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Readers should learn how to interpret cardiac troponins (cTn) in patients with suspected acute coronary syndrome (ACS).
Should become familiar with the Universal myocardial infarction (MI) definition and subtypes of MI.
Should know how to select between the different diagnostic algorithms for diagnosis of MI.
Should learn about the most common limitations and caveats of testing with high-sensitivity (hs) cTn assays.
Should be aware of non-ACS-related reasons for cTn and particularly hsTn elevations.
Should know how to use cTn for risk stratification in pulmonary embolism and other acute settings such as acute heart failure.
Should consider serial cTn measurements for monitoring of chemotoxicity in cancer treatment and monitoring of response to pharmacological therapy in heart failure treatment.
Cardiac troponins (cTn) are components of the thin filament of the sarcomere of striated muscle regulating excitation–contraction coupling in the heart.1 2 Owing to their superior sensitivity and cardiac tissue specificity compared with cardiac enzymes or creatine kinase-MB mass, cardiac troponin T or I (cTn) are now considered the preferred biomarkers for the diagnosis of myocardial injury.3 4 Reasons for elevated cTn with or without kinetic changes are numerous and sometimes multifactorial while in some cases a reason cannot be identified despite intensive diagnostic work-up.4
Use of high-sensitivity (hs) troponin assays allow more accurate and earlier detection of myocardial infarction (MI).5–7 Higher analytical sensitivity increases the number of patients with analytically true positive cTn result due to non-ST-elevation MI but also due to numerous acute or chronic diseases in the absence of overt ischaemic heart disease. Use of hsTn has also enabled to determine a 99th percentile value of a healthy reference population and to demonstrate lower reference values for women than for men.5 8 For diagnosis, prognosis and management of acute coronary syndrome (ACS), cTn should—with few exceptions—be measured serially and should be interpreted as a continuous rather than as a dichotomous variable.3 The term negative troponin should be used to describe cTn concentrations below the limit of detection (LoD) whereas detectable cTn values include normal values below the 99th percentile cut-off and elevated cTn above the 99th percentile value.9 The term ‘false positive’ should be restricted to those with a true false positive cTn, which is rare (~1%) due to analyser malfunction, heterophilic and mouse antibodies, macro-troponins or analytical issues.9 This term should, however, not be misused for patients with analytically true positive cTn elevation in the absence of a culprit lesion on a coronary angiogram.
The sensitivity of hs-troponin assays varies widely. Currently, the International Federation of Clinical Chemistry (IFCC) Task Force guidelines10 support the concept that hsTn assays are differentiated from contemporary or conventional cTn assays, including almost all commercially available point-of-care (POC) assays, by their ability to measure cTn values above the LoD in >50% normal subjects. An imprecision of ≤10% coefficient of variation (CV) at the 99th percentile upper reference limit (URL) represents an important qualifying requirement for hsTn assays.9 10 On the other hand, cTn assays with CV >20% at the 99th percentile URL should not be used in clinical routine nor in clinical trials.9
Acute coronary syndromes
Measurement of cTnT or cTnI is recommended by the Universal MI definition (Joint European Society of Cardiology (ESC)/American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/WHF Task Force for the redefinition of myocardial infarction) and ESC guidelines3 4 as the preferred marker for the diagnosis of an acute MI. To discriminate myocardial injury from an acute MI, the ESC guidelines and Universal MI Task Force uniformly recommend three major criteria for a diagnosis of MI.4 First, a cTn exceeding the 99th percentile of a healthy reference population indicating myocardial cell death. Second, a relevant rise and or fall of cTn concentration within a pre-specified interval of a few hours standing for an acute event as compared with a chronic cTn elevation. Third, the clinical context of myocardial ischaemia as suggested by the presence of ischaemic symptoms, ECG changes, wall motion abnormalities in echocardiography, evidence for loss of viability or visualisation of an intracoronary thrombus (box 1).
