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Biomarkers in acute coronary syndromes 

Biomarkers in acute coronary syndromes
Biomarkers in acute coronary syndromes

Evangelos Giannitsis

and Hugo A Katus



Introduction of MINOCA to describe acute myocardial infarction in the presence of non-obstructive coronary artery disease

Modification of risk stratification and timing of invasive strategy according to 2015 ESC guidelines on NSTE-ACS

Updated on 22 February 2018. The previous version of this content can be found here.
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date: 18 October 2019


Biomarker testing in the evaluation of a patient with acute chest pain is best established for cardiac troponins that allow the diagnosis of myocardial infarction, risk estimation of short- and long-term risk of death and myocardial infarction, and guidance of pharmacological therapy, as well as the need and timing of invasive strategy. Newer, more sensitive troponin assays have become commercially available and have the capability to detect myocardial infarction earlier and more sensitively than standard assays, but they are hampered by a lack of clinical specificity, i.e. the ability to discriminate myocardial ischaemia from myocardial necrosis not related to ischaemia such as myocarditis, pulmonary embolism, or decompensated heart failure. Strategies to improve clinical specificity (including strict adherence to the universal myocardial infarction definition and the need for serial troponin measurements to detect an acute rise and/or fall of cardiac troponin) will improve the interpretation of the increasing number of positive results.

Other biomarkers of inflammation, activated coagulation/fibrinolysis, and increased ventricular stress mirror different aspects of the underlying disease activity and may help to improve our understanding of the pathophysiological mechanisms of acute coronary syndromes. Among the flood of new biomarkers, there are several novel promising biomarkers, such as copeptin that allows an earlier rule-out of myocardial infarction in combination with cardiac troponin, whereas MR-proANP and MR-proADM appear to allow a refinement of cardiovascular risk. GDF-15 might help to identify patients at higher risk of bleeding

A multi-marker approach to biomarkers becomes more and more attractive, as increasing evidence suggests that a combination of several biomarkers may help to predict individual risk and treatment benefits, particularly among subjects with normal troponin. Future goals include the acceleration of rule-in and rule-out of patients with suspected acute coronary syndrome, in order to shorten lengths of stay in the emergency department, and to optimize patient management and the use of health care resources. New algorithms using high-sensitivity cardiac troponin assays at low cut-offs alone, or in combination with additional biomarkers or clinical scores, allow to establish accelerated rule-out algorithms within 1 or 2 hours.

Introduction: pathophysiology and classification of acute coronary syndromes—the role of biomarkers

The aetiology of acute coronary syndromes (ACS) is complex and involves multiple interrelated mechanisms, of which many have yet not been fully understood (see Biomarkers in acute coronary syndromes Chapters 35, 43, and 46). Our current understanding is that a plaque may rupture or erode, in response to inflammation, leading to local occlusive or non-occlusive thrombosis [1]. Depending on the degree and reversibility of this dynamic obstruction, the clinical manifestations of ACS comprise a continuous spectrum of risk that progresses from unstable angina (UA) to non-ST-segment elevation myocardial infarction (NSTEMI) to ST-segment elevation myocardial infarction (STEMI). NSTEMI is distinguished from UA by ischaemia sufficiently severe in intensity and duration to cause myocyte necrosis, which is recognized by the detection of cTn, the most sensitive and specific biomarker of myocardial injury [2, 3].

The most recent achievement with biomarker testing is the implementation of hscTn assays, instead of the conventional, less sensitive troponin assays, in patients with suspected ACS [4]. The higher analytical sensitivity and precision of the more sensitive assays have facilitated an earlier and more accurate detection of NSTEMI [58]. Accordingly, recent European Society of Cardiology (ESC) guidelines [4] recommend the implementation of hscTn assays with a second sample after 3 hours, and if the diagnosis is still uncertain at later time points, in order to rule out NSTEMI earlier than with standard cardiac troponin (cTn) assays. As an alternative, a 1-hour diagnostic protocol can be used if validated hsTn assays are available, a 2-hour accelerated diagnostic protocol with cTn, or an instant rule-out using a single hsTn with a cutoff at the detection limit, or a combination of a normal cTn or hsTn together with a normal copeptin (see Biomarkers in acute coronary syndromes Chapter 46).

Other biomarkers representing inflammation, activation of coagulation, myocyte necrosis, vascular damage, and haemodynamic stress—while less helpful for diagnosis—may improve risk stratification and the selection of invasive vs conservative treatment strategy, and allow insights into individual components of the pathophysiological process of atherosclerosis and the relative contribution at different stages of the disease (see Biomarkers in acute coronary syndromes Figure 36.1).

Figure 36.1 Representative biomarkers involved in the process of atherosclerosis at different stages of the disease

Figure 36.1
Representative biomarkers involved in the process of atherosclerosis at different stages of the disease

Cardiac troponins

cTnT and cTnI are now considered as the preferred biomarkers for the diagnosis of myocardial injury, as the cardiac isoforms of troponin T or I are expressed exclusively in myocytes on the thin myofilament of the contractile apparatus and, to a lower degree (3–6%), as unbound proteins in the cytoplasm of myocytes [2, 3]. Thus, cTn constitute the most sensitive and specific biochemical markers of myocardial damage presently available. According to the criteria of the third updated version of the Universal definition [9], an MI is diagnosed when cTn is rising and/or falling, with at least one value in serial blood sampling above the 99th percentile of a reference control group, and in the presence of signs or symptoms of myocardial ischaemia (see Biomarkers in acute coronary syndromes Table 36.1). Myocardial ischaemia is suspected in the presence of symptoms of ischaemia, typical ECG changes indicative of ischaemia, new Q waves, imaging evidence of new loss of viable myocardium, new regional wall motion abnormalities, or the detection of intracoronary thrombus on coronary angiography.

Table 36.1 Joint ESC/ACCF/AHA/WHF Task Force definition of acute myocardial infarction

Myocardial infarction should be diagnosed when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischaemia. Under these conditions the following criteria meet the diagnosis for myocardial infarction:

  • Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit (URL), together with evidence of myocardial ischaemia with at least one of the following:

    • Symptoms of ischaemia

    • ECG changes indicative of new ischaemia(new ST-T changes or new left bundle branch block [LBBB])

    • Development of pathological Q waves in the electrocardiogram (ECG)

    • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

    • Identification of an intracoronary thrombus on coronary angiography or autopsy

The Universal myocardial infarction (MI) definition [9] further differentiates five subtypes that are clearly defined (see Biomarkers in acute coronary syndromes Table 36.2). In the third version of the Universal MI definition [9], the criteria for the definition of post-procedural MI have been modified; after an elective PCI, a post-procedural MI should only be diagnosed if cTn exceeds the upper limit of normal (99th percentile) by >5 times, together with symptoms, ST-segment changes, new Q waves, or other signs of myocardial ischaemia. An isolated increase of cTn of any magnitude, or an increase to <5 times the upper limit of normal, without an indicator of myocardial ischaemia, should not be labelled as MI but as myocardial injury. Accordingly, a type 5 MI, following an elective CABG, requires a rise of cTn of >10 times the upper limit of normal, along with additional evidence of myocardial ischaemia. A great challenge is to discriminate a type 1 MI, as a consequence of rupture, erosion, fissuring, or dissection of a vulnerable plaque, from a type 2 MI that is caused by myocardial ischaemia due to an imbalance between O2 demand and supply, without the anatomical information from coronary angiography (see Biomarkers in acute coronary syndromes Figure 36.2 ). Although peak cTn values may be lower in type 2 MI [10, 11], a discrimination of type 1 from type 2 MI can rarely be accomplished prospectively without a coronary angiogram [12, 13]. Recently the term “MINOCA” has been introduced particularly for patients with an acute myocardial infarction based on the criteria of the universal acute myocardial infarction (AMI) criteria (4) in the absence of obstructive coronary artery disease (≥ 50% stenosis) on the coronary angiogram, and no overt cause for the clinical presentation at the time of angiography such as takotsubo cardiomyopathy. MINOCA should be considered as a ‘working diagnosis’, analogous to heart failure, and thus prompts further evaluation regarding its underlying mechanism(s) (Agewall, 2017). Cardiac magnetic resonance imaging is the key diagnostic tool to be employed in MINOCA patients since late gadolinium enhancement (LGE), when present, permits localization of the area of myocardial damage and provides insight into mechanisms. Other suggested include echocardiography to assess wall motion, intracoronary imaging at the time of cardiac catheterization with intravascular ultrasound or optical coherence tomography to identify atherosclerotic plaque disruption and plaque erosion as well as coronary dissection or thrombosis, CT coronary angiography to obtain further information regarding underlying atherosclerosis, CT pulmonary angiography to exclude suspected pulmonary embolism, The term MINOCA is not synonymous with type 2 MI, and the advocats of the term MINOCA indicate that type 2 MI is one of the potential aetiologies for MINOCA (Agewall, 2017). A type 3 MI should be diagnosed in patients who died suddenly with signs or symptoms suggestive of myocardial ischaemia, with death occurring before blood samples could be obtained, or who died before cTn appeared in blood [9].

Table 36.2 Subtypes of MI

Type 1

Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as plaque erosion or rupture, fissuring or dissection

Type 2

Myocardial infarction secondary to ischemia due to imbalance between oxygen demand and supply e.g. coronary spasm, anemia, or hypotension

Type 3

Sudden cardiac death with symptoms of ischemia, accompanied by new ST elevation or left bundle branch block (LBBB), or verified coronary thrombus by angiography or autopsy, but death occurring before blood samples could be obtained

Type 4a

Myocardial infarction associated with percutaneous coronary intervention (PCI)

Type 4b

Myocardial infarction associated with verified stent thrombosis

Type 5

Myocardial infarction associated with coronary artery bypass grafting (CABG)

Figure 36.2 Putative mechanisms related to the development of type 1 or type 2 MI

Figure 36.2
Putative mechanisms related to the development of type 1 or type 2 MI

Elevated cTn values in patients with acute ischaemic presentations are related to more extensive coronary artery disease (CAD), procoagulant activity, and lower Thrombolysis in Myocardial Infarction (TIMI) flow grades [14]. Angioscopic and angiographic evidence suggests a clear relationship between the presence and concentration of cTn and the presence and magnitude of intracoronary thrombus [15]. As such, an elevated cTn indicates a higher risk for acute coronary events, due to the increased prothrombotic activity and the development of cardiac events during mid- and long-term follow-up, due to its relation to disease severity and persistent inflammatory activity of the atherosclerotic plaque. Consistently, benefits of more aggressive antithrombotic or antiplatelet therapies with dalteparin [16], and antiplatelet therapies with abciximab [17], tirofiban [18], lamifiban [19], or triple antiplatelet therapy, followed by early coronary intervention [20], were almost restricted to patients with cTn elevations.

The diagnosis of an AMI requires a relevant rise and/or fall of cTn, with at least one cTn value exceeding the 99th percentile [9]. Therefore, cTn has to be measured serially to distinguish an acute from a chronic cTn elevation. According to current ESC guideline recommendations [4], cTn must be measured on presentation and at 6–9 hours after admission, unless a hscTn assay is being used [4, 21]. In patients with an intermediate or high clinical index of suspicion, who remain troponin-normal, and after recurrence of typical symptoms, a later measurement at 12–24 hours should be considered, in order not to miss a late rise in cTn.

Clinical indicators, other than cTn, also provide an estimate of the acute thrombotic risk such as dynamic ST-segment deviations, refractory angina, diabetes mellitus, renal failure, older age, and an intermediate or high GRACE or TIMI risk score [4]. Current ESC guidelines therefore advocate that the decision and timing of an early invasive treatment strategy should be based on individual risk stratification. Patients at higher risk were found to benefit from an early invasive strategy within 72 hours. Patients with a high GRACE score exceeding 140 points, dynamic ST-segment changes, or a relevant rise and/or fall of cTn qualify for an invasive strategy within 24 hours (see Biomarkers in acute coronary syndromes Table 36.3). An immediate invasive strategy within 2 hours is recommended in patients with very high-risk features.

Table 36.3 Need and timing of invasive strategy according to 2015 ESC guidelines for NSTE-ACS (4)

Risk category

Timing of coronary angiography

Very high risk

Immediate invasive(<120 min)

  • Hemodynamic instability or cardiogenic shock

  • Recurrent or ongoing chest pain refractory to medical therapy

  • Life-threatening arrhythmias or cardiac arrest

  • Mechanical complications of MI

  • Acute heart Failzre

  • Recurrent dynamic ST-T wave changes, particularly with intermittent ST elevation

High risk

Early invasive (<24 hours)

  • Rise or fall in cardiac troponin compatible with MI

  • Dynamic ST- or T-wave changes (symptomatic or silent)

  • GRACE score > 140

Intermediate risk

Invasive (<72 hours)

  • Diabetes

  • Renal insufficiency (eGFR <60 ml/min/1.73m2

  • LVEF < 40% or congestive heart failure

  • Early postinfarct angina

  • Prior PCI

  • Prior CABG

  • GRACE score > 109 and < 140

Low risk

Non-invasive testing if appropriate

Any characteristics not mentioned above

An early invasive strategy (<24 h) is recommended in patients with high risk features, i.e. a GRACE score >140 or a rise or fall of cardiac troponin compatible with an MI (level of recommendation IA). Patients at intermediate risk should undergo an invasive strategy within 72 hours. A selective invasdive strategy can be followed in patients with low risk who remain asymptomatic following optimal medical therapy and do not disclosae myocardial ischemia on stress testing, preferably stress imaging.

Other biomarkers of myocardial necrosis, including total creatine kinase (CK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST), have historical significance and should not be used for the diagnosis of MI, because they have low specificity for cardiac injury. In the rare instance that cTn is not available, the next best alternative is CK-MB (measured by mass assay). A still useful application of CK-MB is in the detection of reinfarction in the very early phase following an MI when cTn is less useful, due to its more prolonged elevation. In other instances, serial measurements of cTn provide the same degree of evidence for reinfarction as CK or CK-MB.

High-sensitivity cardiac troponin assays

Several years ago, manufacturers started to develop novel high-sensitivity generations of cTn assays, in order to comply with the precision criteria of the ESC/ACC [22]. It has been proposed that a cardiac troponin (cTn) assay should be designated as ‘high-sensitivity’ assay if cTn can be measured in at least 50% of healthy individuals, in order to ensure a high clinical sensitivity [23]. These high-sensitivity assays are characterized by a substantially higher analytical sensitivity than conventional sensitive assays, allowing the measurement of cTn in ng/L, rather than microgram/L [24]. The more sensitive hscTn assays differ regarding their analytical characteristics. In direct comparison, 19 cTn assays were found to show very heterogenous analytical characteristics regarding the 99th percentile value and their analytical sensitivity, as reflected by the proportion of detectable cTn concentrations in a healthy reference population [25]. Whether the clinical performance of the different hscTn assays is similar is unsettled as yet only a few studies have directly compared hscTn assays head to head for the detection of reversible ischaemia [26], diagnosis, and prognosis [8, 27, 28].

