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In August 2018, the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force published an updated universal definition of myocardial infarction (MI).1
This consensus document provides newly revised criteria for the definition of MI,1 driven by recent advances of modern cardiology. So, what was new in this Fourth Universal Definition of MI and how will this consensus paper affect everyday clinical practice?
The condition
Coronary heart disease is one of the leading causes of morbidity and mortality worldwide.2 MI represents the most common, as well as deleterious, form of coronary heart disease, generating a high epidemiological and economic burden of disease.1,2
Considering the high incidence and high global health burden, establishing a general and uniform definition of MI has been attempted over the last decades.1,3 However, different clinical presentations as well as past and ongoing diagnostic advances have given rise to different definitions of MI, leading to controversy and confusion in clinical practice.1
The first general definition of MI dates back to the 1950s, when working groups from the World Health Organization (WHO) established a MI definition mainly on the basis of electrocardiographic (ECG) criteria.1,4
The introduction of cardiac biomarkers with high discriminatory power has particularly revolutionised the detection and diagnosis of MI and necessitated revisions of the global MI definition.1 Modern high-sensitivity cardiac troponin (cTn) assays allow both early detection and fast rule out of MI, which is crucial in daily clinical routine.5,6
By contrast, however, the broad implementation of high-sensitivity troponins into routine laboratory testing has led to a sharply increasing number of incidental findings of elevated troponins without any clinical evidence of ischaemia, frequently leading to clinical misinterpretation.5
The differentiation of such a clinical scenario of myocardial injury without ischaemia from actual MI was a central focus of the newly revised 2018 Universal Definition of MI.1
Fourth Universal Definition of MI
According to the 2018 consensus document, MI is defined as: (1) acute myocardial injury detected by abnormal cardiac biomarkers; and (2), in a clinical setting with evidence of myocardial ischaemia.1
Abnormality of cardiac biomarkers is defined by a detection of elevated cTn values with at least one value above the 99th percentile upper reference limit (URL).1 If, in addition, a dynamic rise and/or fall of cTn concentrations is detected, the myocardial injury is considered as acute.1
In contrast, a setting of persistently elevated cTn levels without any dynamics would be referred to as chronic myocardial injury.1 Above and beyond acute myocardial injury, evidence of acute myocardial ischaemia is required for the diagnosis of MI.
One or more of the following clinical features affirm acute myocardial ischaemia: typical symptoms of myocardial ischaemia; new ischaemic electrocardiographic changes as well as development of pathological Q waves; imaging evidence of new loss of viable myocardium or new regional wall motion abnormality; and identification of a coronary thrombus by angiography or autopsy.1
Primarily in light of revascularisation strategies, in the early setting of acute coronary syndrome a categorisation into ST-elevation myocardial infarction (STEMI) and non-STEMI is nowadays common clinical practice.1 Beyond these clinical categories used in the early stage, MI can be classified in different types depending on differences in clinical, pathological and prognostic features.1
In the fourth update of the Universal Definition of MI, the five previously proposed types of MI have undergone only slight modifications.1 The criteria of the different MI types are summarised in brief below.
- Type 1 MI
Type 1 MI describes the classical concept of atherothrombotic MI caused by a disruption (rupture or erosion) of an atherosclerotic plaque on the basis of coronary artery disease.1 The resulting thrombus can either be occlusive or non-occlusive.1
- Type 2 MI
The concept of type 2 MI is more complicated and multifactoral, defined by myocardial ischaemia due to a mismatch between oxygen supply and oxygen demand unrelated to coronary atherothrombosis.1 This type of MI remains the most challenging for clinicians because a plethora of different clinical scenarios can lead to type 2 MI.