ESC/ACCF/AHA/WHF Task Force redefinition of myocardial infarction
For diagnosis of acute MI, objective evidence of myocardial necrosis must be present in the context of acute myocardial ischaemia (3). In this setting, a rise and/or fall of cardiac biomarkers, preferably cardiac troponin, with at least one value above the 99th percentile upper reference limit is mandatory. The criteria for diagnosis of MI are met, when additionally at least one of the following is present:
Symptoms of ischaemia.
New or presumed new significant ST-segment–T wave (ST–T) changes or new left bundle branch block.
Development of pathological Q waves in the ECG.
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
Evidence of intracoronary thrombus by angiography or autopsy.
Along with the general definition of MI, five subtypes of MI (box 2) are listed.
Subtypes of MI according to the ESC/ACCF/AHA/WHF Task Force redefinition of myocardial infarction
Type 1: Spontaneous myocardial infarction
Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, erosion or dissection with resulting intraluminal thrombus in one or more of the coronary arteries leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. The patient may have underlying severe coronary artery disease (CAD) but on occasion non-obstructive or no CAD.
Type 2: Myocardial infarction secondary to an ischaemic imbalance in instances of myocardial injury with necrosis where a condition other than CAD contributes to an imbalance between myocardial oxygen supply and/or demand, for example, coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachyarrhythmia/bradyarrhythmia, anaemia, respiratory failure, hypotension and hypertension with or without left ventricular hypertrophy.
Type 3: Myocardial infarction resulting in death when biomarker values are unavailable:
Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes or new left bundle branch block (LBBB), but death occurring before blood samples could be obtained, before cardiac biomarker could rise, or in rare cases cardiac biomarkers were not collected.
Type 4a: Myocardial infarction associated with percutaneous coronary intervention is arbitrarily defined by elevation of cTn values >5×99th percentile upper reference limit (URL) in patients with normal baseline values (≤99th percentile URL) or a rise of cTn values >20% if the baseline values are elevated and are stable or falling. In addition, either (1) symptoms suggestive of myocardial ischaemia, or (2) new ischaemic ECG changes or new LBBB, or (3) angiographic loss of patency of a major coronary artery or a side branch or persistent slow or no-flow or embolisation, or (4) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required.
Type 4b: Myocardial infarction related to stent thrombosis:
Myocardial infarction associated with stent thrombosis is detected by coronary angiography or autopsy in the setting of myocardial ischaemia and with a rise and/or fall of cardiac biomarker values with at least one value above the 99th percentile URL.
Type 5: Myocardial infarction related to coronary artery bypass grafting (CABG):
Myocardial infarction associated with CABG is arbitrarily defined by elevation of cardiac biomarker values >10×99 th percentile URL in patients with normal baseline cTn values (≤99th percentile URL).
In addition, either (1) new pathological Q waves or new LBBB, or (2) angiographic documented new graft or new native coronary artery occlusion, or (3) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
Most controversies exist regarding type 2 (T2MI) versus type 1 MI (T1MI) and regarding type 4 and type 5 MIs. T2MI is more frequently encountered after the introduction of hsTn assays requiring discrimination from T1MI and myocardial injury.4 11 By definition, the pathomechanism leading to T2MI is the presence of a significant imbalance between myocardial oxygen supply and/or demand but in the absence of plaque rupture. Due to the lack of clear diagnostic criteria, frequencies of T2MI are variable ranging from 1.6% to 29.6% of the total numbers of MI.11 12 The distinction of T2MI from T1MI based on hsTn measurements is challenging. Although higher peak values have been reported in T1MI versus T2MI, it seems that concentration changes of cTn do not help in distinguishing T1MI from T2MI.11 The most important advantage with the use of hsTn is the earlier and more accurate detection of MI. Whereas early ESC guidelines had recommended to obtain a second blood sample after 6 to 9 hours after the admission sample, the current ESC guidelines advocate the use of a hsTn assay and promote a 3-hour interval from presentation for the second sample (figure 1). Using this standard protocol, there are only two exceptions that allow to obviate a follow-up sample. First, the second sample can be omitted if a patient presents with a normal hsTn and the last chest pain episode occurred 6 hours or longer before presentation, assuming that an evolving myocardial injury would become detectable after more than 6 hours.8 Second, very high hsTn concentrations at presentation raise suspicion for a large evolving MI such as a strict posterior MI, prompting the need for an immediate invasive management without a second blood sample in order to minimise jeopardised myocardium.13 The exact value defining relevant rise and/or fall has been specified by a consensus group based on few studies and on expert opinion.9 If baseline hsTnT or hsTnI levels are below the 99th percentile value, a significant concentration change is defined as a rise and/or fall of more than 50% change of the URL based on two clinical trials using the Roche hsTnT14 and the Siemens Advia Centaur contemporary sensitive cTnI assay.15 These absolute concentration changes are assay dependent and cannot be generalised to new hsTn assays that become commercially available without independent validation. If baseline hsTn values are elevated, a 20% change from baseline is still recommended9 based on a former National Academy of Clinical Biochemistry recommendation for patients with end-stage renal failure.16 There is increasing evidence supporting the usefulness of different metrics such as absolute concentration changes14 15 or reference change values17 within short sampling intervals to discriminate acute from chronic hsTn elevation.