The key differentiating feature of hscTn assays, when compared to the conventional sensitive cTn assays, is not apparent at higher values but is restricted to the area around the 99th percentile cut-off. The clinical interpretation of hscTn concentrations in this range is challenging, but important, as most of the increased sensitivity for the detection of myocardial injury is at the low concentration level.

In clinical routine, there is substantial evidence that the use of more sensitive cTn assays enables more accurate and earlier detection of myocardial infarction (MI) [58]. Numerous trials [7, 8, 29] and a recent meta-analysis [30] now provide substantial evidence that high-sensitivity assays, using the 99th percentile as the threshold for positivity, can achieve sensitivity at presentation of 90% or more. A higher analytical sensitivity changes the spectrum of ACS, as hscTn assays used at lower thresholds increase the incidence of non-ST-segment elevation myocardial infarction (NSTEMI), particularly small MI, that would have been mislabelled as unstable angina (UA) [31, 32]. Maximizing early sensitivity results in some loss of clinical specificity [33]. Thus, lowering the diagnostic cut-off increases the number of patients with analytically true cTn elevations that are related to myocardial injury, but not to MI (see Biomarkers in acute coronary syndromes Figure 36.3). Compared to conventional sensitive assays, the prevalence of detectable and elevated cTn values increases with the use of hscTn assays in various study populations, including patients with acute [34] or chronic heart failure [35, 36, 37], stable coronary artery disease (CAD) [38], and in general populations of middle-aged individuals [3941], and patients with structural heart disease are identified at earlier clinical stages [35, 42]. Not uncommonly, patients with suspected ACS may present with symptoms other than typical chest pain (CP). Therefore, the diagnosis may be uncertain in many patients who require strategies to overcome the loss of clinical specificity. Such strategies to increase the clinical specificity without a loss of sensitivity include a strict adherence to the Universal MI definition, the use of recommended cut-offs, and relevant concentration change in serial testing. A working group of the ESC [43] recommends, by consensus, an increase of >50% of the 99th percentile value if the baseline value lies below the 99th percentile and the second value exceeds the 99th percentile. In cases where the initial cTn value is already above the 99th percentile value, an increase of only 20% on the second sample is necessary to diagnose NSTEMI [43].

Figure 36.3 Increasing numbers of differential diagnoses with the use of more sensitive and highly sensitive cardiac troponin assays.

Figure 36.3
Increasing numbers of differential diagnoses with the use of more sensitive and highly sensitive cardiac troponin assays.

Patients with a rising pattern of hscTn to high peak values most likely have an acute aetiology such as NSTEMI, acute heart failure (AHF), stress cardiomyopathy, myocarditis, or PE [44]. On the other hand, if the pattern of the hscTn values is not changing, chronic structural heart disease should be suspected. Irrespective of the cause of myocardial injury, elevations of hscTn are associated with an adverse clinical outcome in most clinical conditions [45]. The higher the cTn concentrations on admission, the less likely a differential diagnosis other than an AMI is [46], particularly among those who present with AHF [47].

Risk stratification and selection of invasive vs medical treatment

In the era of previously less sensitive assay generations, a positive cTn result strongly predicted the acute thrombotic risk within 30 days after the index event, but also the long-term outcomes for several years [48, 49]. As a proof of principle that cTn was also a surrogate for intracoronary thrombus and platelet reactivity, following the rupture of a vulnerable plaque, a positive cTn result was found to be associated with treatment benefits from more potent anticoagulants, antiplatelet therapies, or an early invasive strategy [1620]. In line with the observation that risk stratification improves as cTn cut-offs of the same assay are lowered [50], new hscTn assays used at the 99th percentile demonstrated an excellent prediction of the risk for death or MI [5053], even in patients with cTn levels below the lower limit of detection of conventional sensitive assays [28, 51]. However, the question of whether very low decision cut-offs using hscTn assays warrant the selection of an invasive strategy vs that of medical treatment is still unresolved. The GUSTO IV trial reported an excess of death/MI among patients who underwent an early invasive treatment, compared to a conservative approach, if patients were stratified as low-risk patients, as suggested by undetectable cTnT levels and low NT-proBNP values [54]. On the other hand, the TACTICS TIMI 18 trial found that rates of death and MI were significantly reduced in patients who received tirofiban and underwent an early invasive treatment within 48 hours if conventional cTnT values were elevated [55]. At present, there is some evidence that hscTn assays may be useful to improve in-hospital management and outcomes, particularly in the intermediate range of cTn elevation [56]. In addition, a biomarker substudy from the Platelet Inhibition and Patient Outcomes (PLATO) trial investigated the relationship between hscTnT status and the benefits of ticagrelor, a more potent P2Y12 inhibitor, compared to clopidogrel, across the entire spectrum of ACS. Patients with hscTnT values above the 99th percentile and a diagnosis of NSTEMI derived benefits from ticagrelor by reducing cardiac endpoints, regardless of whether they underwent an invasive or a conservative treatment [57]. Conversely, patients with a normal hscTnT result (UA) did not derive the same amount of benefit from ticagrelor, compared to clopidogrel. If treated invasively during index hospitalization, there was an increase of the primary endpoint, driven by higher rates of procedure-related MIs and significant excess of major bleedings, particularly procedural non-CABG-related major bleeding [58]. Thus, it appears that patients with UA represent a low-risk cohort that may not benefit from treatment strategies outlined for the NSTEMI cohorts. In agreement, the current ESC guidelines recommend not to perform an early routine coronary angiography in normal-cTn patients, but to base the decision on the recurrence of CP or on a positive stress test [4].

Point-of-care testing

Cardiac troponin testing on point-of-care systems

The National Academy of Clinical Biochemistry (NACB) recommends the use of point-of-care testing (POCT) when central laboratory testing is not available, or when turnaround times exceed 60 min [21]. The use of POCT has been shown to reduce turnaround times and can lead to reduced time to anti-ischaemic treatment and need for hospital admission [59], but effects on admission and length of stay were inconsistent and varied between centres [60, 61]. There are two major shortcomings that limit the usefulness of POCT of cTn in acute cardiac care. First, several POCT do not achieve a comparable level of analytical sensitivity, compared to cTn assays measured in a central laboratory [23, 25]. In addition, there is an issue, both with standardization between different cTnI assays and between point-of-care and central laboratories, even with the use of a cTnI or cTnT assay from the same manufacturer. Strategies on how to improve the analytical sensitivity of cTn on point-of-care systems or how to implement current point-of-care systems for an accurate and safe rule-out of NSTEMI are under investigation. Recently, four different POCT cTn assays were compared to a contemporary sensitive central laboratory assay [62]. On the one hand, this study demonstrates the continuous improvement of point-of-care systems and assays, as two point-of-care assays, using of a cut-off at the 99th percentile, yielded a diagnostic accuracy on admission that was comparable to that of the central laboratory test. On the other hand, this study also underscores the issue regarding the clinical and analytical variability of point-of-care assays, particularly the lack of standardization and harmonization of point-of-care assays. However, in this study, the conventional central laboratory assay had a sensitivity on admission of only 68%, which is inferior to sensitivities on admission of 90% or higher reported for hscTn central laboratory assays [7, 8, 29, 30]. Thus, it becomes clear that the role of point of care in the era of hscTn assays is even more challenging and will remain a matter of debate until point-of-care assays have been optimized to a hscTn standard.

Modern hscTn assays appear to have a superior early sensitivity to myoglobin and CK-MB [7, 8, 29, 30]. However, at present, there are only few, if any at all, commercially available point-of-care systems that meet the criteria of a hscTn assay, and small NSTEMIs may escape detection, due to the lower diagnostic sensitivity.

