-offs in interpreting the patient’s values. If these variables are reported, it provides an indirect standardization across different facilities and systems. For example, in our hospital, we test our patients using high sensitivity troponin T Cobas 600 analyzer from Roche, for which the manufacturer recommended cut off is 14 ng/L. Usually, we discharge our patients in chest pain clinic with values <5 ng/L (particularly ones with low pretest probability) and the rest of the patients undergo serial troponins for definitive evaluation.
Table 3: Different commercially available troponin assays and their manufacturer recommended cut-offs
Myocardial injury versus Infarction – The crucial distinctionThe most common mistake in interpreting high sensitivity troponins arises from the inability to differentiate between nonischemic causes of myocardial injury from MI.[ 11 ] Detection of an elevated cTn value above the 99th percentile URL is defined as myocardial injury . Acute myocardial injury , when caused by myocardial ischemia, is designated as an acute MI. Although elevated cTn values reflect injury to myocardial cells, they do not indicate the underlying pathophysiological mechanisms and can arise following preload-induced mechanical stretch or physiological stresses in otherwise normal hearts. The common nonischemic causes of myocardial injury are shown in Table 4 .
Table 4: Common nonischemic causes of myocardial injury and troponin elevation
High sensitivity Troponin I versus Troponin T-what does the data say?
Current biochemical data indicate that injured skeletal muscle expresses proteins that are detected by the cTnT assay, which can lead to higher false-positive rates. However, for practical purposes, both high sensitivity cTn (hs-cTn) T and I can be used in the diagnosis of MI with high accuracy.[ 12 ]
Rapid rule-in and rapid rule-out protocols in emergency – Need for speed
80% to 85% of patients presenting in the ED with chest pain do not have an MI. The accelerated diagnostic protocols are now the driver for what we do in the emergency, trying to get the mass of people sorted out rapidly. The negative predictive value for MI in patients assigned “rule-out” exceeded 98% in several large validation cohorts. 2015 ESC guidelines for the management of acute coronary syndromes recommend a rapid rule-out protocol at 0 and 3 h if, high sensitivity troponins are available (class I)[ 13 ] A rapid rule-out and rule-in protocol at 0 and 1 h is recommended when a 0/1 h algorithm is available. Routine use of copeptin as an additional biomarker for the early rule-out of MI is recommended whenever sensitive or high-sensitivity cTn assays are not available. Copeptin may have some added value even over high-sensitivity cTn in the early rule-out of MI.[ 14 ] At our center, we use the 0–3 h algorithm and resort to additional testing at 6 h if the initial measurements are inconclusive and the clinical condition is still suggestive of an acute coronary syndrome.
Point-of-care troponin testing – The technology to bedside
Successful implementation of rapid algorithms for the diagnosis of MI can be more efficient with the availability of POC testing. It testing can reduce the turnaround time as compared to the central laboratory by 30–60 min[ 15 ] and also allows rapid and cost-effective testing at peripheral centers. In our center, we use POC HS Trop I bundled with brain natriuretic peptide (BNP), D-dimer, Fibrinogen, and CK-MB in a single POC test from Roche. We use this test as an “emergency cardiac profile,” predominantly for patients with acute HF syndromes, which helps us to diagnose underlying acute myocardial injury as well at the same time rapidly. However, the obvious advantage of point-of-care tests, namely the shorter turnaround time, is counterbalanced by lower sensitivity, lower diagnostic accuracy, and lower negative predictive value.[ 13 ]
Definition of periprocedural myocardial infarction – Controversies and beyond