Due to the capability of hsTn assays to reduce time to diagnosis, the 2015 ESC guidelines3 recommended the use of faster diagnostic algorithms using serial hsTn measurement after 1 to 3 hours, or single hsTn measurements in the presence of very low initial hsTn values, or together with copeptin, preferably with the concomitant use of a conventional, a contemporary cTn or a POC assay as an alternative.3 Accumulating evidence summarised in a recent editorial18 and based on two meta-analyses19 20 on more than 9000 patients each, and individual observational cohorts21 22 support the use of a single admission hsTnT at the LoB or the LoD to rule-out MI. Correspondingly, several studies demonstrate excellent instant rule-out of MI using hsTnI at cut-offs at or close to the LoD including the UTROPIA study23 (Use of TROPonin In Acute coronary syndromes) in the USA, High-STEACS Study24 in Scotland, a High-STEACS substudy,25 the Biomarkers in Acute Cardiac Care (BACC) Study26 in Germany and a pooled analysis of five international (Australia, New Zealand and England) observational cohort studies.27 As an alternative to the single hsTn value-based instant rule-out of MI, the dual marker strategy (DMS) based on copeptin and cTn/hsTn has been recommended by ESC guidelines as an alternative based on numerous clinical trials3 and two meta-analyses, and because DMS has been demonstrated in a large randomised intervention trial28 to allow an earlier discharge that is at least as safe as a standard diagnostic strategy. However, costs and labour-intensive measurement on a separate laboratory analyser currently limit adoption into clinical routine.
The use of the faster 0/1 hour algorithm requires the use of a validated hsTn assay and is currently only suggested for the hsTnT and the Abbott Architect STAT hsTnI assay (figure 2). Early and late presenters may limit the ability of cTn/hsTn to rule-in or rule-out MI correctly as the time interval from onset of symptoms may be too short to detect hsTnI or hsTnT in peripheral blood, that is, among patients presenting <3 hours after onset of symptoms. Therefore, in some patients, follow-up testing beyond 3 to 6 hours may be required and is encouraged by ESC guidelines.3 However, the negative predictive value (NPV) of the 0/1 hour algorithm is similar in patients presenting <2 or ≥2 hours as demonstrated in several studies21 22 29 30 including the TRAPID AMI study22 that actively enriched rates of early presenters. However, rule-out algorithm based on a single very low hsTnI or a hsTnT below the LoD is problematic when the last chest pain episode occurred <3 hours before presentation.3 22 30 Therefore, the ESC guidelines3 discourage the use of a single-value rule-out in patients with the last chest pain episode <3 hours before presentation. In addition, a consistent performance of the 0/1 hour protocol was demonstrated for older age, severe renal failure, sex and history of CAD.22 29 30 Similar to hsTnT, there is substantial supporting evidence for the accuracy of accelerated diagnostic protocols with sampling at presentation and within 1 to 2 hours using hsTnI (online supplementary table 1 with corresponding references). Another issue regarding optimal diagnosis of MI in suspected ACS using hsTn assays relates to the use of sex-specific cut-offs. Lower hsTn values and thus lower 99th percentile values in women as compared with men are biologically plausible. The use of sex-specific cut-offs has been recommended by the Universal MI definition4 and the IFCC,10 but the role of sex-specific cut-offs has not been convincingly demonstrated in clinical routine. So far, sex-specific hsTn 99th percentiles have shown clinical net benefit in only one hsTnI study assessing patients with chest pain.31 For hsTnI, recent findings32 33 rather suggest that considerably lower uniform cut-offs obtained at a single measurement, for example, <3 or <5 ng/L and void of further differentiation by sex, performed better than the manufacturer-recommended 99th percentile value.21 22 For the hsTnT assay with relative close sex-specific cut-offs, reclassification rates are small.34 35
