Recently, the fourth Universal Definition of Myocardial Infarction was released, with simultaneous online publications in The Journal of the American College of Cardiology,¹ Circulation,² European Heart Journal,³ and Global Heart,⁴ in recognition of the joint sponsorship from the American College of Cardiology, the American Heart Association, the European College of Cardiology, and the World Heart Federation.

A fourth update of the Universal Definition of Myocardial Infarction was necessary for multiple reasons, including the ascendency of high-sensitivity cardiac troponin (cTn) assays. These assays have substantially changed the way in which the evaluation of myocardial infarction (MI) proceeds, although the clinical criteria for MI have not been changed. It is still defined by myocardial injury detected by abnormal cardiac biomarkers in the setting of acute myocardial ischemia. However, the increased sensitivity of cTn assays have unmasked the fact that there are a large number of circumstances in which myocardial injury can exist as an entity in itself in the absence of acute ischemic heart disease.^1-4 The essence of this concept includes the following (Figure 1):

1. The need for the presence of myocardial injury as defined with a cTn value above the 99th percentile upper reference limit (URL). A rising and/or falling pattern of cTn values indicates acute myocardial injury, whereas chronic myocardial injury is characterized by continuing elevated cTn values (less than 20% variation). Such a pattern may be easy to observe over a short period of time in those patients who present early after the onset of symptoms but may take longer time to manifest in patients who present later.⁵
2. The need for evidence of the presence or absence of acute myocardial ischemia. Often, symptoms and signs and electrocardiogram changes are sufficient to be assured that acute ischemia is present. However, there are times when a paucity of information exists to suggest that the mechanism of myocardial injury is due to acute ischemia and times where there is ambiguity. In those circumstances, a diagnosis of acute myocardial injury should be made. However, many patients (for example, elderly patients, those with diabetes, and women) present atypically.⁶ If there is clinical suspicion of MI or difficulty in understanding or explaining the etiology of the acute myocardial injury, additional evaluations and especially imaging studies may be necessary. If they eventually document that the mechanism for cTn increases is related to acute myocardial ischemia, then a diagnosis of MI can be made at that point.

It should be appreciated that those with a diagnosis of either acute or chronic myocardial injury have an adverse prognosis, both short and long term, so that any inferences that such elevations are not important are inappropriate.⁷ It should also be appreciated that those with underlying obstructive coronary artery disease are in general at greater risk.⁸

Figure 1: Model for Clarifying Myocardial Injury and MI

If a diagnosis of MI is appropriate, the fourth Universal Definition of Myocardial Infarction retains the five types of MI as described in the third Universal Definition of Myocardial Infarction, though with modifications.⁶

Type 1

Type 1 MI is due to acute coronary atherothrombotic myocardial injury with either plaque rupture or erosion and, often, associated thrombosis. Most patients with ST-segment elevation MI (STEMI) and many with non-ST-segment elevation MI (NSTEMI) fit into this category. Such patients are benefited by management according to recent guidelines.^9-11

Type 2

Type 2 MI includes patients with evidence of acute myocardial ischemia who do not have acute coronary atherothrombotic injury but instead have oxygen supply-demand imbalance from other reasons. This occurs most often due to the presence of coronary artery disease, which limits increases in coronary perfusion in cases of severe anemia, significant arrhythmias and other stressors. However, the presence of fixed coronary obstruction is not obligatory, including primary coronary causes such as vasospasm, coronary embolus, and coronary artery dissection. All of these can lead to a disparity between oxygen supply and demand in the myocardium. Most of these individuals do not have STEMI but more often have NSTEMI at presentation. Often, the distinction between type 1 and type 2 MIs can be made clinically based on the presentation; however, there are circumstances in which there is ambiguity, at which point imaging studies including angiography and, at times, more sophisticated coronary imaging may be helpful. It should be evident, however, that the complexity and severity of the underlying coronary and/or myocardial disorder are pivotal in determining the ischemic threshold and thus have important prognostic implications.¹¹

Type 3

Type 3 MI continues the concept that there may be an occasional patient who has characteristic symptoms of myocardial ischemia but whose cTn values have not become elevated because the patient succumbs before values are measured or who is stricken by sudden death with evidence of MI by autopsy.

