The Third Universal Definition of Myocardial Infarction: Clinical Insights &...

Updated:Jun 18,2014

The Third Universal Definition of Myocardial Infarction: Clinical Insights and Implications

Disclosure: Dr. Jneid has nothing to disclose.
Pub Date: Saturday, Aug. 25, 2012
Author: Hani Jneid, MD, FACC, FAHA, FSCAI
Affiliation: Baylor College of Medicine
                    The Michael E. DeBakey VA Medical Center
 
 

Citation

Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD; the Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Circulation. 2012: published online before print August 25, 2012, 10.1161/CIR.0b013e31826e1058.
http://circ.ahajournals.org/lookup/doi/10.1161/CIR.0b013e31826e1058

Article Text

The multinational third global MI Task Force recently was tasked with updating the universal definition of myocardial infarction (MI). Under the auspices of the European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the World Heart Federation, the Task Force published the Third Universal Definition of MI expert consensus document.1 This document contained scientifically robust, concise and clear definitions and classification of MI that are suitable to different clinical scenarios and can be easily adopted by the medical community. I hereby present a critical review of this important document and summarize a few of its important recommendations.

Historical Perspective

In 1971, the WHO issued a standardized definition of MI using criteria based on epidemiological principles. The WHO criteria lacked in specificity, were open to biased interpretation, and did not incorporate biomarkers. At the time, the biomarker assays of myocardial necrosis were nonspecific and not highly reproducible. To improve the clinical accuracy of MI diagnosis, multinational task forces met repeatedly in order to develop a simple, clinically oriented, and reproducible universal definition of MI for use in daily practice and clinical investigation. This resulted in the publication of the first universal definition of myocardial infarction2 and its subsequent revision in 2007.3

With the emergence of cardiac troponin T (cTn T) in the late 1980s and troponin I (cTn I) in the early 1990s, the measurement of these biomarkers became central to the universal definition of MI2 and its subsequent updates.1,3 In 2000, the First Global MI Task Force presented a new definition of MI, which implied that any necrosis in the setting of myocardial ischemia should be labeled as MI. It also added qualifications to characterize the MI (infarct size; circumstances leading to the infarct - e.g., spontaneous or procedure related; and timing of myocardial necrosis – e.g., evolving, healing, or MI).2 The Second Global MI Task Force, leading to the 2007 Universal Definition of MI, emphasized the different conditions that lead to an MI and provided a universal classification of MI (types 1 through 5).3 Given the development of more sensitive assays for markers of myocardial necrosis, revision of the definitions for myocardial necrosis, particularly in the setting of critical illness and after revascularization, prompted the publication of the Third Universal Definition of MI.1

The Third Universal Definition of Myocardial Infarction

The hallmark of the Third Universal Definition of MI1 is the detection of a rise and/or fall of cardiac biomarker values, with at least one of the values being elevated (i.e., > 99th percentile upper reference limit, URL).1 The preferred cardiac biomarker of necrosis is the highly sensitive and specific cTn. In addition, at least one of the five following diagnostic criteria should be met:

  1. Symptoms of ischemia
  2. New (or presumably new) significant ST/T wave changes or left bundle-branch block (LBBB)
  3. Development of pathological Q waves on ECG
  4. Imaging evidence of new loss of viable myocardium or regional wall motion abnormality
  5. Identification of intracoronary thrombus by angiography or autopsy

While this definition is comparable to that of the 2007 Task Force,3 the fifth criterion is an added diagnostic measure,1 and recognizes the diagnostic utility of angiography and autopsy. Overall, similar to the prior definition, the third definition remains comprehensive and incorporates a number of different clinical, electrocardiographic, biochemical, imaging, and pathological characteristics.

In addition, the third global MI Task Force updated the universal classification of MI with few notable modifications. The universal classification of MI complements the initial ECG classification of MI (as STEMI vs. non-STEMI), which should still be used clinically upfront to dictate immediate reperfusion strategy. In the third universal classification of MI, MI types 1 and 2 represent spontaneous MI (induced by plaque rupture, erosion, fissuring - with overlying coronary thrombosis) and MI induced by demand-supply imbalance in myocardial ischemia, respectively. Type 3 is MI resulting in cardiac death, while types 4 and 5 are PCI- and CABG-related MI.