Supplementary file 1
Management of low-risk patients with suspected ACS following risk stratification remains an area of uncertainty. Except the Biomarker-in-Cardiology 8 trial28 that tested the safety of early discharge in a randomised interventional trial using a copeptin versus a standard protocol, evidence for safe discharge using fast diagnostic algorithms is limited. In the BIC-8 trial, enrolment was limited to patients with a low to intermediate risk based on the Global Registry of Acute Coronary Events score. However, no other clinical trial excluded patients at high risk from diagnostic testing.28 However, in most studies, further management of patients regarding the decision to admit or discharge was restricted to patients at low risk, estimated either by ECG together with a clinical score,36–38 or ECG and clinical assessment21 22 (online supplementary table 2).
However, implementation of 0/1 hour algorithm in a patient with end-stage renal failure is not recommended as fast algorithms including the 0/3 hour standard algorithms have not been validated in patients with renal failure requiring long-term haemodialysis, those with trauma, cardioversion, defibrillation or thrombolytic therapy before inclusion, individuals receiving CABG within the last month or hospitalised for an acute MI within the last 3 weeks, and pregnant and breastfeeding women.22
Cumulative evidence from several observational validation studies suggests that faster protocols allow an earlier rule-out and rule-in in almost two-thirds of consecutive patients.21 22 29 30 32 Rule-out of MI is extraordinarily effective with sensitivities and NPVs above 99% and specificities and positive predictive values between 75% and 85%.22 32 However, 0/1 hour algorithm has created an observational zone that ranges between 25% and 40% depending on the population and the biomarker definitions (figure 3), with the largest observational zone reported in the BACC Study.32 Patients categorised into this zone have a 1-year mortality rate that is at least as high as mortality rates in patients with an MI requiring an investigation of the underlying non-coronary cardiac or extracardiac causes.22 Clinical assessment, additional cTn measurements beyond the initial 6 hours to identify MIs in early or late presenters, extended laboratory tests including the measurement of natriuretic peptides to detect heart failure, and liberal use of echocardiography and other cardiac imaging technologies are strongly recommended for diagnostic work-up and differential diagnosis.3 According to 2015 ESC guidelines, patients without cTn elevation do not require rhythm monitoring and can be considered for referral to a peripheral ward or hospital discharge. The latter represents an unresolved issue because the safety of an earlier discharge from ED using faster protocols has not been tested prospectively in an interventional study. Management of patients with ACS should be guided by risk stratification. In support, admission of low-risk patients in a Swedish registry39 was associated with higher rates of coronary angiography, coronary revascularisation, re-visits to an emergency department with subsequent hospital admission. Consistently, a substudy of the PLATO trial40 on 1232 patients with non-ST-segment elevation ACS and normal hsTnT or s-cTnI (Beckman AccuTnI) at randomisation, that is, unstable angina, demonstrated that an early invasive strategy as compared with a conservative management was associated with higher numbers of post-procedural myocardial injuries and type IV MI and was also associated with a more than sixfold increase in the rates of non-CABG procedure-related major bleedings, regardless whether patients were randomised to ticagrelor or clopidogrel.
