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PGMJ Online First, published on May 22, 2015 as 10.1136/postgradmedj-2014-133129 Review
Troponins and other biomarkers in the early diagnosis of acute myocardial infarction Annette Maznyczka,1 Thomas Kaier,2 Michael Marber1 1
King’s College London, British Heart Foundation Centre of Research Excellence, London, UK 2 Department of Cardiology, Royal Free Hospital, London, UK Correspondence to Dr Annette Maznyczka, NIHR Academic Clinical Fellow, Kings College London—The Rayne Institute Cardiovascular Division, St. Thomas’ Hospital, London SE1 7EH, UK; [email protected] Received 8 November 2014 Revised 3 April 2015 Accepted 8 May 2015
ABSTRACT Chest pain is a common presenting symptom; however, the majority of emergency chest pain admissions are not due to acute myocardial infarction (AMI). AMI can be life threatening and early diagnosis or rule out of AMI might potentially improve morbidity and mortality, as well as reduce time to decision and therefore overall treatment costs. High-sensitivity troponin (hs-troponin) assays have been developed that enable precise quantification of extremely low troponin concentrations. Such hs-troponin assays are recommended in early ruleout protocols for AMI, when measured at presentation and again at 3–6 h. However, troponin is less than ideally suited for early diagnosis of acute myocardial injury because of its slow rise, late peak and low specificity for coronary plaque rupture. A new biomarker with a more rapid elevation to peak concentration than hs-troponin and lower background levels in patients with chronic cardiovascular conditions would be a preferred diagnostic test. This review discusses the development of hs-troponin assays and other biomarkers, evaluates their place in the early diagnosis of AMI, discusses troponin elevation without AMI and discusses current guideline recommendations.
INTRODUCTION
To cite: Maznyczka A, Kaier T, Marber M. Postgrad Med J Published Online First: [ please include Day Month Year] doi:10.1136/ postgradmedj-2014-133129
Acute myocardial infarction (AMI) can be life threatening, but early use of evidence-based medical therapy can improve survival (HR 0.54; 95% CI 0.40 to 0.72).1 Chest pain accounts for as much as 27% of unplanned hospital admissions.2 However, only about 20% of emergency chest pain admissions are attributable to AMI.3 ECG shows no ischaemic changes in approximately 60% of patients presenting with non-ST segment elevation myocardial infarction (NSTEMI).4 Therefore, despite most hospital admissions with chest pain being for reasons other than AMI, precautionary surveillance is required until the results of a second troponin are available. Early diagnosis or rule out of AMI might possibly improve morbidity and mortality, as well as facilitate early discharge from emergency departments. Troponin is less than ideally suited for early diagnosis of acute myocardial injury because of its slow rise and late peak.5 Serum troponin can also remain elevated for as long as 2 weeks after myocardial necrosis,6 making diagnosis of reinfarction problematic. In order to improve early rule out of AMI, high-sensitivity troponin (hs-troponin) assays were developed with improved sensitivity and precision at low troponin concentrations (figure 1).7 8 However, a shortcoming of hs-troponin assays is lack of specificity for the plaque rupture events that underlie AMI. Therefore, research is ongoing into
whether other biomarkers may add value to hs-troponin in the early diagnosis of AMI. This review discusses the development of hs-troponin assays and other biomarkers, evaluates their place in the early diagnosis of AMI, discusses troponin elevation without AMI and discusses current guideline recommendations.
SEARCH STRATEGY AND SELECTION CRITERIA MEDLINE and PubMed were sourced from 2009 to date, for reference to hs-troponin, biomarkers and AMI. The search syntax for the databases included the terms ‘high sensitivity troponin’, ‘copeptin’, ‘cardiac myosin binding Protein C’, ‘heart fatty acid binding protein’, ‘NSTEMI’, ‘non ST segment elevation acute coronary syndromes’, ‘acute myocardial infarction’ and ‘chest pain’. Relevant studies were also identified by review of the references of included studies. The search was restricted to English language.
DIAGNOSING MYOCARDIAL INFARCTION According to the third universal definition,9 AMI is determined by detection of a rise or fall of cardiac biomarker ( preferably troponin), with at least one value above the 99th centile upper reference limit. In addition, one or more of the following is required: i. symptoms of ischaemia; ii. new significant ST segment or T wave changes, left bundle branch block or Q waves in the ECG; iii. imaging evidence of new loss of viable myocardium or new regional wall motion abnormality; iv. identification of an intracoronary thrombus by angiography or autopsy. AMI is further classified into five types (table 1). Type 1 (spontaneous) AMI relates to ischaemia due to a primary coronary event such as plaque erosion, rupture, fissuring or dissection, with consequent myocardial necrosis from decreased myocardial blood flow. Type 2 AMI refers to troponin release related to myocardial oxygen supply–demand imbalance. For example, heart failure, arrhythmias, hypotension/sepsis and anaemia. Discrimination of type 2 from type 1 AMI is challenging but necessary to avoid patients being exposed to inappropriate medications and interventions.
BIOCHEMICAL CHARACTERISTICS OF TROPONIN Cardiac troponins regulate muscle contraction through interaction with actin and myosin. The troponin–tropomyosin complex is composed of three subunits: troponins T, I and C. Troponin C binds calcium ions released from the sarcoplasmic
Maznyczka A, et al. Postgrad Med J 2015;0:1–9. doi:10.1136/postgradmedj-2014-133129
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1
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Review Figure 1 Diagram illustrating that high-sensitivity troponin (hs-Tn) assays detect troponin concentrations at the 99th centile of a healthy reference population.
reticulum. However, there is no cardiac-specific isoform of troponin C, so it cannot form the basis of a serum assay for cardiac, over skeletal, muscle injury. Troponin T anchors the troponin complex to tropomyosin on thin myofibril filaments. Troponin I inhibits the binding of myosin with actin. Both troponins I and T display biphasic release profiles in acute myocardial injury10 and the time to peak depends on reperfusion of the infarct-related coronary artery. Troponin T peaks within 24–96 h.11 Whereas troponin I peaks earlier, at approximately 12–24 h.12
DEVELOPMENT OF HS-TROPONIN ASSAYS Troponin assays first became commercially available in the 1990s. Early generations of troponin assays require serial blood sampling over 6–12 h due to inadequate precision at the lower limit of detection.13 These early assays were superseded by hs-troponin assays. Such hs-troponin assays have substantially higher analytical sensitivity than conventional assays,14 enabling precise quantification of low troponin concentrations. The analytical criteria of hs-troponin assays are listed in table 2. There
Table 1 Universal classification for different types of myocardial infarction Type 1
Type 2
Type 3 Type 4 a b Type 5
2
Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, erosion or dissection, with resulting intraluminal thrombus and consequent decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis Troponin release associated with myocardial oxygen supply– demand imbalance, such as heart failure, arrhythmias, coronary embolism, hypertension, hypotension, coronary artery spasm and anaemia Sudden unexpected cardiac death, suggestive of myocardial infarction, but biomarker values unavailable
are at least three hs-troponin assays that meet these criteria: ARCHITECT STAT hs-troponin I (Abbott Diagnostics), AccuTnI+3 hs-troponin I (Beckman Coulter) and Elecsys hs-troponin T (Roche Diagnostics) assays (table 3).