Thus, for most point-of-care systems, the potential for reduced times to decision making needs to be weighed against a loss of sensitivity, when compared to hscTn assays in central laboratories.

Other biomarkers

A variety of different biomarkers have been studied to investigate their potential role in diagnosis and prognosis. Elevation of representative biomarkers mirror components of the pathophysiological process of atherosclerosis such as inflammation, myocardial stress, haemostasis and fibrinolysis, or myocardial ischaemia.

Early markers of ischaemia

Several markers, including heart-type fatty acid-binding protein (h-FABP), ischaemia-modified albumin (IMA), and myoglobin, have been proposed to detect myocardial necrosis, before cTn becomes measurable in blood. Myoglobin and h-FABP are among the biomarkers that have been studied extensively in the past for this purpose. A recent meta-analysis [30] demonstrates a pooled sensitivity of myoglobin of only 62%, disqualifying myoglobin measurement as a stand-alone strategy. For h-FABP assays, a pooled sensitivity of 81% for quantitative, but only 68% for qualitative, assays has been reported [30]. Due to an inadequate tissue specificity of most additional biomarkers, their use has only been advocated in combination with cTn [63]. Combination of cTn with h-FABP, copeptin, IMA, and myoglobin improved sensitivity for MI at presentation, but at the expense of a loss of specificity [30]. In recent guidelines [4], a strategy combining a normal copeptin on admission with a normal cTn or hsTn on admission received a recommendation for instant rule-out of MI.

With the use of hscTn assays, the usefulness of earlier ischaemia biomarkers has been challenged, as a similar diagnostic accuracy can be achieved with cTn as a single test by using a high-sensitivity assay [7, 8, 29, 30].

Prognostic biomarkers

From carefully conducted meta-analyses [30], there was some evidence that BNP, NT-proBNP, MPO, and h-FABP can provide additional prognostic value beyond cTn, whereas CRP, PAPP-A, and h-FABP can predict major adverse cardiac events (MACEs) in normal-troponin patients. Regarding CRP, results from studies on the prognostic value are conflicting. For some other biomarkers, such as GDF-15 [64, 65] or copeptin [6670], there is increasing supporting evidence for a prognostic value, particularly among normal-cTn patients. However, the number of studies is still too small to draw definite conclusions.

In summary, findings on a large variety of biomarkers are based on small numbers of heterogeneous studies, and the utility of the prognostic value of most biomarkers is unclear. In particular, little is known about the added value of representative biomarkers of inflammation, myocardial stress, or ischaemia listed when hscTn is used, instead of conventional cTn. Recently, the utility of 14 novel biomarkers for prognostic assessment in ACS patients with undetectable conventional cTn levels was investigated [65]. Along with hscTn, independent prognostic information was conferred only by GDF-15 and MR-proADM. In another study, copeptin not only improved rapid rule-out of an emerging NSTEMI when cTn was low, but also helped to identify patients at higher risk for adverse outcomes, if copeptin levels were high [70].

Novel biomarkers: copeptin, MR-proatrial natriuretic peptide, and MR-proadrenomedullin


There is accumulating evidence indicating that copeptin, the stable fragment of vasopressin, can improve rapid rule-out of MI when measured together with a conventional [66, 67], or with a hscTn, assay [68]. Following an index event, such as a small infarct, copeptin is rapidly released from the pituitary gland and appears rapidly in the blood in patients with an evolving MI, while cTn is still normal [66]. Copeptin concentrations decline fast to normal as cTn levels rise above the 99th percentile. Copeptin levels do not increase in patients with uncomplicated UA. Accordingly, patients who are measured normal for copeptin and cTn on presentation are unlikely to develop an NSTEMI at serial testing [6668]. The performance of copeptin is excellent, in combination with a conventional cTnT or cTnI assay, with NPVs of about 99% when using copeptin cut-off levels of 10 pmol/L, for example [66, 67]. The added benefit of copeptin, combined with a hscTn assay, is smaller, but still significant [68]. In a randomized interventional trial, discharge of patients with suspected ACS at low-to-moderate risk using copeptin and troponin in combination was earlier and at least as safe as the standard protocol using serial cTn or hsTn [69]. In addition, copeptin not only improved a rapid rule-out of an emerging NSTEMI, but also helped to identify patients at higher risk for adverse outcomes, if copeptin levels were high [70].

Atrial natriuretic peptide (MR-proatrial natriuretic peptide)

ANP is derived from the cleavage of its precursor proatrial natriuretic peptide (proANP) [71]. MR-proatrial natriuretic peptide (MR-proANP) has so far been shown to offer comparable diagnostic and prognostic performance to other natriuretic peptides in heart failure [72]. More recently, there is some evidence for a prognostic role for ANP in different settings of ACS [7375].

The LAMP study (Leicester AMI Peptide study) reported that, post-MI, MR-proANP added prognostic information, independently of established conventional risk factors [73]. As a shortcoming, STEMI was over-represented, and results of MR-proANP were not evaluated against a hscTn assay.

In another study, Meune et al. [74] investigated the diagnostic and prognostic value of admission MR-proANP in a cohort of 675 patients with CP and compared it with conventional and hscTn. MR-proANP was an independent predictor for the composite of death or MI at 360 days of follow-up and conferred additive discriminatory effects for prognosis to fourth-generation cTnT and hscTn. However, MR-pro ANP failed to improve diagnosis, in combination with a conventional sensitive cTn assay. In another cohort of 1386 consecutive patients with suspected ACS, Tzikas et al. [75] reported that an increment of the log-transformed MR-proANP by 1 SD was associated with an adjusted 2.55-fold risk of death or non-fatal MI. MR-proANP appeared in blood earlier than BNP and MR-proADM, and it delivered robust predictive values on admission. However, further serial measurements did not add any relevant prognostic information.


Khan et al. [76] used a combined primary endpoint of death or heart failure to evaluate the prognostic value of MR-proadrenomedullin (MR-proADM) in a large cohort of patients after AMI. Investigators in the LAMP II study [77] provided additional evidence on the prognostic utility of MR-proADM in a large cohort of NSTEMI patients, even beyond that of the GRACE score. In another study by Tzikas et al. [75], MR-proADM was measured in 1386 consecutive patients with suspected ACS. Adjusted risk for risk of death and non-fatal MI was 1.91-fold per 1 SD increment of MR-proADM, and resulted in a significant reclassification of patients when added to the GRACE risk score.

In summary, novel biomarkers, such as copeptin, MR-proANP, and MR-proADM, provide promising results for the diagnostic and prognostic assessment in suspected ACS. Copeptin may facilitate a rapid rule-out of NSTEMI on presentation, when combined with cTn or hscTn assays. In addition, elevated copeptin levels indicate higher mortality rates at 1 year, in the absence of an elevated cTn using a hscTn assay. Likewise, measurements of MR-proANP and MR-proADM improved the prognostic assessment in suspected ACS, independent of, and additive to, the GRACE score [75].

Biomarkers of renal function

An impaired renal function is associated with higher mortality in patients with ACS (see Biomarkers in acute coronary syndromes Chapters 17 and 39) [78].

It is believed that the renal function indicates the cumulative extent of vascular damage caused by hypertension, dyslipidaemia, and diabetes. Knowledge of the renal function is important for risk assessment and for dose adjustment of anticoagulation and antiplatelet therapies, as patients with renal failure are prone to excess bleeding, due to overdosing. GFR estimates, based on creatinine levels, are the accepted standard for quantifying the renal function in most clinical settings, but this has limitations, as serum creatinine concentrations may be affected by tubular secretion, age, sex, muscle mass, physical activity, and diet.