Types 4 and 5

Types 4 and 5 MIs are related to coronary procedural events. The criteria for a procedural MI have, to some extent, remained unchanged from the third Universal Definition of Myocardial Infarction.⁶ However, it is emphasized that an isolated procedural elevation of cTn values is indicative of cardiac procedural myocardial injury that does not alone meet the criteria for percutaneous coronary intervention (PCI)-related type 4a MI or for coronary artery bypass grafting (CABG)-related type 5 MI. These MI categories that are applied within 48 hours of the index procedure include an elevation of cTn values greater than 5 times the 99th percentile URL in the case of PCI and greater than 10 times the indicated URL in the case of CABG, along with evidence of new myocardial ischemia. Ischemia can be recognized by electrocardiogram changes, findings on imaging procedures, or as a result of a procedure-related complication that lead to reduced coronary blood flow. The selection of these biomarker cut-points rests on the assumption that the pre-procedural cTn values have a normal baseline. In patients with elevated pre-procedural values in whom the cTn level are stable (≤20% variation) or falling, the post-procedural values must rise by >20% but still must be more than 5 or 10 times the URL. The literature has questioned the clinical importance of post-PCI elevations when the baseline cTn values are elevated.¹² However, recent data regarding PCI suggest that in case of normal baseline, the fivefold increase of post-procedural high sensitivity cTn values is prognostically important.^13,14 For the sake of completeness, it should be added that the presence of procedure-related stent thrombosis (i.e., type 4b MI) and post-procedural restenosis (i.e., type 4c MI) are diagnosed applying the same criteria utilized for type 1 MI.

The fourth Universal Definition of Myocardial Infarction document takes an opportunity to clarify issues related to MI with non-obstructive coronary arteries and to describe the approaches that may be helpful in patients with heart failure and chronic kidney disease and those undergoing non-cardiac surgery where symptoms and signs are vague. A new section on takotsubo syndrome is also included. Furthermore, clarification has been made concerning the measurement of ST-segment change and the use of left and right bundle branch block as criteria for angiography when possible STEMI is suspected. The document also suggests an accentuated role for imaging in patients when there is diagnostic ambiguity.

The fourth Universal Definition of Myocardial Infarction document is a substantial resource for clinicians and is therefore worth reading for all who care for patients with possible acute MI.

References

1. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). J Am Col Cardiol 2018;72:2231-64.
2. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Circulation 2018;138:e618-e651.
3. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Eur Heart J 2018;Aug 25:[Epub ahead of print].
4. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Glob Heart 2018;Aug 23:[Epub ahead of print].
5. Bjurman C, Larsson M, Johanson P, et al. Small changes in troponin T levels are common in patients with non-ST-segment elevation myocardial infarction and are linked to higher mortality. J Am Coll Cardiol 2013;62:1231-8.
6. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J 2012;33:2551-67.
7. Babuin L, Vasile VC, Rio Perez JA, et al. Elevated cardiac troponin is an independent risk factor for short- and long-term mortality in medical intensive care unit patients. Crit Care Med 2008;36:759-65.
8. Cediel G, Gonzalez-Del-Hoyo M, Carrasquer A, Sanchez R, Boqué C, Bardají A. Outcomes with type 2 myocardial infarction compared with non-ischaemic myocardial injury. Heart 2017;103:616-22.
9. Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119–77.
10. Roffi M, Patrono C, Collet JP, et al. 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). Eur Heart J 2016;37:267-315.
11. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139-e228.
12. Ndrepepa G, Colleran R, Braun S, et al. High-Sensitivity Troponin T and Mortality After Elective Percutaneous Coronary Intervention. J Am Coll Cardiol 2016;68:2259-68.
13. Zeitouni M, Silvain J, Guedeney P, et al. Periprocedural myocardial infarction and injury in elective coronary stenting. Eur Heart J 2018;39:1100-9.
14. Thygesen K, Jaffe AS. The prognostic impact of periprocedural myocardial infarction and injury. Eur Heart J 2018;39:1110–12.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), EP Basic Science, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Coronary Artery Disease, Myocardial Infarction, Takotsubo Cardiomyopathy, Bundle-Branch Block, Prognosis, Percutaneous Coronary Intervention, Coronary Artery Bypass, Myocardial Ischemia, Myocardium, Heart Failure, Renal Insufficiency, Chronic, Biomarkers, Coronary Angiography, Troponin, Anemia, Electrocardiography, Diabetes Mellitus, Type 2, Stents

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