Specificity and sensitivity of hs-troponin assays Hs-troponin assays have the potential to rule out AMI earlier than conventional less-sensitive assay. Numerous trials have shown that hs-troponin assays, using the 99th centile as the threshold for positivity, can achieve sensitivity at presentation of ≥90%, and performance further improves with subsequent measurement at 3 h.15–22 Positive predictive values of 96% have been reported for ruling in AMI when using serial hs-troponin values obtained by 3 h, together with the 99th centile cut-off.16 Specificities as high as 90%19 to 94%15 have been reported and by 3 h negative predictive values of almost 100% have been reported, thus, supporting the usefulness of earlier rule-out protocols.15 16 19 Other studies have reported lower specificities for detecting AMI. For example, one study23 found that the specificity for detecting AMI, verified by coronary angiography, was only 45% using the 99th centile cut-off. Discrepancies between studies may be due to different definitions of AMI and different cohorts. Furthermore, previous studies that did not verify the diagnosis of AMI by angiography potentially may have overestimated specificity. An important consideration is that the conventional troponin assays were used to validate hs-troponin assays. Thus, whilst the sensitivity of an hs-troponin measurement at 3 h after
Table 2 assays i
Myocardial infarction associated with percutaneous coronary intervention Myocardial infarction associated with stent thrombosis Myocardial infarction associated with coronary artery bypass graft surgery
ii iii iv
Analytical characteristics of high-sensitivity troponin
Coefficient of variation 50% within 2 h suggests a rising pattern and may optimise the overall accuracy of an AMI diagnosis. Thus, a relative increase >50% may be required to indicate a significant change, when interpreting serial troponin results, close to the 99th centile. At these low concentrations, an absolute difference of 3–4 ng/L could exceed a 20% reference change value threshold. A study that evaluated serial troponin changes using the Abbott hs-troponin I assay in 1818 patients from three German chest pain units suggested reference change values to give optimal specificity for diagnosing AMI.16 For patients with baseline troponin values that were modestly elevated above the upper reference limit, a >50% relative increase in troponin I at 3 h was reported to give optimal specificity for diagnosing AMI. Whereas for patients with baseline troponin values that were below the upper reference limit, a relative increase >250% at 3 h was reported to give optimal specificity for AMI. However, a reference change value of >250% was associated with a sensitivity of only 39.2%, thus Keller et al16 suggested the lower threshold of >50% could be of interest. Another study that looked at troponin T concentration changes measured by hs-troponin at baseline and at 3 h in AMI/ unstable angina patients, with initial negative troponin T tests, demonstrated that the optimal reference change value to differentiate AMI from unstable angina was ≥117%.27 This reference change value of >117% yielded a specificity of 100% and a sensitivity between 69% and 76%.27
Role of age and gender in interpreting hs-troponin assays The 99th centile thresholds for troponin are higher for men than women,28 which may in part be related to the smaller size of a woman’s heart. Therefore, a single diagnostic threshold will potentially overestimate the incidence of AMI in men and underestimate it in women. Higher 99th centiles for hs-troponin assays in older individuals have also been reported.28 Current data are insufficient to derive sex-specific or agespecific upper reference limits, partly due to limited information regarding phenotypic characteristics in some studies,18 relatively few older age groups included in other studies and small sample sizes.29 In an attempt to address this, Gore29 performed age-stratified and sex-stratified analyses of troponin concentrations measured using the hs-troponin T assay in three clearly defined subcohorts from the Dallas Heart Study,30 Atherosclerosis Risk in Communities Study31 and Cardiovascular Health Study.32 A total of 12 618 adults were analysed, and the study showed that 99th centile values for hs-troponin T assays were greater in men than women, and rise with increasing age. Gore suggested29 that a cut-off value of 14 ng/L for the hs-troponin T assay should only be for men 65 years. Another study suggested using a higher cut-off of three times the 99th centile upper reference limit for AMI in persons >70 years.33 However, further research is needed to validate the findings for troponin I and to determine whether these age-specific and sex-specific cut-off 4
values reduce ‘false positives’, enhancing specificity without creating ‘false negatives’ and diminishing sensitivity.