The third global MI Task Force reinforced the notion that ECG is an integral part of the diagnostic work-up of patients with suspected MI and should be timely acquired and interpreted.1 Serial ECG recordings to detect dynamic changes were advocated. The third global MI Task Force1 adopted similar ECG criteria as the 2007 expert consensus document for the diagnosis of acute myocardial injury/ischemia and prior MI (criteria pertaining to the ST-segment shift and Q waves/QS complexes, respectively). The 2012 Task Force also summarized the ECG abnormalities that can mimic myocardial ischemia or MI (LBBB, pre-excitation, early repolarization, etc.).1 In addition, the 2012 Task Force recognized the increasing capabilities of imaging techniques to assess myocardial perfusion, viability, myocardial thickness, thickening and motion, and fibrosis (all of which help in the diagnosis and characterization of MI), and included brief discussions on the utility of different imaging modalities.1 

The Central Role of Cardiac Troponin Biomarkers

Troponins are part of the contractile apparatus of the myocyte, and myocardial necrosis is accompanied by the release of these structural proteins into the cardiac interstitium and the circulation as a consequence of compromise of the integrity of the myocyte cellular membranes. cTnI and cTnT have isoforms that are unique to cardiac myocytes and may be measured by assays employing monoclonal antibodies specific to epitopes of the cardiac form. Their advantage over other biomarkers of necrosis has been firmly established in clinical studies, and their use was associated with fewer false-positive results in the setting of concomitant skeletal muscle injury. cTn assays also provide superior discrimination of myocardial injury when CK-MB levels are normal or minimally increased. Moreover, the association between an increased concentration of cardiac troponin and a higher risk of recurrent cardiac events in patients with normal CK-MB levels has further confirmed the clinical relevance of detecting circulating cTn.4 CK-MB constitutes 1% to 3% of the CK in skeletal muscle, and is present in minor quantities in intestine, diaphragm, uterus, and prostate. Therefore, the specificity of CK-MB may be impaired in the setting of major injury to these organs, especially skeletal muscle.

cTn elevation indicates myocardial injury, but does not identify the underlying pathophysiology. Myocardial necrosis related to ischemia is designated as MI, but it is important to note that several mechanisms underlying myocardial injury and cTn elevation exist, as outlined by the 2012 global MI Task Force1:

I. injury related to primary myocardial ischemia (plaque rupture/erosion/fissuring with superimposed thrombus formation)
II. injury related to supply-demand ischemia imbalance (vasospasm, tachyarrhythmias, severe anemia, hypotension, etc.)
III. injury unrelated to ischemia (myocarditis, cardiac contusion, cardiotoxic agents, etc.)
IV. multifactorial or indeterminant injury (heart failure, renal failure, stress cardiomyopathy, etc.)

A cTn value exceeding the 99th percentile URL (in ng/L or pg/mL) is considered elevated, and is the decision level for the diagnosis of MI. This cutoff should be determined for each specific assay in each laboratory and should be characterized by an optimal precision, described by a coefficient of variation (CV) ≤ 10%. Blood samples for the measurement of cTn should be drawn serially (on initial assessment and 3–6 h later, when further ischemic episodes occur, or when the timing of the initial symptoms is unclear). To establish the diagnosis of MI, a rise and/or fall in values with at least one value above the decision level is required, coupled with a strong clinical suspicion.

The third Global Task Force1 de-emphasized the use of other cardiac biomarkers, and indicated that CK-MB (measured by mass assay) may be used as an alternative to the cTn assay, when the latter is not available for MI decision. Other biomarkers (including total CK, CK-MB activity, lactate dehydrogenase, aspartate aminotransferase, etc.) were not mentioned in the third Universal Definition of MI document,1 and there is consensus among experts that they are largely historical and should no longer be used to diagnose MI.5

MI Related to PCI

The third global MI Task Force defined PCI-related MI (type 4a) by an elevation of cTn values > 5 x 99th percentile URL occurring within 48 h of the procedure (in patients with normal baseline values).1 This is a departure from the 2007 definition,3 which used a cutoff of cardiac biomarkers of > 3 x 99th percentile URL. In addition, the 2012 Task Force1 characterized PCI-related MI in patients with elevated (but stable or falling) baseline values using a cutoff rise of cTn values > 20%. This added criterion is especially important with the recognition that a sizeable proportion of patients with stable CAD (up to 6%) had elevated pre-PCI cTn levels, which appears to independently predict increased ischemic complications.6 The new cTn cutoff was arbitrarily defined, and should be associated with one of the following for an event to be labeled as a PCI-related MI:

I. symptoms of myocardial ischemia
II. new ischemic ECG changes
III. angiographic findings consistent with a procedural complication
IV. imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality.

