State-of-the-art diagnosis of myocardial infarction

Types of acute MI

Based on pathophysiologic, clinical and prognostic differences, five types of MI are differentiated (Thygesen et al. [4], used with permission of Oxford University Press):

Type 1: Spontaneous myocardial infarction

Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. The patient may have underlying severe CAD but on occasion non-obstructive or no CAD.

Type 2: Myocardial infarction secondary to an ischemic imbalance

In instances of myocardial injury with necrosis where a condition other than CAD contributes to an imbalance between myocardial oxygen supply and/or demand, e.g. coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachy-/brady-arrhythmias, anemia, respiratory failure, hypotension, and hypertension with or without LVH.

Type 3: Myocardial infarction resulting in death when biomarker values are unavailable

Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes or new LBBB, but death occurring before blood samples could be obtained, before cardiac biomarker could rise, or in rare cases cardiac biomarkers were not collected.

Type 4a: Myocardial infarction associated with PCI is arbitrarily defined by elevation of cTn values >5×99th percentile URL in patients with normal baseline values (≤99th percentile URL) or a rise of cTn values >20% if the baseline values are elevated and are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischemia, or (ii) new ischemic ECG changes or new LBBB, or (iii) angiographic loss of patency of a major coronary artery or a side branch or persistent slow or no-flow or embolization, or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required.

Type 4b: Myocardial infarction related to stent thrombosis

Myocardial infarction associated with stent thrombosis is detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarkers values with at least one value above the 99th percentile URL.

Type 5: Myocardial infarction related to coronary artery bypass grafting (CABG)

Myocardial infarction associated with CABG is arbitrarily defined by elevation of cardiac biomarker values >10×99th percentile URL in patients with normal baseline cTn values (≤99th percentile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographic documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

Differentiation of type 1 and type 2 myocardial infarction

Differentiating type 1 MI from type 2 MI can be very challenging and may in some cases be even impossible before coronary anatomy is known. While myocardial ischemia is present in both subtypes, a coronary stenosis or intracoronary thrombus is often present in type 1 MI. In patients with type 2 MI, an imbalance of myocardial oxygen demand and supply is present, which may be due to various reasons such as coronary spasms, tachy-/bradyarrhythmias, heart failure and cardiogenic, hypovolemic or septic shock.

Depending on the subtype of MI, the most appropriate treatment strategy will vary. Most patients with type 1 MI are treated with antiplatelet therapy and coronary angiography is performed. In patients with type 2 MI, the underlying problem should be treated, which is why treatment strategies may vary widely. Due to a lack of specific guidelines for indication and timing of coronary angiography in this particular subgroup, the extent of biomarker-elevation as well as results of cardiac imaging tests can be useful for risk stratification. In all cases of troponin elevations, an immediate further workup should be performed, as troponin elevations due to any cause are associated with increased mortality [6]. However, troponin elevations without signs of myocardial ischemia should be classified as myocardial injury.

Updated definition of type 4a MI (MI associated with PCI)

Troponin-elevations after PCI are very common. Around 15% of all patients treated with PCI were classified as having type 4a MI according to the previous universal definition of MI from 2007 [7]. According to that classification, any troponin elevation above 3× of the URL was classified as a peri-procedural MI, even when there were no clinical signs of myocardial ischemia. As the prognostic value of such elevations is not well established, one aim of the updated criteria was a reduction in the number of type 4a MI diagnoses while increasing their prognostic relevance. The current definition requires the presence of clinical signs for myocardial ischemia as well as an elevation above 5× of the URL when troponin levels are not elevated before PCI. When troponin-levels are already elevated before PCI, an association can only be made if troponin levels are stable or falling beforehand, in which case an increase of 20% is considered diagnostic.

The electrocardiogram – integral part of the diagnostic workup

The electrocardiogram (ECG) is an indispensable diagnostic measure and should be acquired and interpreted by a physician within 10 min after admission [8]. In patients with significant ST-elevations on ECG or presumed new left bundle branch block, immediate coronary angiography should be performed. All other patients should undergo risk stratification and a risk-based diagnostic and therapeutic algorithm.

ECG criteria were modified in the current definition, appreciating age- and gender-specific differences in regard to leads V2–V3, where ST-segment elevations are considered significant when the J-point is elevated ≥0.15 mV in women, ≥0.25 mV in men under 40 years and ≥0.2 mV in men ≥40 years. In all other leads, an elevation ≥0.1 mV is considered diagnostic (Table 1).