TROPONIN ELEVATION WITHOUT AMI It is well known that elevated serum troponin can occur in many conditions, not only AMI. Moreover, heterophilic antibodies can rarely cause analytic false positive troponin elevations,34 whilst skeletal muscle disease may result in ectopic expression of troponin forms that cross-react.35
Predicting adverse prognosis with hs-troponin Evidence from earlier conventional troponin assays suggests that serum troponin predicts adverse outcomes in numerous conditions and hs-troponin assays used at the 99th centile may improve risk stratification further.36 For example, hs-troponin assays have been shown to predict adverse outcomes in pulmonary embolism,37–39 chronic obstructive pulmonary disease,40 41 chronic42 43 or acute44 heart failure, stable coronary artery disease,45 46 aortic stenosis,47 atrial fibrillation,48 chronic renal failure,49–51 diabetes mellitus,52 stroke,53 54 sepsis55 56 and even in healthy people without known coronary or cerebrovascular disease.57 Troponin can also be elevated in patients with myocarditis or in patients with pericarditis with myocardial involvement.58 59 However, troponin release in myopericarditis does not seem to carry an adverse prognosis, and these patients usually have a good long-term outcome.60
hs-troponin in stable coronary artery disease One study reported that 10% of patients with stable coronary artery disease have troponin I levels above the 99% centile of 0.04 ng/L when measured 6 weeks after AMI.46 These findings were corroborated by Omland who reported that 11.1% of stable patients with coronary artery disease had hs-troponin T values at or above the 99th centile cut-off.45 In another study, 37% of stable angina patients with coronary plaque visible on computerised tomographic coronary angiography had hs-troponin T levels greater than the 99% centile cut-off.61 Furthermore, close correlations were found between hs-troponin T and non-calcified plaque volume.61
hs-troponin in heart failure In stable patients with heart failure, 92% had elevated troponin T measured by hs-troponin assay, whereas standard troponin was elevated in only 10.4% of this cohort.62 The median concentration for troponin T was 12 ng/L, which is very close to the 99th centile upper reference limit for the hs-troponin T assay.62 In another study, of stable non-ischaemic dilated cardiomyopathy patients, 54% had elevated hs-troponin T (≥0.01 ng/mL) levels, whereas standard troponin T was elevated in only 2% of patients.42
hs-troponin in renal disease Ambulatory hs-troponin concentrations have been shown to be elevated in patients with chronic renal disease. For example, in a cohort of asymptomatic patients with end-stage renal disease, 100% of patients had a troponin T concentration exceeding the 99th centile.63 In another study, hs-troponin T was detected in 81% of subjects with chronic kidney disease and absence of selfreported cardiovascular disease.64
hs-troponin in stroke The aetiology of troponin elevation in stroke65–67 is incompletely understood. A meta-analysis reported that the prevalence
Maznyczka A, et al. Postgrad Med J 2015;0:1–9. doi:10.1136/postgradmedj-2014-133129
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Review of troponin elevation in patients with stroke varied from 0% to 34%.68 However, the type of troponin assay and cut-off levels used varied between studies, making them difficult to compare.68 In another study, 53.4% of patients with acute stroke had troponin levels above the upper reference level.69 In this study, patients with elevated hs-troponin values were significantly more likely to have ischaemic ECG changes, suggesting AMI may be underdiagnosed in patients with acute ischemic stroke.69
Pathophysiology of chronic troponin leakage Several explanations for chronic troponin ‘leakage’ have been suggested. These include impaired cell membrane integrity due to systemic inflammation, apoptosis with subsequent spillage of macrophage contents into the circulation,70 myocardial stretch resulting in increased membrane permeability mediated by stretch responsive integrins,71 shortening of diastole during tachycardia with subsequent ischaemia72 and clinically silent coronary plaque rupture.61
Clinical implications of indiscriminate hs-troponin testing The extensive list of non-coronary causes of elevated hs-troponin emphasises the point that broad, indiscriminate testing of hs-troponin has the potential to find ‘false positives’, while capturing relatively few additional AMI cases. Therefore, broad testing of hs-troponin in patients with chest pain, in whom the suspicion of AMI is low, is likely to be counterproductive and should be resisted. Indeed, a large observational study (n=773) in the emergency care setting reported that in patients presenting with chest pain who had hs-troponin measured at 3–4 and 6–7 h after symptom onset, less than half of recorded troponin elevations were true positives for AMI.73
EMERGING BIOMARKERS OF MYOCARDIAL NECROSIS The limitations of troponin have driven research into other biomarkers of myocardial necrosis. A new biomarker with a more rapid elevation to peak concentration than hs-troponin and lower background levels in patients with chronic cardiovascular conditions would be a preferred diagnostic test. The most interest has been in copeptin, heart fatty acid binding protein (H-FABP) and recently cardiac myosin binding protein C (MyC).
Copeptin Copeptin is the C terminal part of pro-vasopressin and is a stable surrogate marker of vasopressin secretion from the pituitary gland. Vasopressin, also known as antidiuretic hormone, causes vasoconstriction and regulates water retention in kidneys. The function of copeptin is unknown, although it is a purported marker of severe stress.74 The concentration of copeptin increases early (0–4 h) after AMI75 and falls after 45 h; however, it is not specific for myocardial injury. It has been hypothesised that the combination of copeptin with troponin might allow early rule out of AMI without the need for serial troponin testing in low-risk to intermediate-risk patients.76 One of the two main trials in support of this hypothesis by Reichlin77 reported that combined use of troponin and copeptin at presentation yielded a negative predictive value for the diagnosis of AMI of 99.7%. The other trial by Keller et al78 reported a negative predictive value of 92.4%. Recently, the BIC-8 multicentre trial79 randomised low-risk to intermediate-risk patients with suspected AMI into a standard group undergoing serial troponin measurements and a copeptin group undergoing both troponin and copeptin measurement. In the latter group, further management was decided using the
copeptin result. Four of the five sites used hs-troponin assays. In the copeptin group, those who tested positive were admitted for standard workup, whereas copeptin-negative patients were discharged. At 30 days, the proportion of major adverse cardiac events was similar in the copeptin group (5.17%) compared with the standard group (5.19%). However, secondary end point analysis showed that patients in the copeptin group were discharged from the emergency department earlier than the standard therapy group (median length of stay for AMI exclusion 4 h in the copeptin group vs 7 h in the standard group). A recent meta-analysis by Lipinski et al80 demonstrated that addition of copeptin to hs-troponin can improve the sensitivity of the test. that is, 95.7% (for copeptin and hs-troponin) versus 87.8% (for hs-troponin). However, reduced specificity with the addition of copeptin to hs-troponin reduces its diagnostic performance, that is, 59.2% (for copeptin and hs-troponin) versus 78.7% (for hs-troponin). The majority of studies compared copeptin with less-sensitive troponin assays instead of hs-troponin assays. Furthermore, findings from studies on copeptin have been inconsistent,75 which may in part be due to different cut-off values for the copeptin assay, and variation in the timing of copeptin sampling between studies. Overall, recent data do not support adding copeptin to troponin for the early diagnosis of AMI.81
Heart fatty acid binding protein H-FABP is a cytoplasmic protein involved in fatty acid transport for mitochondrial oxidation.81 H-FABP levels peak early (within 6 h),82 which stimulated interest in this protein as an early biomarker of myocardial necrosis. However, H-FABP is not cardiac specific since it is expressed in other tissues. Furthermore, recent data do not support a benefit for adding H-FABP to troponin in the early diagnosis of AMI.83 84
Cardiac MyC Early evidence suggests that MyC may have potential as an early-stage biomarker of myocardial necrosis. MyC is a cardiacspecific sarcomeric protein involved in regulating cardiac structure and function.85 Plasma MyC has been shown to be elevated in models of AMI in rodents86 and in humans.87–89 Furthermore, MyC was shown to rise and peak earlier after myocardial injury than troponin,88 in porcine models of AMI and in humans undergoing transcoronary ablation of septal hypertrophy in hypertrophic cardiomyopathy. MyC may also have more rapid clearance than troponin.90 This could be advantageous in the diagnosis of reinfarction and may also result in MyC having lower background concentrations in patients with chronic structural cardiac disease.