Therefore, the 2012 Task Force is using higher thresholds of biomarkers and more stringent criteria for revascularization-related MI. This reflects the recognition that very small amounts of myocardial injury can occur and be detected by very sensitive biochemical markers and/or imaging tools, but that not all of them necessarily constitute revascularization-related MIs. Using the 2007 definition (> 3 x the 99th percentile URL), ≥ 15% of patients undergoing PCI would be defined as having a PCI-related MI.7,8 This has widespread implications in the interventional cardiology community, especially with the increased performance of complex and aggressive multi-vessel coronary interventions.

The ACCF/AHA 2011 PCI guideline still maintained that CK-MB and cTn should be measured in patients with signs or symptoms of peri-procedural MI or in asymptomatic patients with significant persistent angiographic complications (class IC). 9 The ACCF/AHA 2011 PCI guideline adopted the 2007 universal definition of MI, and emphasized that the usefulness of routine measurement of biomarkers in all patients undergoing PCI is not well established (class IIb C).9

An important addition to the classification of MI is the new MI subcategory type 4c, which is PCI-related MI occurring in the setting of restenosis.1 This reflects the increasingly recognized notion that restenosis following PCI is not a benign entity and may be associated with MI in up to 10% of patients.10,11 In the third universal definition of MI,1 type 4c MI is characterized by a rise and/or fall of cTn values in patients with ≥ 50% stenosis at coronary angiography (or a complex lesion) in the absence of more obstructive CAD following initially successful stenting or balloon angioplasty. MI associated with stent thrombosis remains an important subcategory (type 4b) in the current classification of MI.1

MI Related to CABG

CABG-related MI was redefined by the 2012 Task Force1 using an arbitrarily defined cutoff of an elevation of cardiac biomarker > 10 x 99th percentile URL during the first 48 h following CABG (in patients with normal baseline cTn values). CABG-related MI should also satisfy one of the following additional diagnostic criteria: (i) new pathological Q waves or LBBB, or (ii) angiographically-documented new graft or native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. The 2012 global MI Task Force1 emphasized that the aforementioned threshold is more robust for isolated on-pump CABG. Cardiac biomarker release is, however, considerably higher after valve replacement with CABG than with CABG alone, and with on- vs. off-pump CABG.

According to the 2011 ACCF/AHA CABG guideline, the measurement of biomarkers of myonecrosis (e.g., CK-MB, troponin) is reasonable in the first 24 hours after CABG.12 The 2011 ACCF/AHA CABG guideline emphasized that cTn is the optimal indicator of myonecrosis (in preference to CK-MB). 

Reinfarction vs. Recurrent MI

In accordance with the 2008-2009 revision of the WHO definition of MI,13 the third global MI Task Force differentiated between recurrent MI and reinfarction.1 The term reinfarction is used for an acute MI occurring within 28 days of an incident or recurrent MI. The 2012 Task Force1 did not recommend CK-MB measurements in these patients but rather serial cTn measurements, with the reinfarction diagnosis established when ≥ 20% increase in cTn values is observed in the repeated measurement. On the other hand, if characteristics of MI occur after 28 days following an incident MI, it is considered to be a recurrent MI. Incident MI is defined as the individual’s first MI. The aforementioned definitions have important implications on the adjudication of outcomes in clinical research studies.
 
Additional Considerations

The 2012 Task Force1 included new sections pertinent to myocardial injury and MI in patients undergoing cardiac and non-cardiac procedures, in the critically-ill patients, and in patients with HF.