The Universal MI definition distinguishes several MI subtypes including T1MI from T2MI.4 The distinction is important because both infarct types differ regarding the underlying pathology, treatment options and outcomes.11 Both infarct types fulfil the criteria of the Universal MI definition and cannot be distinguished by leading presenting symptoms, or cTn elevation demonstrating a rise and/or fall. Classification of T2MI remains challenging and is often made prospectively or retrospectively without a confirmatory coronary angiography. Only on an angiogram, the qualifying presence of a rupture, dissection and erosion of a plaque in T1MI can be visualised whereas T2MI is characterised by a mismatch between oxygen supply and demand, regardless the presence of a coronary obstruction.3 11 Equivocal definitions of T2MI may explain the extremely variable proportion of T2MI in clinical trials.11 41 While it is unclear whether patients with T2MI require dual antiplatelet therapy and anticoagulation, it is important to note that patients with T2MI are older, more often women, with more comorbidities including renal failure, heart failure and diabetes and might require specific treatment of underlying condition and/or intensified prevention measures.42 43 Several reports indicate that T2MI is associated with mortality rates that are least as high as mortality rates in T1MI.42 44
Another obstacle with implementation of hsTn assays is the increased detection rate of elevated cTn concentrations in patients without an ACS. The use of hsTn assays now enables detection of cardiovascular diseases at earlier stages and with higher prevalence than with the use of conventional sensitive assays. Elevated troponin concentrations can be found not only in the ED in patients without an MI but also in hospitalised patients with primary disorders across all medical disciplines (box 3).
Differential diagnoses of elevated cTn/hsTn
Cardiac contusion, including ablation, pacing, cardioversion or endomyocardial biopsy.
Congestive heart failure—acute and chronic.
Aortic dissection, aortic valve disease or hypertrophic cardiomyopathy.
Tachycardia or bradycardia, or heart block.
Apical ballooning syndrome.
Rhabdomyolysis with cardiac injury.
Pulmonary embolism, severe pulmonary hypertension.
Acute neurological disease including stroke or subarachnoidal haemorrhage.
Infiltrative diseases, for example, amyloidosis, haemochromatosis, sarcoidosis and scleroderma.
Inflammatory diseases, for example, myocarditis, or myocardial extension of endocarditis/pericarditis.
Drug toxicity, for example, adriamycin, 5-fluorouracil, herceptin and snake venom.
Critically ill patients, especially with respiratory failure or sepsis.
Burns, especially if affecting >30% of body surface area.
Therefore, troponin results must be interpreted in the appropriate clinical context and alternative explanations such as pre-analytical confounders or positive results in the absence of an MI must be considered.9 There is evidence coming from small observational studies that cTnT but not cTnI might be expressed or re-expressed in chronic skeletal muscle disease.45 Thus, correct detection of circulating cTnT (which cannot be labelled as ‘false positive’) in a patient with suspected ACS and for example muscular dystrophy could result into a diagnostic misclassification unless cTnT results are interpreted in the appropriate clinical context.
No hsTn assay was available for routine use in the USA until hsTnT was cleared by the Food and Drug Administration in February 2017, with some modifications for label use in the USA. A prospective, observational study46 on 1600 patients with suspected ACS at 15 emergency departments in the USA demonstrated that a single hsTnT level less than 6 ng/L at baseline had a NPV for acute myocardial infarction of 99.4%, and the NPV for 30-day acute coronary events was 99.3% when both 0 hour and 3 hour hsTnT levels were 19 ng/L or less.
In several non-ACS settings, cTn might be particularly helpful for diagnosis, risk stratification, guidance of therapy and monitoring of disease.47 Not all recommendations are yet established nor represented in guideline documents. Conditions of particular interest include pulmonary embolism, acute and chronic heart failure, primary and secondary prevention, cancer therapy and guided pharmacotherapy.