There is no universally accepted or standardized definition of periprocedural MI. The recent debate and controversy over the results of the EXCEL trial[ 16 ] are due to disagreement with the definition of periprocedural MI. Different periprocedural MI definitions advocated by various scientific societies and the ones used in major trials are shown in Table 5 . EXCEL investigators used the SCAI definition for procedural MI.[ 17 , 18 ] The principal investigators from intervention group argued that this definition unifies the criteria for both percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG), thereby limiting the ascertainment bias and allowing better comparability. Similar kind of definition, although with different thresholds, was used in the SYNTAX trial.[ 19 , 20 ] In some previous studies, 7–10-fold CK-MB elevation postintervention correlates better with the adverse outcomes than 70-fold elevation in troponins.[ 21 ] The surgical group argued that the SCAI definition overestimates MI rates in CABG and is favorable to the PCI group. Periprocedural troponins were not measured in most of the patients in the EXCEL trial, and hence, universal definition of MI rates could not be assessed. Recent ISCHEMIA trial[ 22 ] defined two endpoints, primary and secondary as shown in Table 5 . The primary definition used CK-MB as a preferred marker to troponins and secondary definition used troponin as a preferred marker. They measured primary and secondary endpoints using both the definitions and concluded that the outcomes are very sensitive to the definitions used for MI. One more interesting hypothesis from the interpretation of the ISCHEMIA trial is that spontaneous (type I) MI rates are higher in the long-term with conservative arm and periprocedural MI (types 4a and 5) are more common with the invasive arm. Sub-analysis showed that spontaneous type 1 MI correlated significantly with more adverse events and these rates are lower with procedural MI. We do not know for sure how significant is the effect of periprocedural MI on the outcomes. Finally, it appears reasonable that, findings of EXCEL cannot be incorporated into major guidelines for the lack of convincing unequivocal definition for procedural MI, an important endpoint. At what levels of myocardial injury in the periprocedural period does it affect the outcomes and what should be the ideal definition for that to make both groups (PCI and CABG) comparable is the main question. Long-term follow-up from the ISCHEMIA trial cohorts may tell us about the significance of types of MI and its effect on outcomes. We desperately need a unifying definition for periprocedural MI to define the appropriate endpoints and proceed with future randomized controlled trials.[ 23 ]
Table 5: Various definitions of periprocedural myocardial infarction
CK-MB versus troponins in periprocedural myocardial infarction – Which is the preferred biomarker?
The existing evidence tips toward the use of periprocedural CK-MB monitoring over troponins though troponins remain a precise and reliable marker of cardiac damage. Periprocedural CK-MB has correlated better with outcomes when compared to troponins and troponins were criticized to be over sensitive and to have inconsistent correlation with outcomes. Many argue that cTn holds little prognostic relevance until the degree of elevation is extremely high.[ 21 ] However, latest Universal definition of MI continues to retain troponin as the preferred marker to CK-MB as in the third universal definition for the lack of unequivocal scientific evidence in this setting.
Routine measurement of cardiac biomarkers after PCI – Is it justified?
Most interventionalists currently do not routinely measure cardiac biomarkers after an uncomplicated PCI. In the most recent ACCF/AHA/SCAI PCI guidelines (2011),[ 24 ] routine assessment of cardiac biomarker levels after PCI is supported with a class I recommendation in the patient with angiographic complications during PCI or clinical symptoms or ECG changes after PCI, but with only a class IIb recommendation after an uncomplicated PCI. If the ECG is normal, cardiac biomarkers need not be drawn. If either clinical symptoms are present post-PCI, and/or transient or sustained angiographic complications occurred, and/or the post-PCI ECG shows new ST-segment depression or elevation, then CK-MB (or cTn in hospitals where CK-MB is not available) should be measured 8–12 h post the procedure. If post-PCI cardiac biomarker elevation > ULN is noted, then serial levels should be drawn every 8–12 h until they are falling. An ECG should also be repeated in 24 h or earlier if symptoms develop.