GUIDELINE RECOMMENDATIONS The ESC91 and National Institute for Health and Care Excellence (NICE)92 guidelines (table 4) recommend early rule out of AMI with a rapid 3 h hs-troponin sampling protocol (class 1, level of evidence B). Only the Elecsys hs-troponin T assay and ARCHITECT STAT hs-troponin I assay are recommended for routine clinical use.91 Guidelines also recommend that at least one result should be above the 99th centile cut-off threshold when making a diagnosis of AMI (figure 2). However, guideline recommendations recognise that clinical judgement should be used when interpreting the results. Thus, measurement of hs-troponin at 6 h may be appropriate. For example, clinicians should take into account the pre-test probability of AMI, the length of time from
Maznyczka A, et al. Postgrad Med J 2015;0:1–9. doi:10.1136/postgradmedj-2014-133129
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Review should surpass the 99th centile cut-off. Recent data do not support a benefit for adding H-FABP or copeptin to hs-troponin in the early diagnosis of AMI.
Table 4 NICE guideline recommendations on hs-troponin assays i
ii iii
iv v
vi
The Elecsys hs-troponin T assay and ARCHITECT STAT hs-troponin-I assay are recommended for the early rule out of NSTEMI in patients presenting with chest pain The AccuTnI+3 hs-troponin assay is recommended for research use and not for routine clinical use hs-troponin assays are recommended for use with early rule-out protocols, which include measuring hs-troponin at initial assessment and then again 3 h later Laboratories should report absolute troponin values and the upper reference limit should be set at the 99th percentile Results should be interpreted along with clinical judgement, and clinicians should take into account the following: pre-test probability of NSTEMI, the length of time since the suspected acute coronary syndrome, the possibility of chronically elevated troponin levels in some patients and that 99th percentile thresholds for troponin I and T may differ between sexes When NSTEMI is not ruled out using an early rule-out protocol, further clinical assessment is required to determine whether a diagnosis of NSTEMI is appropriate
Main messages ▸ Measure high-sensitivity troponin (hs-troponin) on admission and 3–6 h later. ▸ A change in concentration with serial hs-troponin testing is required to make a diagnosis of acute myocardial infarction (AMI). ▸ To make a diagnosis of AMI, at least one hs-troponin level should surpass the 99th centile of hs-troponin levels in a normal reference population. ▸ Many conditions other than AMI increase hs-troponin concentration.
NICE, National Institute for Health and Care Excellence; NSTEMI, non-ST segment elevation myocardial infarction.
symptom onset and the effect of gender on 99th centile thresholds.
FUTURE PERSPECTIVES Further research is warranted to verify the optimal reference change values for interpreting significant serial hs-troponin measurements. This will assume greater importance when the NICE guidelines are implemented since there will be numerous instances when both the initial and 3 h sample are above the 99th centile and it will be necessary to differentiate between acute and pre-existing, chronic troponin elevation. A recent position paper from the study group on biomarkers of the Acute Cardiovascular Care Association has defined criteria for future studies, with the aim of accurate determination of optimal reference change values, to provide robust information to clinicians interpreting serial troponin results.25 Unfortunately, it is possible these reference change values will need to be age and sex, as well as vendor specific. It remains to be determined whether or not hs-troponin assays will improve patient outcomes through better targeted therapies. The high-STE acute coronary syndromes cluster randomised clinical trial (NCT01852123) is currently recruiting patients to investigate whether the introduction of hs-troponin I assays (ARCHITECT STAT) into routine clinical practice is beneficial to patient management and improves outcomes, specifically recurrent AMI or cardiovascular death at 1 year. Our prediction is that implementation of early rule-out protocols for AMI, using hs-troponin assays, may increase the number of patients without an eventual diagnosis of AMI who are misdiagnosed, unnecessarily hospitalised, treated and investigated. Further research is needed to determine whether MyC improves diagnostic performance in this context.
CONCLUSION Early rule out of AMI using hs-troponin assays might have the potential to improve survival, as well as reduce time to decision and therefore total treatment costs. Current guidelines recommend that patients with suspected AMI should have troponin measured by hs-troponin assay on initial assessment and 3–6 h later. To make a diagnosis of AMI, a significant change with serial troponin testing is required and at least one troponin level 6
Current research questions ▸ What is the optimal change in serum concentration of hs-troponin on serial testing to make a diagnosis of acute myocardial infarction (AMI)? ▸ Should age-specific and sex-specific upper reference limit cut-offs for troponin be implemented and what should these be? ▸ Will use of hs-troponin assays in routine clinical practice improve patient outcomes, including reducing cardiovascular death at 1 year?
Key references ▸ NICE diagnostics guidance 15. Myocardial infarction (acute): Early rule out using high-sensitivity troponin tests (Elecsys Troponin T high-sensitive, ARCHITECT STAT High Sensitive Troponin-I and AccuTnI+3 assays). National Institute for Health and Care Excellence. October 2014. ▸ Jaffe AS, Moeckel M, Giannitsis E, et al. In search for the Holy Grail: Suggestions for studies to define delta changes to diagnose or exclude acute myocardial infarction: a position paper from the study group on biomarkers of the Acute Cardiovascular Care Association. Eur Heart J Acute Cardiovasc Care 2014;4:313–16. ▸ Thygesen K, Mair J, Giannitsis E, et al. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J 2012;33:2252–7. ▸ Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J 2012;33: 2551–67. ▸ Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999–3054.
Maznyczka A, et al. Postgrad Med J 2015;0:1–9. doi:10.1136/postgradmedj-2014-133129
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Review REFERENCES Self assessment questions
1
Answer true (T) or false (F) for the below.