The third global MI Task Force1 reiterated that some cardiac procedures may be associated with injury, including transcatheter aortic valve implantation (TAVI) or mitral clip, through direct trauma or regional ischemia. For TAVI-related MI, they advocated using the same criteria of CABG-related MI, despite the lack of supporting evidence. They also cautioned against mislabeling myocardial necrosis associated with the ablation of arrhythmias as MI. The 2012 Task Force1 also recommended the routine monitoring of cardiac biomarkers in high-risk patients, both prior to and 48–72 h after major non-cardiac surgery. Although they did not define what constitutes a major non-cardiac surgery, vascular surgery (aortic/peripheral vascular surgery, with reported peri-operative cardiac risk > 5%) is usually considered a high-risk or major surgery according to the 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care.14

cTn elevations are also common in patients in the intensive care unit and are associated with adverse prognosis, regardless of the underlying pathophysiology. They can occur as a result of demand-supply ischemic imbalance (type 2), as a direct ischemia-unrelated injury, and sometimes as a manifestation of type 1 MI. Clinical judgment as to the timing and extent of evaluation of CAD after patient recovery should be exercised. The 2012 Task Force1 also emphasized that measurable cTn concentrations are present in nearly all patients with HF, with significant percentage exceeding the 99th percentile URL (as in severe or acutely decompensated HF). They recognized that MI type 1 is an important cause of acutely decompensated HF, but that other causes exist, including MI type 2, apoptosis secondary to excessive wall stretch, direct cellular toxicity (e.g., inflammation, circulating neurohormones), etc. Irrespective of its associated pathobiology, the magnitude and persistence of cTn elevation in HF is an independent predictor of adverse outcomes in both acute and chronic HF patients. 

Implications and Conclusions    

MI remains a major cause of death and disability worldwide. Each year, an estimated 785,000 persons will have a new MI in the United States alone, and approximately 470,000 patients will have a recurrent MI.15 Approximately every 25 seconds, an American will have a MI, and approximately every minute, someone will die of one.15 MI is an important outcome measure in research studies. The prevalence of MI also provides useful data regarding the burden of CAD, and can provide insights into health care planning and policy and resource allocation. The importance of accurately and reproducibly defining MI as an outcome measure is self-evident. All in all, the 2012 third global MI Task Force1 did excellent work incorporating  patient symptoms, ECG changes, the highly sensitive cTn biochemical markers, and information gleaned from various imaging techniques into comprehensive, clinically oriented, and reproducible definitions of MI.  

References

  1. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. European Heart Journal 2012.
  2. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined--a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959-69.
  3. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 2007;116:2634-53.
  4. Kontos MC, de Lemos JA, Ou FS, et al. Troponin-positive, MB-negative patients with non-ST-elevation myocardial infarction: An undertreated but high-risk patient group: Results from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network-Get With The Guidelines (NCDR ACTION-GWTG) Registry. Am Heart J 2010;160:819-25.
  5. Morrow DA, Cannon CP, Jesse RL, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical characteristics and utilization of biochemical markers in acute coronary syndromes. Circulation 2007;115:e356-75.
  6. Jeremias A, Kleiman NS, Nassif D, et al. Prevalence and prognostic significance of preprocedural cardiac troponin elevation among patients with stable coronary artery disease undergoing percutaneous coronary intervention: results from the evaluation of drug eluting stents and ischemic events registry. Circulation 2008;118:632-8.
  7. Testa L, Van Gaal WJ, Biondi Zoccai GG, et al. Myocardial infarction after percutaneous coronary intervention: a meta-analysis of troponin elevation applying the new universal definition. QJM 2009;102:369-78.
  8. Alcock RF, Roy P, Adorini K, et al. Incidence and determinants of myocardial infarction following percutaneous coronary interventions according to the revised Joint Task Force definition of troponin T elevation. Int J Cardiol 2010;140:66-72.
  9. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011;124:e574-651.
  10. Chen MS, John JM, Chew DP, Lee DS, Ellis SG, Bhatt DL. Bare metal stent restenosis is not a benign clinical entity. Am Heart J 2006;151:1260-4.
  11. Lee MS, Pessegueiro A, Zimmer R, Jurewitz D, Tobis J. Clinical presentation of patients with in-stent restenosis in the drug-eluting stent era. J Invasive Cardiol 2008;20:401-3.
  12. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:e652-735.
  13. Mendis S, Thygesen K, Kuulasmaa K, et al. World Health Organization definition of myocardial infarction: 2008-09 revision. Int J Epidemiol 2011;40:139-46.
  14. Fleisher LA, Beckman JA, Brown KA, et al. 2009 ACCF/AHA focused update on perioperative beta blockade incorporated into the ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation 2009;120:e169-276.
  15. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation 2012;125:e2-e220.


-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --

AHA Scientific Journals

AHA Scientific Journals


Connect with AHA Science News

Follow AHAScience on Twitter (opens in new window)
Like AHA Science News on Facebook (opens in new window)

Commentaries View All

Science News View All