Sex and gender differences in cut-offs – The underperceived
Another issue with various troponin assays is that there is no consensus for the definition of “reference healthy population” among hs-cTn manufacturing companies. Men have significantly higher URL levels compared to women. Using the same URL for men and women causes the underdiagnosis of MI in women. Sex-specific hs-cTnT cut-offs for ruling out MI at the time of presentation may offer improved classification performance compared to universal rule-out cut-offs.[ 25 ] TRAPID-AMI (The hs-cTn T Assay for Rapid Rule-out of Acute MI) study showed that the use of different cut-offs resulted in an increase of acute MI rates in females (from 16.6% to 22.6%) and a decrease in males, however, this did not lead to outcome differences.[ 26 ] Furthermore, a large retrospective study showed slightly higher rates of diagnostic reclassification (8.4%) and an increase (+3.3%) in MI prevalence in women when using sex-specific cutoffs by using sex-specific reference values (10–12 ng/L for women and 14 ng/L for men).[ 27 ] In High-STEACS (The hs-cTn T Assay for Rapid Rule-out of Acute MI) study, using sex-specific cut-offs for Trop I (34 ng/mL in women and 16 ng/mL in men) reclassification occurred in 17% of patients. Again, no significant differences were observed in 1-year outcomes.[ 8 ] Similarly, the URL level is substantially higher in the elderly as compared with younger patients. Elevated levels of cTn are found in up to 22% of people greater than 70 years of age.[ 28 , 29 ]
Cut-offs in chronic kidney disease patients – The challenging subset
With hs-cTn assays, the majority of patients with end-stage renal disease will have an elevation of hs-cTn values above the 99th percentile URL and the diagnosis of MI in these patients is challenging. In CKD patients, the false-positive rate is higher with hs-cTn T compared to hs-cTn I. The mechanisms of troponin elevation include decreased renal clearance, increased ventricular pressure, small-vessel coronary obstruction, anemia, hypotension, and possibly direct toxic effects on the myocardium associated with the uremic state.[ 30 ] Serial elevations of troponins and associated changes in ECG or cardiac imaging can be helpful in the diagnosis of MI. However, only a rising and/or falling pattern can also be seen in acute volume overload or congestive HF and cautious interpretation is required.[ 31 ]
Baseline troponins in stable ischemic heart disease – Are we there yet?
Everett et al . studied patients with type 2 diabetes and stable ischemic heart disease and concluded that troponin T concentration was an independent predictor of death from cardiovascular causes, MI, or stroke. Elevations of hsTnI are also independently associated with HF or death, but not with ischemic events, even after controlling for a large number of variables. This predictive ability disappears in patients with glomerular filtration rate < 60 mL/min/1.73 m2 again signifying the higher cut-offs of troponins in CKD patients.[ 32 ] In another study, the prognostic value was not incremental over N-terminal pro–B-type natriuretic peptide and echocardiographic evidence of cardiac abnormalities.[ 33 ] Further studies are needed to clarify whether the use of troponins in daily clinical practice can improve the management of patients with stable ischemic heart disease.
Issues of silent myocardial infarction , recurrent myocardial infarction , re-infarction, and late presentation
For diagnosis of silent/unrecognized MI, any one of the following criteria must be met: Pathological Q waves with or without symptoms, in the absence of nonischemic causes; Imaging evidence of loss of viable myocardium in a pattern consistent with ischemic etiology; Pathological findings of a prior MI. Incident MI is defined as the individual’s first MI. When features of MI occur in the first 28 days after an incident event, the second event is not counted as a new MI for epidemiological purposes. If characteristics of MI occur after 28 days following an incident MI, it is considered to be a recurrent MI. The term re-infarction is used clinically for an acute MI that occurs within 28 days of an incident or recurrent MI. The ECG diagnosis of suspected re-infarction following the initial MI may be confounded by the initial evolutionary ECG changes. Re-infarction should be considered when ST elevation ≥1 mm recurs or new pathognomonic Q waves appear in at least 2 contiguous leads, particularly when associated with ischemic symptoms. However, re-elevation of the ST segment can also be seen in threatened myocardial rupture or cases of pericarditis and requires cautious consideration.[ 3 ] Late presentation is a common problem and sought with challenges such as associated HF, ventricular arrythmias, and nonviable myocardium. Troponins being a time bound phenomenon, may not correlate with the amount of myocardial injury and values depend on the duration after clinical symptoms. In patients presenting late, ECG and echocardiographic abnormalities, duration and severity of clinical symptoms, concomitant complications, and additional cardiac imaging for viability assessment play an important role over biomarkers in planning the management strategy.