Importantly, in contrast to coronary atherothrombosis, coronary artery disease per se without plaque disruption does not exclude type 2 MI.1 Indeed, the mismatch between oxygen supply and demand that defines type 2 MI often occurs on the basis of underlying coronary artery disease.1
Potential causes of MI type 2 are acute stressors including severe arrhythmias, severe anaemia, severe hypertension or hypotension, and respiratory failure.1 Such stressors might induce myocardial ischaemia in patients with and without coronary artery disease, whereas individual ischaemic thresholds differ depending on the presence and severity of the underlying coronary artery disease.1
Besides the described mechanistic stressors causing oxygen supply and demand mismatch, coronary pathologies beyond atherothrombosis, such as coronary artery dissection, coronary spasm or coronary embolism, might result in type 2 MI.1
- Type 3 MI
MI type 3 denotes the clinical scenario of cardiac death with symptoms suggestive of myocardial ischaemia and concomitant presumed new ischaemic ECG changes or ventricular fibrillation, but occurrence of death before blood samples for cardiac biomarkers can be obtained.1 Cardiac death with proven MI by autopsy is also referred to as type 3 MI.1
- Type 4 and 5 MI
Infarctions in the context of coronary procedures, either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), are defined as type 4 or type 5 MI, respectively.1
Type 4 MI refers to PCI-related infarcts, whereas three subtypes (4a, 4b and 4c) have been suggested in the Fourth Universal Definition of MI.1 Type 4a MI is defined as peri-procedural MI directly related to the index PCI (≤48h after the procedure).1
The criteria of PCI-related MI are arbitrarily defined as elevation of cTn values >5-times the 99th percentile URL in cases of normal baseline values, or increase of >20% in cases of chronically elevated pre-procedural cTn concentrations.1 To allow for definite diagnosis of 4a MI, objective parameters of myocardial ischaemia are required in addition to cTn dynamics.1
Such clinical criteria of myocardial ischaemia are new ischaemic ECG changes and pathological Q waves, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality as well as angiographic findings of procedural flow-limiting complications including coronary dissection, occlusion of an epicardial artery, disruption of collateral flow and distal embolisation.1
Other subtypes of MI associated with PCI are stent or scaffold thrombosis (type 4b MI) and restenosis following PCI (type 4c MI).1 MI type 4b is defined as stent/scaffold thrombosis as detected by angiography or autopsy applying the same formal criteria as used for MI type 1.1
According to the timing of thrombosis occurrence after the index PCI, it should be distinguished between acute (0 to 24 h), subacute (>24 h to 30 days), late (>30 days to 1 year) and very late (>1 year) stent/scaffold thrombosis.1 Type 4c MI describes an in-stent restenosis or restenosis after balloon angioplasty in the infarct-related artery.1
Finally, type 5 MI denotes peri-procedural infarctions in the setting of CABG.1 In contrast to type 4a MI (PCI-related MI), type 5 MI is defined as increase of cTn >10-times the 99th percentile URL in case of normal baseline cTn, or increase of post-procedural cTn >20% in case of chronically elevated pre-procedural cTn-concentration.1
In addition to cTn dynamics, elements of ischaemia including new pathological Q waves, new graft occlusion or native coronary artery occlusion as detected by angiography or loss of viable myocardium or new regional wall motion abnormality by cardiac imaging are necessary for the diagnosis of type 5 MI.1
Key clinical messages
One of the most important elements of the updated Universal MI Definition is the emphasis on the differentiation between myocardial injury and MI. Only the laboratory finding of elevated cTn or increase of cTn in serial measurements without any clinical evidence of ischaemia should not be labelled as MI but as myocardial injury.1
Moreover, the new consensus paper highlights that myocardial injury should not only be clearly differentiated from MI but also represents an entity in itself, which comprises a variety of diseases requiring further diagnostic workup.
A large number of cardiac (for example, heart failure, myocarditis, Takotsubo syndrome, revascularisation procedure, catheter ablation, defibrillator shocks, cardiac contusion) and non-cardiac (for example, sepsis, chronic kidney disease, stroke or subarachnoid haemorrhage, pulmonary embolism, chemotherapy) pathologies and conditions can lead to myocardial injury unrelated to ischaemia.1
Depending on the presence or absence of a dynamic cTn pattern, the condition of myocardial injury should be declared as acute or chronic.1 The clinical differentiation between the various causes of myocardial injury can be challenging and often requires comprehensive diagnostics.