2
1. For early rule out of AMI, which troponin isoforms are measured? A. Troponin C, or troponin I or troponin T isoforms B. Troponin I or troponin T isoforms C. Troponin I isoform only D. Troponin T isoform only E. Troponin T or troponin C isoforms 2. Which of the following is true/false regarding hs-troponin assays? A. Troponin concentrations that surpass the 99th centile troponin in a healthy reference population can be detected. B. Heterophilic antibodies may cause analytic false positive troponin elevations. C. 99th centile hs-troponin thresholds are higher for women than men. D. 99th centile hs-troponin thresholds are higher for older individuals. E. hs-troponin assays have coefficient of variation
PGMJ Online First, published on May 22, 2015 as 10.1136/postgradmedj-2014-133129 Review
Troponins and other biomarkers in the early diagnosis of acute myocardial infarction Annette Maznyczka,1 Thomas Kaier,2 Michael Marber1 1
King’s College London, British Heart Foundation Centre of Research Excellence, London, UK 2 Department of Cardiology, Royal Free Hospital, London, UK Correspondence to Dr Annette Maznyczka, NIHR Academic Clinical Fellow, Kings College London—The Rayne Institute Cardiovascular Division, St. Thomas’ Hospital, London SE1 7EH, UK; [email protected] Received 8 November 2014 Revised 3 April 2015 Accepted 8 May 2015
ABSTRACT Chest pain is a common presenting symptom; however, the majority of emergency chest pain admissions are not due to acute myocardial infarction (AMI). AMI can be life threatening and early diagnosis or rule out of AMI might potentially improve morbidity and mortality, as well as reduce time to decision and therefore overall treatment costs. High-sensitivity troponin (hs-troponin) assays have been developed that enable precise quantification of extremely low troponin concentrations. Such hs-troponin assays are recommended in early ruleout protocols for AMI, when measured at presentation and again at 3–6 h. However, troponin is less than ideally suited for early diagnosis of acute myocardial injury because of its slow rise, late peak and low specificity for coronary plaque rupture. A new biomarker with a more rapid elevation to peak concentration than hs-troponin and lower background levels in patients with chronic cardiovascular conditions would be a preferred diagnostic test. This review discusses the development of hs-troponin assays and other biomarkers, evaluates their place in the early diagnosis of AMI, discusses troponin elevation without AMI and discusses current guideline recommendations.
INTRODUCTION
To cite: Maznyczka A, Kaier T, Marber M. Postgrad Med J Published Online First: [ please include Day Month Year] doi:10.1136/ postgradmedj-2014-133129
Acute myocardial infarction (AMI) can be life threatening, but early use of evidence-based medical therapy can improve survival (HR 0.54; 95% CI 0.40 to 0.72).1 Chest pain accounts for as much as 27% of unplanned hospital admissions.2 However, only about 20% of emergency chest pain admissions are attributable to AMI.3 ECG shows no ischaemic changes in approximately 60% of patients presenting with non-ST segment elevation myocardial infarction (NSTEMI).4 Therefore, despite most hospital admissions with chest pain being for reasons other than AMI, precautionary surveillance is required until the results of a second troponin are available. Early diagnosis or rule out of AMI might possibly improve morbidity and mortality, as well as facilitate early discharge from emergency departments. Troponin is less than ideally suited for early diagnosis of acute myocardial injury because of its slow rise and late peak.5 Serum troponin can also remain elevated for as long as 2 weeks after myocardial necrosis,6 making diagnosis of reinfarction problematic. In order to improve early rule out of AMI, high-sensitivity troponin (hs-troponin) assays were developed with improved sensitivity and precision at low troponin concentrations (figure 1).7 8 However, a shortcoming of hs-troponin assays is lack of specificity for the plaque rupture events that underlie AMI. Therefore, research is ongoing into
whether other biomarkers may add value to hs-troponin in the early diagnosis of AMI. This review discusses the development of hs-troponin assays and other biomarkers, evaluates their place in the early diagnosis of AMI, discusses troponin elevation without AMI and discusses current guideline recommendations.
SEARCH STRATEGY AND SELECTION CRITERIA MEDLINE and PubMed were sourced from 2009 to date, for reference to hs-troponin, biomarkers and AMI. The search syntax for the databases included the terms ‘high sensitivity troponin’, ‘copeptin’, ‘cardiac myosin binding Protein C’, ‘heart fatty acid binding protein’, ‘NSTEMI’, ‘non ST segment elevation acute coronary syndromes’, ‘acute myocardial infarction’ and ‘chest pain’. Relevant studies were also identified by review of the references of included studies. The search was restricted to English language.
DIAGNOSING MYOCARDIAL INFARCTION According to the third universal definition,9 AMI is determined by detection of a rise or fall of cardiac biomarker ( preferably troponin), with at least one value above the 99th centile upper reference limit. In addition, one or more of the following is required: i. symptoms of ischaemia; ii. new significant ST segment or T wave changes, left bundle branch block or Q waves in the ECG; iii. imaging evidence of new loss of viable myocardium or new regional wall motion abnormality; iv. identification of an intracoronary thrombus by angiography or autopsy. AMI is further classified into five types (table 1). Type 1 (spontaneous) AMI relates to ischaemia due to a primary coronary event such as plaque erosion, rupture, fissuring or dissection, with consequent myocardial necrosis from decreased myocardial blood flow. Type 2 AMI refers to troponin release related to myocardial oxygen supply–demand imbalance. For example, heart failure, arrhythmias, hypotension/sepsis and anaemia. Discrimination of type 2 from type 1 AMI is challenging but necessary to avoid patients being exposed to inappropriate medications and interventions.
BIOCHEMICAL CHARACTERISTICS OF TROPONIN Cardiac troponins regulate muscle contraction through interaction with actin and myosin. The troponin–tropomyosin complex is composed of three subunits: troponins T, I and C. Troponin C binds calcium ions released from the sarcoplasmic
Maznyczka A, et al. Postgrad Med J 2015;0:1–9. doi:10.1136/postgradmedj-2014-133129
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
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Review Figure 1 Diagram illustrating that high-sensitivity troponin (hs-Tn) assays detect troponin concentrations at the 99th centile of a healthy reference population.