Troponins and heart failure – The often-missed ischemia link
Troponin elevations may be indicative of myocardial injury in patients with HF, both with reduced ejection fraction (EF) and with preserved EF. Beyond type 1 MI, multiple mechanisms have been proposed to explain the elevation. Increased transmural pressure, small-vessel coronary obstruction, endothelial dysfunction, anemia, or hypotension, direct cellular toxicity related to inflammation, circulating neurohormones have all been identified as various mechanisms for myocardial injury .[ 34 ] It is important to rule out treatable causes like myocardial ischemia by performing serial ECG, serial troponins and identifying new wall motion abnormalities. It is easy to miss coronary ischemia in this setting and a high level of suspicion is required. A meta-analysis by Doshi et al . found that in patients with new-onset HF, coronary artery testing is underutilized before discharge missing the window of opportunity for treating the precipitant cause itself.[ 35 ] Cardiac magnetic resonance imaging (CMR) and other myocardial perfusion imaging modalities are very useful in the diagnosis of myocardial ischemia and assessing viability as well to select patients suitable for revascularization.[ 36 ]
Takotsubo syndrome – Disease with myriad presentations
Approximately 2% of patients who present to hospital with suspected acute coronary syndrome have TTS. Mortality is higher than initially thought, and recurrence is seen in 1.2% of patients within 6 months and nearly 5% at 6 years, with no preventive therapy currently available.[ 37 ] The onset of TTS is often triggered by intense emotional or physical stresses, such as bereavement. However, this is not obligatory and it can also be seen in other settings such as pheochromocytoma, central nervous system disorders (Stroke, subarachnoid hemorrhage), perioperative stress or rarely after exposure to catecholamines. When baseline echocardiography is not available in the later scenarios, the diagnosis can be challenging. Postmenopausal women constitute over 90% of the patients. The ST-segment elevation is common (44%), but the extent of the ST-segment elevation is usually widespread across the lateral and precordial leads, beyond that of a single coronary artery distribution. ST-segment depression occurs in <10% of patients followed by deep, symmetric T wave inversions typically. There are usually elevations in cTn levels, but the peak cTn values observed are modest, and contrast with the large territory of ECG changes or left ventricular (LV) dysfunction. Recovery of LV function and QTc prolongation are two distinguishing features from MI. The diagnosis of TTS should be suspected when the clinical manifestations and ECG abnormalities are out of proportion to the degree of elevation of cTn values, and when the distribution of the LV wall motion abnormalities does not correlate with a single coronary artery distribution. Based on current knowledge, a new international diagnostic criteria have been developed for the diagnosis that may help to improve identification and stratification of TTS. Invasive coronary angiography and ventriculography are often needed. Evidence of myocardial edema is seen on CMR but LGE is usually absent.[ 38 , 39 ]
A new outfit for myocardial injury – myocardial infarction with nonobstructive coronary arteries
The term MINOCA has been coined for patients with MI and no angiographic obstructive CAD (>50% diameter stenosis in a major epicardial vessel).[ 40 ] The prevalence of MINOCA is estimated to be 6% to 8% among patients diagnosed with MI and more common in women than men, as well as in patients presenting with NSTEMI compared with STEMI. Potential underlying mechanisms include coronary causes such as coronary spasm, coronary microvascular dysfunction, plaque disruption, spontaneous coronary thrombosis/emboli, and coronary dissection. TTS has to be separated from MINOCA and not an umbrella term anymore according to latest universal definition of MI.[ 41 ] The mechanisms responsible for the myocyte injury are ischemic in origin (as opposed to TTS) and MINOCA is a diagnosis of exclusion. Invasive coronary angiography, additional intravascular imaging (Intravascular ultrasound/Optical coherence tomography), functional testing methods like Fractional flow reserve (FFR), and CMR may be required for the appropriate diagnosis.[ 42 ]
Troponins in intensive care unit and other nonischemic acute conditions
Troponin elevations are common in patients in the intensive care unit and are associated with adverse prognosis regardless of the underlying disease state.[ 43 ] Some elevation of cTn values may reflect type 2 MI due to underlying coronary artery disease and increased myocardial oxygen demand, whereas in other patients, type 1 MI may occur because of plaque disruption leading to thrombosis in a coronary artery. Sepsis can also cause myocardial dysfunction and troponin elevation. Pulmonary thromboembolism is a great masquerade and can present with ECG changes, chest pain, and troponin elevation.[ 44 ] It is frequently challenging for the clinician caring for a critically ill patient to decide on a plan of action when the patient has elevated cTn values. The general condition of the patient, clinical symptoms, ECG changes, echocardiographic abnormalities, and serial troponins are all considered in deciding the treatment plan.