In this regard, the 2018 Universal Definition of MI has particularly emphasised the use of cardiac magnetic resonance (CMR) imaging to define the aetiology of myocardial injury.1 Indeed, CMR enables a unique in vivo view on myocardial tissues and the use of late gadolinium-enhanced sequences allows for a reliable distinction between ischaemic and non-ischaemic patterns of myocardial scarring.1,7,8
Contingent upon the primary disease, a clear differentiation between myocardial injury and MI might be difficult. As highlighted by a new section in the 2018 consensus document, chronic kidney disease (CKD) especially represents a condition that often results in clinical misinterpretation because a high proportion of patients with CKD displays elevated cTn concentrations.1
Importantly, renal clearance of cTn has only minor effects on serum cTn concentrations9, whereas increased ventricular pressure, microvascular dysfunction, anaemia, hypotension and direct toxic effects of uraemia are considered as main mechanisms explaining the myocardial injury in CKD patients.1,10
Acute volume overload in CKD, for example, may lead to both acute myocardial injury and type 2 MI; a clear differentiation, however, may be challenging and often remains insufficient in clinical routine.1 Not only in CKD patients, but also in a large number of other patients, including patients with multiple morbidities or those who are critically ill, the differentiation between myocardial injury and type 2 MI has remained the key clinical challenge following publication of the 2018 Universal Definition of MI.1
Routine primary PCI in the acute setting of MI has revealed that a considerable proportion of MI patients (approximately 10%) does not show significant coronary artery disease.11,12 This clinical scenario has gained more and more attention over the past few years and is referred to as MI with non-obstructive coronary arteries (MINOCA).13
After publication of a position paper of the ESC working group in 2017,13 MINOCA has now for the first time been included in the Universal Definition of MI.1 As the name implies, MINOCA is defined as MI according to the criteria as described in detail above as well as non-obstructive coronary arteries (no coronary artery stenosis of ≥50%) as displayed by acute angiography.13
MINOCA is a heterogeneous entity with several potential underlying causes that should be elucidated by a comprehensive diagnostic algorithm incorporating additional imaging modalities including CMR.1,13
Conclusions
The Fourth Universal Definition of MI published in 2018 provides updated criteria for the definition of the five types of MI established by the preceding consensus documents, with particular focus on the differentiation between myocardial injury and MI.
The entity of myocardial injury describes a clinical scenario of elevated or increasing cTn concentration without any signs of ischaemia. Particularly due to therapeutic consequences, it is crucial to distinguish myocardial injury from MI, which displays both cTn dynamics and clinical evidence of ischaemia.
References
1 Thygesen K et al. Fourth Universal definition of myocardial infarction 2018. Circulation 2018;138:e618–e651.
2 Roth GA et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol 2017;70:1–25.
3 Thygesen K et al. Universal definition of myocardial infarction. Circulation 2007;116:2634–53.
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5 Mair J. High-sensitivity cardiac troponins in everyday clinical practice. World J Cardiol 2014;6:175–82.
6 Twerenbold R et al. Clinical use of high-sensitivity cardiac troponin in patients with suspected myocardial infarction. J Am Coll Cardiol 2017;70: 996–1012.
7 Reinstadler SJ, Thiele H, Eitel I. Risk stratification by cardiac magnetic resonance imaging after ST-elevation myocardial infarction. Curr Opin Cardiol 2015;30:681–9.
8 Motwani M et al. Advances in cardiovascular magnetic resonance in ischaemic heart disease and non-ischaemic cardiomyopathies. Heart 2014;100:1722–33.
9 Friden V et al. Clearance of cardiac troponin T with and without kidney function. Clin Biochem 2017;50:468–74.
10 Januzzi JL Jr et al. 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.
11 DeWood MA et al. Coronary arteriographic findings soon after non-Q-wave myocardial infarction. N Engl J Med 1986;315:417–23.
12 Gehrie ER et al. Characterization and outcomes of women and men with non-ST-segment elevation myocardial infarction and nonobstructive coronary artery disease: results from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) quality improvement initiative. Am Heart J 2009;158:688–94.
13 Agewall S et al. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J 2017;38:143–53.