In pulmonary embolism (PE), only D-dimers are being recommended for diagnosis after assessment of pretest probability.48 Risk stratification is among the next important steps after confirmation of PE because the presence of myocardial injury, as indicated by elevated cTn, or the presence of right ventricular dysfunction as suggested by elevated levels of natriuretic peptides and clinical variables were clearly associated with an increased hazard of death or complication in PE.48 Current ESC guidelines on PE48 recommend the calculation of the Pulmonary Embolism Severity Index (PESI) or the simplified PESI (sPESI) score and the measurement of cTn or natriuretic peptides (or FABP) among patients at intermediate risk in order to identify detect low-risk patients who could be discharged and treated at home as compared with intermediate-risk patients requiring continuous monitoring with the option for fibrinolytic therapy after haemodynamic deterioration.49
Numerous studies47 50 51 have demonstrated an adverse association between acute and chronic heart failure (HF) and cTnT or cTnI. Using conventional sensitive troponin assays, an elevation of troponin was infrequent but associated with severe HF.50 Now, the use of hsTn assays has enabled the detection of myocardial injury with a higher prevalence at earlier stages of HF.51 Putative pathomechanisms in HF leading to myocardial injury are heterogenous including volume overload, biventricular strain, myocardial ischaemia stimulating increased rate of myocardial cell turnover with cell death or apoptosis.47 Regardless of the exact reason for cTn elevations, already concentrations near the 99th percentile value predict risk of death or hospitalisation for HF.51 ESC guidelines on acute and chronic HF52 recommend that cTn should be measured in all patients with acute HF at admission (LOE IC) in order to identify precipitants/causes leading to decompensation that needs urgent management. Coexistence of ACS and acute HF identifies a very-high-risk group where an immediate invasive management (ie, 2 hours from hospital admission) is recommended, irrespective of ECG or biomarker findings.52 In patients presenting with dyspnoea rather than chest pain, the diagnostic performance of hsTn is inferior than in patients presenting with chest pain and MI is more likely in the presence of higher baseline cTn concentrations.47 The change in the troponin value on serial measurements and the absolute peak value provide important diagnostic and prognostic information.53 In particular, higher absolute concentration changes have been demonstrated to improve diagnosis of an ACS.47 Although there is some novel evidence that hsTn might be useful to guide pharmacological therapies in patients without ACS,54 55 still elevated cTn level is limited in its ability to create an actionable trigger for therapy such as increasing neurohormonal blockade, adding anti-anginals such as nitrates or ranolazine, or increasing diuresis.
Previous studies showing that elevated cTn is associated with the risk of incident stroke among individuals with documented atrial fibrillation (AF) but also among those with incident stroke without initially documented AF suggesting an association of cTn with AF burden.56–58 The reason for elevated cTn has not been clarified completely. However, AF is thought to be a disease with multiple reasons and triggers. Reasons include structural remodelling of the atria and ventricles, fibrosis and myocardial ischaemia.59 Potential trigger of an AF episode include hypertension, myocardial ischaemia, infection or inflammation and frequently multifactorial. Although strongly enforced by the guidelines, the CHADS2-Vasc score demonstrates a poor overall performance for prediction of stroke or systemic embolism with areas under the curves between 0.549 and 0.638.60 There is evidence that cTn may complement the CHADS2-Vasc score for prediction of stroke and could be even superior for prediction of death.61 Moreover, measurement of cTn has been recommended to predict the risk of major bleedings following treatment with oral anticoagulants.61 The ESC guidelines59 explicitly recommend the use of the ORBIT score or the ABC score.
Novel indications for cTn/hsTn
Epidemiology and primary prevention
For risk estimation in patients above 40 years, the ESC guidelines on prevention62 are recommending the use of the ESC score that constitutes a clinical score validated for hard endpoints to assess 10-year risk and to refine primary and secondary prevention measures. This score has been developed by the ESC, using data from 12 European cohort studies (n=205 178) covering a wide geographical spread of countries at different levels of cardiovascular risks.63 The score includes gender, age, smoking, systolic blood pressure and total cholesterol as risk factors, and estimates fatal cardiovascular disease events over a 10-year period. Along with this score, several other scores64 have been proposed by National societies such as the QRISK2 by the National Institute for Health and Care Excellence, the JBS3 score by the Joint British Societies and the Atherosclerotic Cardiovascular Disease Risk score jointly by the American Heart Association (AHA) and the American College of Cardiology (ACC). Unfortunately, these clinical scores are inconvenient to use and suffer from poor adoption in clinical routine. There is accumulating evidence that measurement of cardiovascular biomarkers, that is, cTn, could improve risk stratification independent of and in addition to clinical scores in stable outpatients with or without CV disease.65 However, ESC guidelines on prevention62 discourage measurement of any circulating or urinary biomarker for refinement of cardiovascular risk stratification, at present.