Imaging unveils the injury mechanisms – The costly omission
Myocardial imaging is an underutilized entity in the setting of acute myocardial injury for the cost constraints and lack of availability in India. The high tissue contrast and resolution of CMR provide an accurate assessment of myocardial structure and function.[ 45 ] Paramagnetic contrast agents can be used to assess myocardial perfusion and the increase in extracellular space that is associated with the fibrosis of prior MI (detected by LGE-CMR). CMR also can identify the presence and extent of myocardial edema/inflammation, allowing the distinction of acute versus chronic myocardial injury . In patients with possible acute MI but unobstructed coronary arteries, CMR can help to diagnose alternative conditions such as myocarditis, takotsubo cardiomyopathy, MINOCA, embolic infarction, or MI with spontaneous recanalization. In the case of late presentation after suspected MI, the presence of a regional abnormality of myocardial motion, thickening, thinning, or scar in the absence of a nonischemic cause provides supportive evidence of past MI. The spectrum of myocardial injury and various patterns of involvement on CMR is shown in Figure 1 . Similarly, CT coronary angiography (CTCA) may be used to diagnose coronary artery disease in patients with acute coronary syndrome, low-to-intermediate risk, and with normal troponins at presentation. High-sensitive Troponin I followed by CTCA improves acute coronary syndrome risk stratification accuracy and work-up in acute chest pain patients.[ 46 ] CTCA can also identify specific plaque characteristics in acute coronary syndromes, however, this application did find adequate utility in routine clinical practice.[ 47 ]
Figure 1: The spectrum of myocardial injury and cardiac magnetic resonance imaging patterns
Troponins and COVID-19 pandemic
In SARS-CoV-2 infection, hs-cTn elevation was commonly (1 in 5 patients, 19.7%) noted in a Chinese study from Wuhan.[ 48 ] A total of 416 hospitalized patients were studied. Complications were more common in patients with cardiac injury than those without cardiac injury and included higher mortality, acute respiratory distress syndrome, acute kidney injury, electrolyte disturbances, hypoproteinemia, and coagulation disorders. Elevated troponin levels were associated with higher neutrophil counts, and lower lymphocyte counts, longer prothrombin times, shorter activated partial thromboplastin time, higher levels of D-dimer levels, C-reactive protein, and NT-proBNP. Overall, patients with an elevated TnT had 10-fold higher mortality. The overall estimates of the incidence of acute myocardial injury from a multicenter data varied from 8% to 12% on average.[ 49 ] Given multiple mechanisms of myocardial injury as shown in Figure 2 , it is important to identify the precise underlying mechanisms for appropriate management. High-sensitivity cTn can also be used to triage patients to critical care and guide the use of supportive treatments. In the absence of typical anginal chest pain and/or ischemic ECG changes, patients with mild elevations (e. g. <2-3 times the upper limit of normal) do not require work-up and/or treatment.[ 50 ]
Figure 2: SARS-CoV-2 infection and effects on the cardiovascular system
Financial support and sponsorship
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Conflicts of interest
There are no conflicts of interest.
Acknowledgments
We thank Aayush hospital management for support and encouragement.
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