reticulum. However, there is no cardiac-specific isoform of troponin C, so it cannot form the basis of a serum assay for cardiac, over skeletal, muscle injury. Troponin T anchors the troponin complex to tropomyosin on thin myofibril filaments. Troponin I inhibits the binding of myosin with actin. Both troponins I and T display biphasic release profiles in acute myocardial injury10 and the time to peak depends on reperfusion of the infarct-related coronary artery. Troponin T peaks within 24–96 h.11 Whereas troponin I peaks earlier, at approximately 12–24 h.12
DEVELOPMENT OF HS-TROPONIN ASSAYS Troponin assays first became commercially available in the 1990s. Early generations of troponin assays require serial blood sampling over 6–12 h due to inadequate precision at the lower limit of detection.13 These early assays were superseded by hs-troponin assays. Such hs-troponin assays have substantially higher analytical sensitivity than conventional assays,14 enabling precise quantification of low troponin concentrations. The analytical criteria of hs-troponin assays are listed in table 2. There
Table 1 Universal classification for different types of myocardial infarction Type 1
Type 2
Type 3 Type 4 a b Type 5
2
Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, erosion or dissection, with resulting intraluminal thrombus and consequent decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis Troponin release associated with myocardial oxygen supply– demand imbalance, such as heart failure, arrhythmias, coronary embolism, hypertension, hypotension, coronary artery spasm and anaemia Sudden unexpected cardiac death, suggestive of myocardial infarction, but biomarker values unavailable
are at least three hs-troponin assays that meet these criteria: ARCHITECT STAT hs-troponin I (Abbott Diagnostics), AccuTnI+3 hs-troponin I (Beckman Coulter) and Elecsys hs-troponin T (Roche Diagnostics) assays (table 3).
Specificity and sensitivity of hs-troponin assays Hs-troponin assays have the potential to rule out AMI earlier than conventional less-sensitive assay. Numerous trials have shown that hs-troponin assays, using the 99th centile as the threshold for positivity, can achieve sensitivity at presentation of ≥90%, and performance further improves with subsequent measurement at 3 h.15–22 Positive predictive values of 96% have been reported for ruling in AMI when using serial hs-troponin values obtained by 3 h, together with the 99th centile cut-off.16 Specificities as high as 90%19 to 94%15 have been reported and by 3 h negative predictive values of almost 100% have been reported, thus, supporting the usefulness of earlier rule-out protocols.15 16 19 Other studies have reported lower specificities for detecting AMI. For example, one study23 found that the specificity for detecting AMI, verified by coronary angiography, was only 45% using the 99th centile cut-off. Discrepancies between studies may be due to different definitions of AMI and different cohorts. Furthermore, previous studies that did not verify the diagnosis of AMI by angiography potentially may have overestimated specificity. An important consideration is that the conventional troponin assays were used to validate hs-troponin assays. Thus, whilst the sensitivity of an hs-troponin measurement at 3 h after
Table 2 assays i
Myocardial infarction associated with percutaneous coronary intervention Myocardial infarction associated with stent thrombosis Myocardial infarction associated with coronary artery bypass graft surgery
ii iii iv
Analytical characteristics of high-sensitivity troponin
Coefficient of variation 50% within 2 h suggests a rising pattern and may optimise the overall accuracy of an AMI diagnosis. Thus, a relative increase >50% may be required to indicate a significant change, when interpreting serial troponin results, close to the 99th centile. At these low concentrations, an absolute difference of 3–4 ng/L could exceed a 20% reference change value threshold. A study that evaluated serial troponin changes using the Abbott hs-troponin I assay in 1818 patients from three German chest pain units suggested reference change values to give optimal specificity for diagnosing AMI.16 For patients with baseline troponin values that were modestly elevated above the upper reference limit, a >50% relative increase in troponin I at 3 h was reported to give optimal specificity for diagnosing AMI. Whereas for patients with baseline troponin values that were below the upper reference limit, a relative increase >250% at 3 h was reported to give optimal specificity for AMI. However, a reference change value of >250% was associated with a sensitivity of only 39.2%, thus Keller et al16 suggested the lower threshold of >50% could be of interest. Another study that looked at troponin T concentration changes measured by hs-troponin at baseline and at 3 h in AMI/ unstable angina patients, with initial negative troponin T tests, demonstrated that the optimal reference change value to differentiate AMI from unstable angina was ≥117%.27 This reference change value of >117% yielded a specificity of 100% and a sensitivity between 69% and 76%.27
Role of age and gender in interpreting hs-troponin assays The 99th centile thresholds for troponin are higher for men than women,28 which may in part be related to the smaller size of a woman’s heart. Therefore, a single diagnostic threshold will potentially overestimate the incidence of AMI in men and underestimate it in women. Higher 99th centiles for hs-troponin assays in older individuals have also been reported.28 Current data are insufficient to derive sex-specific or agespecific upper reference limits, partly due to limited information regarding phenotypic characteristics in some studies,18 relatively few older age groups included in other studies and small sample sizes.29 In an attempt to address this, Gore29 performed age-stratified and sex-stratified analyses of troponin concentrations measured using the hs-troponin T assay in three clearly defined subcohorts from the Dallas Heart Study,30 Atherosclerosis Risk in Communities Study31 and Cardiovascular Health Study.32 A total of 12 618 adults were analysed, and the study showed that 99th centile values for hs-troponin T assays were greater in men than women, and rise with increasing age. Gore suggested29 that a cut-off value of 14 ng/L for the hs-troponin T assay should only be for men 65 years. Another study suggested using a higher cut-off of three times the 99th centile upper reference limit for AMI in persons >70 years.33 However, further research is needed to validate the findings for troponin I and to determine whether these age-specific and sex-specific cut-off 4
values reduce ‘false positives’, enhancing specificity without creating ‘false negatives’ and diminishing sensitivity.
TROPONIN ELEVATION WITHOUT AMI It is well known that elevated serum troponin can occur in many conditions, not only AMI. Moreover, heterophilic antibodies can rarely cause analytic false positive troponin elevations,34 whilst skeletal muscle disease may result in ectopic expression of troponin forms that cross-react.35
Predicting adverse prognosis with hs-troponin Evidence from earlier conventional troponin assays suggests that serum troponin predicts adverse outcomes in numerous conditions and hs-troponin assays used at the 99th centile may improve risk stratification further.36 For example, hs-troponin assays have been shown to predict adverse outcomes in pulmonary embolism,37–39 chronic obstructive pulmonary disease,40 41 chronic42 43 or acute44 heart failure, stable coronary artery disease,45 46 aortic stenosis,47 atrial fibrillation,48 chronic renal failure,49–51 diabetes mellitus,52 stroke,53 54 sepsis55 56 and even in healthy people without known coronary or cerebrovascular disease.57 Troponin can also be elevated in patients with myocarditis or in patients with pericarditis with myocardial involvement.58 59 However, troponin release in myopericarditis does not seem to carry an adverse prognosis, and these patients usually have a good long-term outcome.60
hs-troponin in stable coronary artery disease One study reported that 10% of patients with stable coronary artery disease have troponin I levels above the 99% centile of 0.04 ng/L when measured 6 weeks after AMI.46 These findings were corroborated by Omland who reported that 11.1% of stable patients with coronary artery disease had hs-troponin T values at or above the 99th centile cut-off.45 In another study, 37% of stable angina patients with coronary plaque visible on computerised tomographic coronary angiography had hs-troponin T levels greater than the 99% centile cut-off.61 Furthermore, close correlations were found between hs-troponin T and non-calcified plaque volume.61
hs-troponin in heart failure In stable patients with heart failure, 92% had elevated troponin T measured by hs-troponin assay, whereas standard troponin was elevated in only 10.4% of this cohort.62 The median concentration for troponin T was 12 ng/L, which is very close to the 99th centile upper reference limit for the hs-troponin T assay.62 In another study, of stable non-ischaemic dilated cardiomyopathy patients, 54% had elevated hs-troponin T (≥0.01 ng/mL) levels, whereas standard troponin T was elevated in only 2% of patients.42
hs-troponin in renal disease Ambulatory hs-troponin concentrations have been shown to be elevated in patients with chronic renal disease. For example, in a cohort of asymptomatic patients with end-stage renal disease, 100% of patients had a troponin T concentration exceeding the 99th centile.63 In another study, hs-troponin T was detected in 81% of subjects with chronic kidney disease and absence of selfreported cardiovascular disease.64
hs-troponin in stroke The aetiology of troponin elevation in stroke65–67 is incompletely understood. A meta-analysis reported that the prevalence
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Review of troponin elevation in patients with stroke varied from 0% to 34%.68 However, the type of troponin assay and cut-off levels used varied between studies, making them difficult to compare.68 In another study, 53.4% of patients with acute stroke had troponin levels above the upper reference level.69 In this study, patients with elevated hs-troponin values were significantly more likely to have ischaemic ECG changes, suggesting AMI may be underdiagnosed in patients with acute ischemic stroke.69
Pathophysiology of chronic troponin leakage Several explanations for chronic troponin ‘leakage’ have been suggested. These include impaired cell membrane integrity due to systemic inflammation, apoptosis with subsequent spillage of macrophage contents into the circulation,70 myocardial stretch resulting in increased membrane permeability mediated by stretch responsive integrins,71 shortening of diastole during tachycardia with subsequent ischaemia72 and clinically silent coronary plaque rupture.61
Clinical implications of indiscriminate hs-troponin testing The extensive list of non-coronary causes of elevated hs-troponin emphasises the point that broad, indiscriminate testing of hs-troponin has the potential to find ‘false positives’, while capturing relatively few additional AMI cases. Therefore, broad testing of hs-troponin in patients with chest pain, in whom the suspicion of AMI is low, is likely to be counterproductive and should be resisted. Indeed, a large observational study (n=773) in the emergency care setting reported that in patients presenting with chest pain who had hs-troponin measured at 3–4 and 6–7 h after symptom onset, less than half of recorded troponin elevations were true positives for AMI.73
EMERGING BIOMARKERS OF MYOCARDIAL NECROSIS The limitations of troponin have driven research into other biomarkers of myocardial necrosis. A new biomarker with a more rapid elevation to peak concentration than hs-troponin and lower background levels in patients with chronic cardiovascular conditions would be a preferred diagnostic test. The most interest has been in copeptin, heart fatty acid binding protein (H-FABP) and recently cardiac myosin binding protein C (MyC).
Copeptin Copeptin is the C terminal part of pro-vasopressin and is a stable surrogate marker of vasopressin secretion from the pituitary gland. Vasopressin, also known as antidiuretic hormone, causes vasoconstriction and regulates water retention in kidneys. The function of copeptin is unknown, although it is a purported marker of severe stress.74 The concentration of copeptin increases early (0–4 h) after AMI75 and falls after 45 h; however, it is not specific for myocardial injury. It has been hypothesised that the combination of copeptin with troponin might allow early rule out of AMI without the need for serial troponin testing in low-risk to intermediate-risk patients.76 One of the two main trials in support of this hypothesis by Reichlin77 reported that combined use of troponin and copeptin at presentation yielded a negative predictive value for the diagnosis of AMI of 99.7%. The other trial by Keller et al78 reported a negative predictive value of 92.4%. Recently, the BIC-8 multicentre trial79 randomised low-risk to intermediate-risk patients with suspected AMI into a standard group undergoing serial troponin measurements and a copeptin group undergoing both troponin and copeptin measurement. In the latter group, further management was decided using the
copeptin result. Four of the five sites used hs-troponin assays. In the copeptin group, those who tested positive were admitted for standard workup, whereas copeptin-negative patients were discharged. At 30 days, the proportion of major adverse cardiac events was similar in the copeptin group (5.17%) compared with the standard group (5.19%). However, secondary end point analysis showed that patients in the copeptin group were discharged from the emergency department earlier than the standard therapy group (median length of stay for AMI exclusion 4 h in the copeptin group vs 7 h in the standard group). A recent meta-analysis by Lipinski et al80 demonstrated that addition of copeptin to hs-troponin can improve the sensitivity of the test. that is, 95.7% (for copeptin and hs-troponin) versus 87.8% (for hs-troponin). However, reduced specificity with the addition of copeptin to hs-troponin reduces its diagnostic performance, that is, 59.2% (for copeptin and hs-troponin) versus 78.7% (for hs-troponin). The majority of studies compared copeptin with less-sensitive troponin assays instead of hs-troponin assays. Furthermore, findings from studies on copeptin have been inconsistent,75 which may in part be due to different cut-off values for the copeptin assay, and variation in the timing of copeptin sampling between studies. Overall, recent data do not support adding copeptin to troponin for the early diagnosis of AMI.81
Heart fatty acid binding protein H-FABP is a cytoplasmic protein involved in fatty acid transport for mitochondrial oxidation.81 H-FABP levels peak early (within 6 h),82 which stimulated interest in this protein as an early biomarker of myocardial necrosis. However, H-FABP is not cardiac specific since it is expressed in other tissues. Furthermore, recent data do not support a benefit for adding H-FABP to troponin in the early diagnosis of AMI.83 84
Cardiac MyC Early evidence suggests that MyC may have potential as an early-stage biomarker of myocardial necrosis. MyC is a cardiacspecific sarcomeric protein involved in regulating cardiac structure and function.85 Plasma MyC has been shown to be elevated in models of AMI in rodents86 and in humans.87–89 Furthermore, MyC was shown to rise and peak earlier after myocardial injury than troponin,88 in porcine models of AMI and in humans undergoing transcoronary ablation of septal hypertrophy in hypertrophic cardiomyopathy. MyC may also have more rapid clearance than troponin.90 This could be advantageous in the diagnosis of reinfarction and may also result in MyC having lower background concentrations in patients with chronic structural cardiac disease.
GUIDELINE RECOMMENDATIONS The ESC91 and National Institute for Health and Care Excellence (NICE)92 guidelines (table 4) recommend early rule out of AMI with a rapid 3 h hs-troponin sampling protocol (class 1, level of evidence B). Only the Elecsys hs-troponin T assay and ARCHITECT STAT hs-troponin I assay are recommended for routine clinical use.91 Guidelines also recommend that at least one result should be above the 99th centile cut-off threshold when making a diagnosis of AMI (figure 2). However, guideline recommendations recognise that clinical judgement should be used when interpreting the results. Thus, measurement of hs-troponin at 6 h may be appropriate. For example, clinicians should take into account the pre-test probability of AMI, the length of time from
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Review should surpass the 99th centile cut-off. Recent data do not support a benefit for adding H-FABP or copeptin to hs-troponin in the early diagnosis of AMI.
Table 4 NICE guideline recommendations on hs-troponin assays i
ii iii
iv v
vi
The Elecsys hs-troponin T assay and ARCHITECT STAT hs-troponin-I assay are recommended for the early rule out of NSTEMI in patients presenting with chest pain The AccuTnI+3 hs-troponin assay is recommended for research use and not for routine clinical use hs-troponin assays are recommended for use with early rule-out protocols, which include measuring hs-troponin at initial assessment and then again 3 h later Laboratories should report absolute troponin values and the upper reference limit should be set at the 99th percentile Results should be interpreted along with clinical judgement, and clinicians should take into account the following: pre-test probability of NSTEMI, the length of time since the suspected acute coronary syndrome, the possibility of chronically elevated troponin levels in some patients and that 99th percentile thresholds for troponin I and T may differ between sexes When NSTEMI is not ruled out using an early rule-out protocol, further clinical assessment is required to determine whether a diagnosis of NSTEMI is appropriate
Main messages ▸ Measure high-sensitivity troponin (hs-troponin) on admission and 3–6 h later. ▸ A change in concentration with serial hs-troponin testing is required to make a diagnosis of acute myocardial infarction (AMI). ▸ To make a diagnosis of AMI, at least one hs-troponin level should surpass the 99th centile of hs-troponin levels in a normal reference population. ▸ Many conditions other than AMI increase hs-troponin concentration.
NICE, National Institute for Health and Care Excellence; NSTEMI, non-ST segment elevation myocardial infarction.
symptom onset and the effect of gender on 99th centile thresholds.
FUTURE PERSPECTIVES Further research is warranted to verify the optimal reference change values for interpreting significant serial hs-troponin measurements. This will assume greater importance when the NICE guidelines are implemented since there will be numerous instances when both the initial and 3 h sample are above the 99th centile and it will be necessary to differentiate between acute and pre-existing, chronic troponin elevation. A recent position paper from the study group on biomarkers of the Acute Cardiovascular Care Association has defined criteria for future studies, with the aim of accurate determination of optimal reference change values, to provide robust information to clinicians interpreting serial troponin results.25 Unfortunately, it is possible these reference change values will need to be age and sex, as well as vendor specific. It remains to be determined whether or not hs-troponin assays will improve patient outcomes through better targeted therapies. The high-STE acute coronary syndromes cluster randomised clinical trial (NCT01852123) is currently recruiting patients to investigate whether the introduction of hs-troponin I assays (ARCHITECT STAT) into routine clinical practice is beneficial to patient management and improves outcomes, specifically recurrent AMI or cardiovascular death at 1 year. Our prediction is that implementation of early rule-out protocols for AMI, using hs-troponin assays, may increase the number of patients without an eventual diagnosis of AMI who are misdiagnosed, unnecessarily hospitalised, treated and investigated. Further research is needed to determine whether MyC improves diagnostic performance in this context.
CONCLUSION Early rule out of AMI using hs-troponin assays might have the potential to improve survival, as well as reduce time to decision and therefore total treatment costs. Current guidelines recommend that patients with suspected AMI should have troponin measured by hs-troponin assay on initial assessment and 3–6 h later. To make a diagnosis of AMI, a significant change with serial troponin testing is required and at least one troponin level 6
Current research questions ▸ What is the optimal change in serum concentration of hs-troponin on serial testing to make a diagnosis of acute myocardial infarction (AMI)? ▸ Should age-specific and sex-specific upper reference limit cut-offs for troponin be implemented and what should these be? ▸ Will use of hs-troponin assays in routine clinical practice improve patient outcomes, including reducing cardiovascular death at 1 year?
Key references ▸ NICE diagnostics guidance 15. Myocardial infarction (acute): Early rule out using high-sensitivity troponin tests (Elecsys Troponin T high-sensitive, ARCHITECT STAT High Sensitive Troponin-I and AccuTnI+3 assays). National Institute for Health and Care Excellence. October 2014. ▸ Jaffe AS, Moeckel M, Giannitsis E, et al. In search for the Holy Grail: Suggestions for studies to define delta changes to diagnose or exclude acute myocardial infarction: a position paper from the study group on biomarkers of the Acute Cardiovascular Care Association. Eur Heart J Acute Cardiovasc Care 2014;4:313–16. ▸ Thygesen K, Mair J, Giannitsis E, et al. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J 2012;33:2252–7. ▸ Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J 2012;33: 2551–67. ▸ Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999–3054.
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Review REFERENCES Self assessment questions
1
Answer true (T) or false (F) for the below.
2
1. For early rule out of AMI, which troponin isoforms are measured? A. Troponin C, or troponin I or troponin T isoforms B. Troponin I or troponin T isoforms C. Troponin I isoform only D. Troponin T isoform only E. Troponin T or troponin C isoforms 2. Which of the following is true/false regarding hs-troponin assays? A. Troponin concentrations that surpass the 99th centile troponin in a healthy reference population can be detected. B. Heterophilic antibodies may cause analytic false positive troponin elevations. C. 99th centile hs-troponin thresholds are higher for women than men. D. 99th centile hs-troponin thresholds are higher for older individuals. E. hs-troponin assays have coefficient of variation