In the past, multiple biomarker testing for risk prediction did not improve the performance of a clinical score.66 Now, novel statistical techniques for discrimination of risk and the advent of new biomarkers confer evidence that testing for hsTnT or hsTnI might be useful in the general population to anticipate the risk for incident death, MI or HF.67 A recent meta-analysis including 11 studies, with data on 65 019 participants, explored the relationship between cTnT and cTnI, and cardiovascular and all-cause mortality in the general population.68 The prevalence of detectable hsTnT ranged between 27% and 93% for hsTnT and 75% and 100% for hsTnI, and cTn levels were associated with the incident risk of death in a concentration-dependent manner. Today, however, there is still not enough evidence to support that monitoring of hsTn might be helpful for the selection of pharmacological and non-pharmacological intervention in order to modify risk. In the Cardiovascular Health Study,69 an epidemiological study in a cohort of community-dwelling adults free of HF, it was also demonstrated that physical activity was inversely associated with the risk of the development of HF. Interestingly, patients at higher activity levels had lower probability for an increase of cTn concentration in serial measurements, raising the suspicion that HF risks associated with increasing cTn levels may be modifiable by changes in lifestyle even at an advanced age. Consistently, a role for serial monitoring was demonstrated with a range of risk reduction for HF and CV death between 25% and 43% in the presence of a reduction of hsTnT levels by ≥50% from baseline.70
Interestingly, the BiomarCare study,71 a large epidemiological study, evaluated in a post hoc analysis from the Jupiter trial the benefits of rosuvastatin in relation to baseline hscTnI concentrations. A hscTnI concentration above a cut-off of 6 ng/L identified patients who derived the greatest absolute risk reduction from rosuvastatin.
These cumulative findings indicate that circulating cTn reflects the magnitude of myocardial injury and that cTn is responsive and thus may represent a possible target for life style or drug interventions.
Cardiac troponins are expressed exclusively in cardiomyocytes and are therefore the preferred biomarkers for detection of myocardial injury and myocardial infarction (MI).
More sensitive assay formats allow for detection of smaller myocardial injury and earlier detection of ongoing MI.
European Society of Cardiology guidelines recommend a fast 0/3 hour algorithm as the standard strategy provided any hsTn assay is available or, as an alternative, a 0/1 hour algorithm for diagnosis of an MI if a validated hsTn assay is available (currently applies only for hsTnT (Roche) or hsTnI Architect STAT (Abbott)).
There are caveats in the interpretation of hsTn results, and management of patients with ACS requires further risk stratification using a score or clinical assessment and diagnostic work-up.
Elevations of cardiac troponins in MI are due to myocardial ischaemia in MI but may also indicate myocardial injury unrelated to ischaemia.
Established indications for cTn/hsTn testing include risk stratification after confirmed pulmonary embolism, in acute heart failure and in atrial fibrillation.
Less established but novel and interesting indications include monitoring of cancer-related cardiotoxicity. Whether hsTn may facilitate monitoring of treatment response in heart failure, or guidance of primary and secondary prevention measures is currently under investigation.
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Contributors EG and HAK contributed equally for concept and draft.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests HAK received honoraria from Bayer Vital, Roche Diagnostics, Daiichi Sankyo. EG received honoraria from Bayer Vital, AstraZeneca, Roche Diagnostics, BRAHMS Germany, MSD Deutschland, Daiichi Sankyo.
Patient consent Not required.
Provenance and peer review Commissioned; externally peer reviewed.
Author note References that include a * have been selected as key references for this paper.
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