ECG interpretation can be difficult in patients with left or right bundle branch block, early repolarization, persisting ST-elevations due to a residual aneurysm, strictly posterior MI or due to incorrectly positioned leads. In patients with pre-existing LBBB, concordant ST-elevations may be the best indicator of ongoing acute MI [9], while more complex algorithms do not seem to provide sufficient diagnostic certainty [10]. When standard leads are inconclusive in patients with suspected ongoing ischemia, additional leads V7–V9 should be acquired.

Cardiac troponin: preferred and gold standard biomarker

Cardiac troponin is a regulatory protein of the myocardial contractile apparatus and consists of three subtypes (T, I and C). As expression of cardiac troponin T (cTnT) or troponin I (cTnI) exclusively takes place in cardiomyocytes, elevated levels indicate myocardial injury [11]. Due to biphasic release kinetics, an early peak within 24 h is observed due to release of a cytoplasmic pool and a plateau after 48–72 h is observed due to proteolytic degradation of the contraction apparatus [12, 13]. A clear rise and/or fall of troponin levels or a markedly elevated troponin level at admission suggest acute myocardial injury while stable values in serial measurements indicate chronic myocardial injury. A very pronounced change is associated with a higher likelihood of acute MI. Earlier recommendations of the American National Academy for Clinical Biochemistry considered a delta change of 20% or more as significant, if initial troponin values are elevated [14]. In patients where the initial cTn-value is under the 99th percentile, an expert consensus committee of the ESC suggested a rise or fall of 50% or more as clinically significant [15]. The 2015 ESC guideline on management of non-STE-ACS defines assay-specific absolute cut-off levels for a 0-h/1-h rule-in and rule-out algorithm.

Assay precision should be ≤10% coefficient of variation (CV) at the 99th percentile URL. Only assays with detectable troponin values in more than 50% of healthy individuals should be classified as high sensitivity assays [16]. Many currently used high sensitivity troponin assays allow measurement of cardiac troponin in almost all healthy individuals [17], leading to higher negative predictive values and allowing earlier detection of MI as compared to less sensitive cTn assays.

Cardiac imaging in diagnosis of MI

Current diagnostic criteria for MI include the presence of new regional wall motion abnormalities in echocardiography, myocardial scars in MRI or in nuclear tests or an intracoronary thrombus during coronary angiography combined with a significant rise and/or fall of cardiac troponin. Echocardiography is also an important tool for diagnosis of non-ischemic causes of chest pain such as myocarditis, valvular disease, cardiomyopathies, pulmonary embolism or aortic dissection. Furthermore, echocardiography is the method of choice for detection of complications such as ventricular wall rupture or secondary mitral valve regurgitation after papillary muscle rupture or ischemia [18]. Cardiac MRI is not as widely and easily available as echocardiography, but is especially helpful in diagnostic evaluation of myocardial disease.

Acute ST-elevation-MI (STEMI)

Diagnosis of STEMI is based on the ECG, where new persistent ST-segment elevations or a presumed new LBBB must be present in a patient presenting with ischemic symptoms. In primary PCI-capable centers, primary PCI should be performed in preferably less than 60 min after first medical contact (FMC) and waiting for results of cardiac biomarkers should not delay treatment [19]. In non-primary PCI-centers, an immediate transfer to a primary PCI-capable center should be initiated if PCI is possible in less than 120 min after FMC. If this is not possible, immediate fibrinolysis should be initiated in preferably less than 30 min after FMC.

Acute non-ST-elevation acute coronary syndromes (unstable angina and non-STEMI)

In patients with suspected non-ST-elevation ACS, measurement of cardiac troponins with sensitive or high-sensitivity cardiac troponin assays is recommended.

Rule-out of MI

In the current ESC guideline, several equivalent rule-out protocols are presented [8]. When high-sensitivity cardiac troponin (hscTn) tests are available, a rapid rule-out protocol at admission (0 h) and after 3 h is recommended.

Alternatively, a rapid rule-out and rule-in protocol at 0 h and after 1 h is considered equally safe if a hscTn assay with a validated 0 h/1 h algorithm is available. In this protocol, assay-specific cut-offs are provided, with the help of which an MI can be ruled out with a single hscTn measurement at presentation when the hscTn concentration is very low and onset of symptoms is more than 3 h before presentation. MI can also be ruled-out, when low admission levels and a lack of a relevant increase is observed after 1 h [20]. When moderate or high elevations are observed at time of presentation or a significant increase is observed after 1 h, an AMI is likely. If the first two cTn measurements are not conclusive, additional testing after 3–6 h is recommended.

There are two further validated strategies, which are also considered safe for rule-out of MI. Firstly, a 2 h rule-out protocol combines hscTn at presentation with the thrombolysis in MI (TIMI) risk score and ECG results [21]. Secondly, normal levels of cardiac troponin combined with low levels of copeptin at presentation allow rule out of MI in patients at low to intermediate risk [22]. The added value of copeptin is especially high when less sensitive cardiac troponin assays are used. Therefore, such a dual marker strategy is recommended in all situations, where sensitive or high sensitivity cardiac troponin assays are unavailable.

It is important to bear in mind that clinicians implementing any of the mentioned algorithms should always take into account all clinical information. In very early presenters who are admitted less than 1 h after onset of chest pain, testing after 3 h is recommended and in all patients with high clinical suspicion or recurrent chest pain, repeat testing is also recommended.

Rhythm monitoring

Rhythm monitoring is recommended for at least 24 h in all patients with STEMI and in patients with non-STEMI with hemodynamic instability, major arrhythmias, an ejection fraction <40%; failed reperfusion, PCI-related complications and additional critical coronary stenting [8, 19]. When none of the mentioned risk criteria are present, cardiopulmonary monitoring for 24 h or PCI, if earlier, is sufficient. In patients with unstable angina, rhythm monitoring is not mandatory. However, when coronary spasms are suspected or symptoms suggestive of arrhythmic events are present, rhythm monitoring should also be considered in this subgroup.

Risk scores

The treatment strategy for patients with non-STE-ACS should be based on individual risk stratification.

GRACE risk score

Purely clinical assessment is not as effective as using the GRACE risk score for assessment of ischemic risk on admission and at discharge. According to the GRACE score, patients can be classified as low-risk (<109), intermediate risk (109–140) and high-risk (>140) using age, systolic blood pressure, pulse rate, serum creatinine level, Killip class at presentation, cardiac arrest at admission, elevated cardiac biomarkers and ST deviation in ECG [8]. The GRACE 2.0 Risk Calculator allows estimation of in-hospital mortality as well as mortality after 6, 12 and 36 months and also provides a modified algorithm incorporating renal failure and use of diuretics when Killip class and serum creatinine values are unknown [23].

CRUSADE bleeding score

The CRUSASE risk score allows bleeding risk assessment in patients undergoing coronary angiography. This is highly relevant, as major bleedings are associated with increased mortality in patients with NSTE-ACS. The CRUSADE score estimates the likelihood of an in-hospital major bleeding using variables such as hematocrit, creatinine value, heart rate, gender, signs of heart failure, systolic blood pressure, known vascular disease or diabetes [24].

Timing of invasive strategy

The timing of invasive strategy should always be based on individual risk stratification. As high cTn elevations above 5× URL are associated with a very high positive predictive value for acute MI, invasive management without retesting of hs-cTn is recommended in this scenario [8].

An immediate invasive strategy with coronary angiography within 2 h is recommended in patients with hemodynamic instability, refractory chest pain, life-threatening arrhythmias or cardiac arrest, mechanical complications of MI, acute heart failure or recurrent dynamic ST–T wave changes.

An early invasive strategy within 24 h is appropriate, if a significant rise or fall of cTn or dynamic ST- or T-wave changes are observed or if the GRACE score is >140.

An invasive strategy within 72 h should be pursued in patients with recurrent symptoms, known ischemia on non-invasive testing or the presence of at least one of the following intermediate risk criteria: history of diabetes, renal insufficiency, reduced ejection fraction <40% or congestive heart failure, recent PCI, prior CABG or a GRACE score between 109 and 140.

Patients without recurrent symptoms or additional risk factors have a low pretest probability for acute myocardial ischemia and a low risk of ischemic events. In this group, a non-invasive stress test, preferably with cardiac imaging, can be helpful in determining, whether an invasive strategy should be pursued.