There is accumulating evidence that plasma cystatin C level is an accurate marker of renal function and an independent predictor of mortality in patients with CAD, but only few studies have evaluated the prognostic role of cystatin C specifically in patients with ACS [79]. In a study on 726 patients with suspected ACS, cystatin C had better discrimination power than creatinine clearance or creatinine, and this suggests that its measurement can improve early risk stratification [79].

Renal function became the strongest predictor for 1-year mortality, in combination with NT-proBNP [80].

Biomarkers of haemostasis and fibrinolysis

Markers of activated thrombosis contain useful information, with regard to the ongoing thrombotic process in ACS (see Biomarkers in acute coronary syndromes Chapter 38) [81]. Previous studies have shown an association between the risk of MI and the concentrations of fibrinogen, soluble fibrin, and markers of the fibrinolytic pathway, including plasminogen activator inhibitor-1 [82, 83]. In addition, many of the novel markers are also associated with the inflammatory atherosclerotic process. However, for several reasons, none of these markers appear to possess enough clinical information to be included in the present recommendations for the management of ACS [81].

Combination of biomarkers—a multimarker approach

The pathophysiology of ACS is complex and cannot be reflected by a single marker (see Biomarkers in acute coronary syndromes Chapter 37). There is growing evidence that combining a biomarker of haemodynamic stress (BNP or NT-proBNP) or a biomarker of inflammation (high-sensitivity CRP) with a biomarker of necrosis (cTn) enhances the risk assessment in patients with ACS [80, 84].

Personal perspective

cTn are anticipated to remain the preferred biomarker for ACS diagnosis and classification, due to its cardiospecificity and superior sensitivity to other cardiac constituents. In addition, it appears that an elevated cTn accurately indicates myocardial injury and thus predicts a higher risk for cardiovascular events, regardless of the underlying aetiology. Thus, elevated hscTn should be viewed as an important tool for risk stratification in ACS and non-ACS conditions, and not as a confounder of ACS diagnosis. Moreover, it is tempting to speculate that cTn levels may be influenced by various forms of intervention (physical activity, lifestyle modification, statin therapy, potent antiplatelet therapies) and thus may be used for the monitoring of disease progression or therapeutic effects.

Another interesting topic is the acceleration of rule-in and rule-out of patients with suspected ACS, in order to shorten the lengths of stay in ED, and to optimize patient management and health care resources. New algorithms using hscTn assays at low cut-offs alone [8587], or in combination with additional biomarkers such as copeptin [6668], may allow the rapid exclusion of an evolving NSTEMI within 1–2 hours and the subsequent safe discharge of patients with suspected ACS who are at low risk for subsequent death or MI.

Further reading

1. Apple FS. A new season for cardiac troponin assays: it’s time to keep a scorecard. Clin Chem 2009;55:1303–6.Find this resource:

2. Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high sensitivity cardiac troponin T assay. Clin Chem 2010;56:254–61.Find this resource:

3. 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.Find this resource:

4. Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009;361:868–77.Find this resource:

5. Latini R, Masson S, Anand I, et al; for the Val-HeFT Investigators. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation 2007;116:1242–9.Find this resource:

6. Omland T, de Lemos JA, Sabatine MS, et al; Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med 2009;361:2538–47.Find this resource:

7. Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 2009;361:858–67.Find this resource:

8. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction, Katus HA, Lindahl B, Morrow DA, et al. Third universal definition of myocardial infarction. Circulation 2012;126:2020-35.Find this resource:

9. Thygesen K, Mair J, Giannitsis E, et al; Consensus Study Group on Biomarkers in Cardiology of ESC Working Group on Acute Cardiac Care. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J 2012;33:2252–7.Find this resource:

10. Thygesen K, Mair J, Katus H, et al; Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. Recommendations for the use of cardiac troponin measurement in acute cardiac care. Eur Heart J 2010;31:2197–204.Find this resource:


1. Braunwald E. Unstable angina: an etiologic approach to management. Circulation. 1998; 98: 2219–22.Find this resource:

2. Katus HA, Remppis A, Scheffold T, et al. Intracellular compartmentation of cardiac troponin T and its release kinetics in patients with reperfused and non-reperfused myocardial infarction. Am J Cardiol 1991; 67: 1360–67.Find this resource:

3. Katus HA, Remppis A, Neumann FJ, et al. Diagnostic efficiency of troponin T measurements in acute myocardial infarction. Circulation 1991; 83: 902–12.Find this resource:

4. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S, Baumgartner H, Gaemperli O, Achenbach S, Agewall S, Badimon L, Baigent C, Bueno H, Bugiardini R, Carerj S, Casselman F, Cuisset T, Erol Ç, Fitzsimons D, Halle M, Hamm C, Hildick-Smith D, Huber K, Iliodromitis E, James S, Lewis BS, Lip GY, Piepoli MF, Richter D, Rosemann T, Sechtem U, Steg PG, Vrints C, Luis Zamorano J. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Management of acute coronary syndromes in patients presenting without persistent st-segment elevation of the European Society of Cardiology. Eur Heart J. 2016; 37: 267–315.Find this resource:

5. Melanson SE, Morrow DA, Jarolim P. Earlier detection of myocardial injury in a preliminary evaluation using a new troponin I assay with improved sensitivity. Am J Clin Pathol. 2007; 128: 282–6.Find this resource:

6. Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical Validation of a High Sensitivity Cardiac Troponin T Assay. Clin Chem 2010 56: 254–61.Find this resource:

7. Keller T, Zeller T, Peetz D, Tzikas S, Roth A, Czyz E, Bickel C, Baldus S, Warnholtz A, Fröhlich M, Sinning CR, Eleftheriadis MS, Wild PS, Schnabel RB, Lubos E, Jachmann N, Genth-Zotz S, Post F, Nicaud V, Tiret L, Lackner KJ, Münzel TF, Blankenberg S. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med. 2009; 361: 868–77.Find this resource:

8. Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S, Biedert S, Schaub N, Buerge C, Potocki M, Noveanu M, Breidthardt T, Twerenbold R, Winkler K, Bingisser R, Mueller C. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med. 2009; 361: 858–67.Find this resource:

9. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction, Katus HA, Lindahl B, Morrow DA, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasché P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S. Collaborators: Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Ž, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S. Third universal definition of myocardial infarction. Circulation. 2012; 126: 2020–35.Find this resource:

10. Javed U, Aftab W, Ambrose JA, Wessel RJ, Mouanoutoua M, Huang G, Barua RS, Weilert M, Sy F, Thatai D. Frequency of elevated troponin I and diagnosis of acute myocardial infarction. Am J Cardiol. 2009; 104: 9–13Find this resource:

11. Saaby L, Poulsen TS, Hosbond S, Larsen TB, Pyndt Diederichsen AC, Hallas J, Thygesen K, Mickley H. Classification of Myocardial Infarction: Frequency and Features of Type 2 Myocardial Infarction. Am J Med. 2013 Jul 12. epub ahead of print.Find this resource:

12. Ambrose JA, Loures-Vale A, Javed U, Buhari CF, Aftab W Angiographic correlates in type 1 and 2 MI by the universal definition. JACC Cardiovasc Imaging. 2012; 5: 463–4.Find this resource:

13. Bonaca MP, Wiviott SD, Braunwald E, Murphy SA, Ruff CT, Antman EM, Morrow DA. American College of Cardiology/American Heart Association/European Society of Cardiology/World Heart Federation universal definition of myocardial infarction classification system and the risk of cardiovascular death: observations from the TRITON-TIMI 38 trial (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38). Circulation. 2012; 125: 577–83.Find this resource:

14. Frey N, Dietz A, Kurowski V, Giannitsis E, Tolg R, Wiegand U, Richardt G, Katus HA. Angiographic correlates of a positive troponin T test in patients with unstable angina. Crit Care Med 2001; 29: 1130–36.Find this resource:

15. Okamatsu K, Takano M, Sakai S, Ishibashi F, Uemura R, Takano T, Mizuno K. Elevated troponin T levels and lesion characteristics in non-ST-elevation acute coronary syndromes. Circ 2004; 109: 465–70.Find this resource:

16. Lindahl B, Venge P, Wallentin L. Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. Fragmin in Unstable Coronary Artery Disease (FRISC) Study Group. J Am Coll Cardiol 1997; 29: 43–8.Find this resource:

17. Hamm CW, Heeschen C, Goldmann B, Vahanian A, Adgey J, Miguel CM, Rutsch W, Berger J, Kootstra J, Simoons ML. Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) Study Investigators. N Engl J Med. 1999; 340: 1623–9.Find this resource:

18. Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N, Neumann FJ, Robertson DH, DeLucca PT, DiBattiste PM, Gibson CM, Braunwald E; TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy)-Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001; 344: 1879–87.Find this resource:

19. Newby LK, Ohman EM, Christenson RH, Moliterno DJ, Harrington RA, White HD, Armstrong PW, Van De Werf F, Pfisterer M, Hasselblad V, Califf RM, Topol EJ. Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin t-positive status: the paragon-B troponin T substudy. Circulation. 2001; 103: 2891–6.Find this resource:

20. Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H, Graf I, Ibrahim M, Pache J, Seyfarth M, Schühlen H, Dirschinger J, Berger PB, Schömig A; Intracoronary Stenting and Antithrombotic: Regimen Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA. 2006; 295: 1531–8.Find this resource:

21. Storrow AB, Apple FS Wu AHB, Jesse RL, Francis GS, Christenson RH, Cannon CP, Morrow DA, Newby KL, Ravkilde J, Tang W. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Point of Care Testing, Oversight, and Administration of Cardiac Biomarkers for Acute Coronary Syndromes. Point of Care J 2007; 6: 215–22.Find this resource:

22. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J. 2007; 28: 1598–60.Find this resource:

23. Apple FS. A new season for cardiac troponin assays: it’s time to keep a scorecard. Clin Chem. 2009; 55: 1303–6.Find this resource:

24. Thygesen K, Mair J, Katus H, Plebani M, Venge P, Collinson P, Lindahl B, Giannitsis E, Hasin Y, Galvani M, Tubaro M, Alpert JS, Biasucci LM, Koenig W, Mueller C, Huber K, Hamm C, Jaffe AS; Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. Recommendations for the use of cardiac troponin measurement in acute cardiac care. Eur Heart J 2010; 31: 2197–4.Find this resource:

25. Apple FS, Ler R, Murakami MM. Determination of 19 cardiac troponin I and T assay 99th percentile values from a common presumably healthy population. Clin Chem 2012; 58: 1574–81.Find this resource:

26. Røsjø, H. et al. Troponin I measured by a high-sensitivity assay in patients with suspected reversible myocardial ischemia: data from the Akershus Cardiac Examination (ACE) 1 study. Clin Chem 2012; 58: 1565–73.Find this resource:

27. Reichlin, T. et al. Risk stratification in patients with unstable angina using absolute serial changes of 3 high-sensitive troponin assays. Am. Heart J 2013; 165: 371–78.Find this resource:

28. Celik S, Giannitsis E, Wollert KC, Schwöbel K, Lossnitzer D, Hilbel T, Lehrke S, Zdunek D, Hess A, Januzzi JL, Katus HA. Cardiac troponin T concentrations above the 99th percentile value as measured by a new high-sensitivity assay predict long-term prognosis in patients with acute coronary syndromes undergoing routine early invasive strategy. Clin Res Cardiol. 2011; 100: 1077–85.Find this resource:

29. Keller T, Zeller T, Ojeda F, Tzikas S, Lillpopp L, Sinning C, Wild P, Genth-Zotz S, Warnholtz A, Giannitsis E, Möckel M, Bickel C, Peetz D, Lackner K, Baldus S, Münzel T, Blankenberg S. Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction. JAMA. 2011; 306: 2684–93.Find this resource:

30. Goodacre S, Thokala P, Carroll C, Stevens JW, Leaviss J, Al Khalaf M, Collinson P, Morris F, Evans P, Wang J. Systematic review, meta-analysis and economic modelling of diagnostic strategies for suspected acute coronary syndrome. Health Technol Assess. 2013; 17: v–vi, 1–188.Find this resource:

31. Kontos MC, Fritz LM, Anderson FP, Tatum JL, Ornato JP, Jesse RL. Impact of the troponin standard on the prevalence of acute myocardial infarction. Am Heart J. 2003; 146: 446–52.Find this resource:

32. Kavsak PA, MacRae AR, Lustig V, Bhargava R, Vandersluis R, Palomaki GE, et al. The impact of the ESC/ACC redefinition of myocardial infarction and new sensitive troponin assays on the frequency of acute myocardial infarction. Am Heart J 2006; 152: 118 –L 25.Find this resource:

33. Giannitsis E, Katus HA. Pros and cons of high-sensitivity assays for cardiac troponin. Nat Rev Cardiol. 2012; 9: 616–8.Find this resource:

34. Pascual-Figal DA, Casas T, Ordonez-Llanos J, Manzano-Fernández S, Bonaque JC, Boronat M, Muñoz-Esparza C, Valdés M, Januzzi JL. Highly sensitive troponin T for risk stratification of acutely destabilized heart failure. Am Heart J. 2012; 163: 1002–10.Find this resource:

35. Latini R, Masson S, Anand I, Missov E, Carlson M, Vago T, et al. for the Val-HeFT Investigators, Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation 2007; 116: 1242–9.Find this resource:

36. Barlera S, Tavazzi L, Franzosi MG, Marchioli R, Raimondi E, Masson S, Urso R, Lucci D, Nicolosi GL, Maggioni AP, Tognoni G; GISSI-HF Investigators. Predictors of Mortality in 6975 Patients with Chronic Heart Failure in the Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico-Heart Failure Trial: Proposal for a Nomogram. Circ Heart Fail. 2013; 6: 31–9.Find this resource:

37. Nagarajan V, Hernandez AV, Tang WH. Prognostic value of cardiac troponin in chronic stable heart failure: a systematic review. Heart. 2012; 98: 1778–86.Find this resource:

38. Omland T, de Lemos JA, Sabatine MS, Christophi CA, Rice MM, Jablonski KA, Tjora S, Domanski MJ, Gersh BJ, Rouleau JL, Pfeffer MA, Braunwald E; Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med. 2009; 361: 2538–47.Find this resource:

39. de Lemos JA, Drazner MH, Omland T, Ayers CR, Khera A, Rohatgi A, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA 2010; 304: 2503–12.Find this resource:

40. deFilippi CR, de Lemos JA, Christenson RH, Gottdiener JS, Kop WJ, Zhan M, Seliger SL. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA 2010; 304: 2494–502.Find this resource:

41. Saunders JT, Nambi V, de Lemos JA, Chambless LE, Virani SS, Boerwinkle E, Hoogeveen RC, Liu X, Astor BC, Mosley TH, Folsom AR, Heiss G, Coresh J, Ballantyne CM. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study. Circulation. 2011; 123: 1367–76.Find this resource:

42. Filusch A, Giannitsis E, Katus HA, Meyer FJ. High-sensitive troponin T: a novel biomarker for prognosis and disease severity in patients with pulmonary arterial hypertension. Clin Sci (Lond). 2010; 119: 207–13.Find this resource:

43. Thygesen K, Mair J, Giannitsis E, Mueller C, Lindahl B, Blankenberg S, Huber K, Plebani M, Biasucci LM, Tubaro M, Collinson P, Venge P, Hasin Y, Galvani M, Koenig W, Hamm C, Alpert JS, Katus H, Jaffe AS; Consensus Study Group on Biomarkers in Cardiology of ESC Working Group on Acute Cardiac Care. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J. 2012; 33: 2252–7.Find this resource:

44. Gassenmaier T, Buchner S, Birner C, Jungbauer CG, Resch M, Debl K, Endemann DH, Riegger GA, Lehn P, Schmitz G, Luchner A. High-sensitive Troponin I in acute cardiac conditions: implications of baseline and sequential measurements for diagnosis of myocardial infarction. Atherosclerosis. 2012; 222: 116–22.Find this resource:

45. Agewall S, Giannitsis E, Jernberg T, Katus H. Troponin elevation in coronary vs. non-coronary disease. Eur Heart J. 2011; 32: 404–11.Find this resource:

46. Reichlin T, Twerenbold R, Reiter M, Steuer S, Bassetti S, Balmelli C, Winkler K, Kurz S, Stelzig C, Freese M, Drexler B, Haaf P, Zellweger C, Osswald S, Mueller C. Introduction of high-sensitivity troponin assays: impact on myocardial infarction incidence and prognosis. Am J Med. 2012; 125: 1205–13.Find this resource:

47. Januzzi JL Jr, Filippatos G, Nieminen M, Gheorghiade M. Troponin elevation in patients with heart failure: on behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section. Eur Heart J. 2012; 33: 2265–71.Find this resource:

48. Ottani F, Galvani M, Nicolini FA, Ferrini D, Pozzati A, Di Pasquale G, Jaffe AS Elevated cardiac troponin levels predict the risk of adverse outcome in patients with acute coronary syndromes. Am Heart J. 2000; 140: 917–27.Find this resource:

49. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med. 2000; 343: 1139–47.Find this resource:

50. James S, Armstrong P, Califf R, Simoons ML, Venge P, Wallentin L., et al. Troponin T levels and risk of 30-day outcomes in patients with the acute coronary syndrome: prospective verification in the GUSTO-IV trial. Am J Med 2003; 115: 178–84.Find this resource:

51. Lindahl B, Venge P, James S. The new high-sensitivity cardiac troponin T assay improves risk assessment in acute coronary syndromes. Am Heart J. 2010; 160: 224–9.Find this resource:

52. Bonaca M, Scirica B, Sabatine M, Dalby A, Spinar J, Murphy SA, Jarolim P, Braunwald E, Morrow DA. Prospective evaluation of the prognostic implications of improved assay performance with a sensitive assay for cardiac troponin I. J Am Coll Cardiol. 2010; 55: 2118–24.Find this resource:

53. Weber M, Bazzino O, Navarro Estrada JL, de Miguel R, Salzberg S, Fuselli JJ, Liebetrau C, Woelken M, Moellmann H, Nef H, Hamm C. Improved diagnostic and prognostic performance of a new high-sensitive troponin T assay in patients with acute coronary syndrome. Am Heart J. 2011; 162: 81–8.Find this resource:

54. James SK, Lindbäck J, Tilly J, Siegbahn A, Venge P, Armstrong P, Califf R, Simoons ML, Wallentin L, Lindahl B. Troponin-T and N-terminal pro-B-type natriuretic peptide predict mortality benefit from coronary revascularization in acute coronary syndromes: a GUSTO-IV substudy. J Am Coll Cardiol. 2006; 48: 1146–54.Find this resource:

55.Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Robertson DH, Hille DA, DeLucca PT, DiBattiste PM, Demopoulos LA, Weintraub WS, Braunwald E; TACTICS-TIMI 18 Investigators. Ability of minor elevations of troponins Iand T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA. 2001 286: 2405–12.Find this resource:

56. Mills NL, Lee KK, McAllister DA, Churchhouse AM, MacLeod M, Stoddart M, Walker S, Denvir MA, Fox KA, Newby DE. Implications of lowering threshold of plasma troponin concentration in diagnosis of myocardial infarction: cohort study. BMJ. 2012; 344: e 1533.Find this resource:

57. Wallentin L, Lindholm D, Siegbahn A, Wernroth L, Becker RC, Cannon CP, Cornel JH, Himmelmann A, Giannitsis E, Harrington RA, Held C, Husted S, Katus HA, Mahaffey KW, Steg PG, Storey RF, James SK; for the PLATO study group. Biomarkers in Relation to the Effects of Ticagrelor Compared with Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed with or without In-Hospital Revascularization: A Substudy from the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial. Circulation. 2013 Oct 29. (Epub ahead of print) Circulation 2012; 126: A15929.Find this resource:

58. Giannitsis E, Wallentin L, James SK, Bertilsson M, Siegbahn A, Storey RF, Husted S, Cannon CP, Armstrong PW, Steg PG, Katus HA; PLATO investigators. Outcomes after planned invasive or conservative treatment strategy in patients with non-ST-elevation acute coronary syndrome and a normal value of high sensitivity troponin at randomisation: A Platelet Inhibition and Patient Outcomes (PLATO) trial biomarker substudy. Eur Heart J Acute Cardiovasc Care. 2016: 2048872616641901. [Epub ahead of print]Find this resource:

59. Goodacre SW, Bradburn M, Cross E, Collinson PO, Gray A, Hall AS on behalf of the RATPAC research team. The RATPAC Trial (Randomised Assessment of Treatment using Panel Assay of Cardiac markers): A randomised controlled trial of point-of-care cardiac markers in the emergency department. Heart. 2011; 97: 190–96.Find this resource:

60. Ryan RJ, Lindsell CJ, Hollander JE, O’Neil B, Jackson R, Schreiber D, Christenson R, Gibler WB. A Multicenter Randomized Controlled Trial Comparing Central Laboratory and Point-of-Care Cardiac Marker Testing Strategies: The Disposition Impacted by Serial Point of Care Markers in Acute Coronary Syndromes (DISPO-ACS) Trial. Ann Emerg Med. 2009; 53: 321–8.Find this resource:

61. Bradburn M, Goodacre S, Fitzgerald P, Coats TJ, Gray AJ, Hassan TB, Humphrey J, Kendall JM, Smith J, Collinson P. Inter-hospital variation in the RATPAC Trial (Randomised Assessment of Treatment using Panel Assay of Cardiac markers). Emerg Med J. 2012; 29: 233–8.Find this resource:

62. Palamalai V, Murakami MM, Apple FS. Diagnostic performance of four point of care cardiac troponin I assays to rule in and rule out acute myocardial infarction. Clin Biochem. 2013 (Epub ahead of print)Find this resource:

63. Morrow DA, Cannon CP, Jesse RL, Newby LK, Ravkilde J, Storrow AB, Wu AH, Christenson RH; National Academy of Clinical Biochemistry. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical characteristics and utilization of biochemical markers in acute coronary syndromes. Circulation. 2007; 115: e 356–75.Find this resource:

64. Widera C, Pencina MJ, Bobadilla M, Reimann I, Guba-Quint A, Marquardt I, Bethmann K, Korf-Klingebiel M, Kempf T, Lichtinghagen R, Katus HA, Giannitsis E, Wollert KC. Incremental Prognostic Value of Biomarkers beyond the GRACE (Global Registry of Acute Coronary Events) Score and High-Sensitivity Cardiac Troponin T in Non-ST-Elevation Acute Coronary Syndrome. Clin Chem. 2013. (Epub ahead of print)Find this resource:

65. Meune C, Balmelli C, Twerenbold R, Reiter M, Reichlin T, Ziller R, Drexler B, Stelzig C, Freese M, Wolf C, Haaf P, Osswald S, Mueller C. Utility of 14 novel biomarkers in patients with acute chest pain and undetectable levels of conventional cardiac troponin. Int J Cardiol. 2012 Apr 14. (Epub ahead of print)Find this resource:

66. Reichlin T, Hochholzer W, Stelzig C, Laule K, Freidank H, Morgenthaler NG, Bergmann A, Potocki M, Noveanu M, Breidthardt T, Christ A, Boldanova T, Merki R, Schaub N, Bingisser R, Christ M, Mueller C. Incremental value of copeptin for rapid rule out of acute myocardial infarction. J Am Coll Cardiol. 2009; 54: 60–8.Find this resource:

67. Keller T, Tzikas S, Zeller T, Czyz E, Lillpopp L, Ojeda FM, Roth A, Bickel C, Baldus S, Sinning CR, Wild PS, Lubos E, Peetz D, Kunde J, Hartmann O, Bergmann A, Post F, Lackner KJ, Genth-Zotz S, Nicaud V, Tiret L, Münzel TF, Blankenberg S. Copeptin improves early diagnosis of acute myocardial infarction. J Am Coll Cardiol. 2010; 55: 2096–106.Find this resource:

68. Giannitsis E, Kehayova T, Vafaie M, Katus HA. Combined testing of high-sensitivity troponin T and copeptin on presentation at prespecified cutoffs improves rapid rule-out of non-ST-segment elevation myocardial infarction. Clin Chem. 2011; 57: 1452–5.Find this resource:

69. Lipinski MJ, Escárcega RO, D’Ascenzo F, Magalhães MA, Baker NC, Torguson R, Chen F, Epstein SE, Miró O, Llorens P, Giannitsis E, Lotze U, Lefebvre S, Sebbane M, Cristol JP, Chenevier-Gobeaux C, Meune C, Eggers KM, Charpentier S, Twerenbold R, Mueller C, Biondi-Zoccai G, Waksman R. A systematic review and collaborative meta-analysis to determine the incremental value of copeptin for rapid rule-out of acute myocardial infarction. Am J Cardiol. 2014; 113: 1581–91.Find this resource:

70. Möckel M, Searle J, Hamm C, Slagman A, Blankenberg S, Huber K, Katus H, Liebetrau C, Müller C, Muller R, Peitsmeyer P, von Recum J, Tajsic M, Vollert JO, Giannitsis E. Early discharge using single cardiac troponin and copeptin testing in patientswith suspected acute coronary syndrome (ACS): a randomized, controlled clinicalprocess study. Eur Heart J. 2015; 36: 369–76.Find this resource:

71. von Haehling S, Papassotiriou J, Morgenthaler NG, Hartmann O, Doehner W, Stellos K, Wurster T, Schuster A, Nagel E, Gawaz M, Bigalke B. Copeptin as a prognostic factor for major adverse cardiovascular events in patients with coronary artery disease. Int J Cardiol. 2012; 162: 27–32.Find this resource:

72. Morgenthaler NG, Struck J, Thomas B, et al. Immunoluminometric assay for the midregion of pro-atrial natriuretic peptide in human plasma. Clin Chem 2004; 50: 234–6.Find this resource:

73. Maisel A, Mueller C, Nowak RM, et al. Midregion prohormone adrenomedullin and prognosis in patients presenting with acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol 2011; 58: 1057–67.Find this resource:

74. Khan SQ, Dhillon O, Kelly D, Squire IB, Struck J, Quinn P, Morgenthaler NG, Bergmann A, Davies JE, Ng LL. Plasma N-terminal B-Type natriuretic peptide as an indicator of long-term survival after acute myocardial infarction: comparison with plasma midregional pro-atrial natriuretic peptide: the LAMP (Leicester Acute Myocardial Infarction Peptide) study. J Am Coll Cardiol. 2008; 51: 1857–64.Find this resource:

75. Meune C, Twerenbold R, Drexler B, et al. Midregional pro-A-type natriuretic peptide for diagnosis and prognosis in patients with suspected acute myocardial infarction. Am J Cardiol 2012; 109: 1117–23.Find this resource:

76. Tzikas S, Keller T, Ojeda FM, Zeller T, Wild PS, Lubos E, Kunde J, Baldus S, Bickel C, Lackner KJ, Münzel TF, Blankenberg S. MR-proANP and MR-proADM for risk stratification of patients with acute chest pain. Heart. 2013; 99: 388–95.Find this resource:

77. Khan SQ, O’Brien RJ, Struck J, et al. Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) study. J Am Coll Cardiol 2007; 49: 1525–32.Find this resource:

78. Dhillon OS, Khan SQ, Narayan HK, et al. Prognostic value of mid-regional pro-adrenomedullin levels taken on admission and discharge in non-ST-elevation myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) II study. J Am Coll Cardiol 2010; 56: 125–33.Find this resource:

79. Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med. 1998; 339: 799–5.Find this resource:

80. Jernberg T, Lindahl B, James S, Larsson A, Hansson LO, Wallentin L. Cystatin C: a novel predictor of outcome in suspected or confirmed non-ST-elevation acute coronary syndrome. Circulation 2004; 110: 2342–48.Find this resource:

81. James SK, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation. 2003; 108: 275–81.Find this resource:

82. Goetze JP. Markers of Activated Coagulation in Acute Coronary Syndromes. J. Am. Coll. Cardiol. 2008; 51: 2430–31.Find this resource:

83. Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction N Engl J Med 1984; 311: 501–5.Find this resource:

84. Hamsten A, Wiman B, de Faire U, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction N Engl J Med 1985; 313: 1557–63.Find this resource:

85. Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein,and B-type natriuretic peptide. Circulation. 2002; 105: 1760–63Find this resource:

86. Than M, Cullen L, Aldous S, Parsonage WA, Reid CM, Greenslade J, Flaws D, Hammett CJ, Beam DM, Ardagh MW, Troughton R, Brown AF, George P, Florkowski CM, Kline JA, Peacock WF, Maisel AS, Lim SH, Lamanna A, Richards AM. 2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial. J Am Coll Cardiol. 2012; 59: 2091–8.Find this resource:

87. Than M, Cullen L, Reid CM, Lim SH, Aldous S, Ardagh MW, Peacock WF, Parsonage WA, Ho HF, Ko HF, Kasliwal RR, Bansal M, Soerianata S, Hu D, Ding R, Hua Q, Seok-Min K, Sritara P, Sae-Lee R, Chiu TF, Tsai KC, Chu FY, Chen WK, Chang WH, Flaws DF, George PM, Richards AM. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet. 2011; 377: 1077–84.Find this resource:

88. Reichlin T, Schindler C, Drexler B, Twerenbold R, Reiter M, Zellweger C, Moehring B, Ziller R, Hoeller R, Rubini Gimenez M, Haaf P, Potocki M, Wildi K, Balmelli C, Freese M, Stelzig C, Freidank H, Osswald S, Mueller C. One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Arch Intern Med. 2012; 172: 1211–8.Find this resource:

89. Agewall S, Beltrame JF, Reynolds HR, Niessner A, Rosano G, Caforio AL, De Caterina R, Zimarino M, Roffi M, Kjeldsen K, Atar D, Kaski JC, Sechtem U, Tornvall P; WG on Cardiovascular Pharmacotherapy. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J 2017; 38: 143-53. doi: 10.1093/eurheartj/ehw149.Find this resource: