Analytic characteristics of biomarkers used in the universal definition of myocardial infarction

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Clinical implications of the third universal definition of myocardial infarction

Clinical implications of the third universal definition of myocardial infarction
1Harvey White Dsc,&Nbsp;2Kristian Thygesen Md,&Nbsp;3Joseph S. Alpert Md,&Nbsp;4Allan Jaffe Md
1Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
2Department of Cardiology, Aarhus University Hospital, Denmark
3Department of Medicine, Univ. of Arizona College of Medicine, Tucson, USA
4Cardiovascular Division, Department of Medicine, Laboratory Medicine and Pathology, Mayo Clinic and Medical School, Rochester, Minnesota, USA

Introduction

The definition of myocardial infarction (MI) continues to evolve as refined ECG criteria, better imaging and more sensitive and specific biomarkers are developed. The definition needs to be accepted globally and to be relevant to clinical practice. With the evolution of diagnostic tools there has been a need for an update to the Universal Definition of MI published in 2007. (¹)The new definition ⁽²⁾ stresses the importance of a careful clinical history (>20 minutes of ischemic symptoms including ischemic surrogates), and careful interpretation of the ECG and imaging [Table 1].

The ECG findings of circumflex artery ischaemia is stressed as these are often overlooked ⁽³⁾ with the recommendation to record leads V₇, V₈ and V₉ in patients with a high clinical suspicion of acute circumflex coronary occlusion (ST depression in V₁-V₃ or non diagnostic ECG with symptoms of ischemia) for which acute reperfusion therapy is indicated. A cutpoint of 0.05mV elevation is recommended.

Imaging has a new emphasis with imaging evidence of new loss of viable myocardium, a new regional wall motion abnormality, or the identification of intracoronary thrombus by angiography in a setting of clinical ischaemia and a rise and/or fall of troponins fulfilling the criteria for the diagnosis of MI.

Myocardial injury, necrosis and infarction

The Concise Oxford Dictionary defines Injury as physical harm or damage, necrosis as death of tissue caused by disease or injury and infarction as dead tissue caused by an inadequate blood supply.
The 3^rd Universal Definition document carefully defines myocardial injury and states:

“Small amounts of myocardial injury with necrosis may be detected which are associated with heart failure, renal failure, myocarditis, arrhythmias, pulmonary embolism or otherwise uneventful percutaneous or surgical coronary procedures. These should not be labelled as MI or a complication of the procedures, but rather as myocardial injury”

and
“It is recognized that the complexity of clinical circumstances may sometimes render it difficult to determine where individual cases my lie (with respect to myocardial injury vs. myocardial infarction).”
Acute myocardial infarction (AMI) is defined as myocardial cell death due to prolonged myocardial ischemia.

Troponins are recommended as the preferred biomarkers for the detection of MI. There should be a rise and/or fall of cardiac troponin (I or T) with at least one value above the 99^th percentile of the upper reference limit (URL) measured with a coefficient of variation ≤10%.⁴When cardiac troponins are not available CKMB mass is acceptable with detection of rise and/or fall with at least one value above the 99^th percentile of the URL measured with a coefficient of variation ≤10%.

Elevations of cardiac troponin because of myocardial injury may occur in four settings [Table 3]:

1.   Injury related to primary myocardial ischemia (MI type 1) with plaque rupture or fissuring and intracranial coronary artery thrombus formation
2.   Injury related to supply/demand imbalance of myocardial ischemia (MI type 2)
3.   Injury not related to myocardial ischemia
4.   Multifactorial or indeterminate myocardial injury

The new definition also uses a typing system with 5 types based on pathological, clinical and prognostic differences along with different treatment strategies [Table 2]. This has proven to be very useful in clinical practice and in trials.

Distinguishing between type 2 and type 1 myocardial infarction

Differentiation between type 2 and type 1 infarction is challenging and requires very careful clinical assessment and judgement. Determination had to be made as to whether the myocardial injury was due to plaque rupture. In addition it needs to be ascertained as to whether the myocardial injury was due to some other process such as sepsis or an imbalance in myocardial oxygen supply or demand (type 2). The distinction is important as the approaches to investigation and management may differ. If it is a type 1 MI then management mandates (in the absence of major contraindications or patient preferences) antithrombotic therapy, angiography and revascularization as appropriate. Whereas if a patient becomes hypotensive after a hysterectomy and develops ischaemic symptoms with ischaemic ECG changes and a rise in troponins, the management is to treat the underlying cause e.g. transfusion for blood loss and a test for inducible ischaemia when appropriate. The need for angiography is then based on the results of the test for inducible ischaemia.
Similarly a patient with known advanced 3 vessel coronary artery disease which is not suitable for revascularization who develops an MI after prostrate surgery may be best treated medically with beta-blockers and nitrates.
However it is often very difficult to distinguish between type 1 and type 2 [Figure 2] without performing angiography which may define plaque rupture with thrombus formation. It is recommended to document that the MI was a type 2 and the pathobiological mechanism leading to the event e.g.: type 2 MI secondary to hypotension and anaemia secondary to blood loss at surgery.
Some patients may have ischemia due to dysfunctional coronary vasomotion, be it a response to a variety of provocative stimuli or a direct problem of transient spasm.

Myocardial Infarction type 4a – percutaneous coronary intervention related MI

The implications for clinical practice of the previous definition of a type 4 MI has been controversial as new data have been published challenging the idea that type 4 MIs (percutaneous coronary intervention (PCI) related MI) are prognostically important. ^(5-8) The 2007 Universal Definition required 3 times elevation of biomarkers with troponins performed. This resulted in large numbers of patients being defined as having had a procedure-related MI and the definition was not embraced by the international and interventional community.
PCI-related MI is defined by elevation of cardiac troponin values >5 X 99^th percentile URL (previously 3X) if the baseline value is normal (<99^th percentile URL). If the baseline is elevated and could be rising, it is impossible to distinguish injury due to a procedure from that of the initial presenting problem. If the baseline value is elevated but declining or stable in serial samples, a 20% increase in values is required. In addition, either (i) symptoms suggestive of myocardial ischemia or (ii) new ischaemic ECG changes or (iii) angiographic findings consistent with a procedural complication or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality
If cardiac troponin values are not elevated >5 X 99^th percentile URL from a normal baseline value or 20% from a stable or declining baseline, then the term myocardial injury should be used. When values are rising, it is impossible to distinguish PCI related injury from that of the initial insult that led to the need for intervention.
The increase from 3X to 5 X 99^th percentile URL and the addition of ischaemic features and or angiographic complications was arbitrarily chosen based on consensus opinion, and on clinical judgment and societal implications of the label of peri-procedural MI. Other factors considered were the lack of convincing data that elevations of 3 X 99^th percentile are prognostically important ⁽⁵⁾ and also consideration was given to making the definition more symmetric with the coronary artery bypass grafting (CABG) definition which requires more than just troponin elevations.
MI related to stent-thrombosis (MI type 4b) is defined by coronary angiography and/or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarkers with at least one value >99^th percentile URL.

Myocardial Infarction type 5 – coronary artery bypass grafting related MI
CABG related MI is defined by elevation of cardiac troponin values >10 X 99^th percentile URL (previously 5X). This choice of cutpoint is arbitrary. In addition, either (i) new pathological Q waves or new left bundle branch block (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.
If cardiac troponin values are not elevated >10 X 99^th percentile URL, then the term myocardial injury should be used.
Potential mechanisms of causes of troponin elevation
There are various potential mechanisms that may cause troponin elevation other than myocyte necrosis [Table 4]. ⁽⁹⁾ Impaired renal excretion, is not thought to cause troponin elevations.
Application of 3^rd Universal Definition of MI in clinical trials
It will be useful in clinical trials to include only patients who may benefit from a potential therapy e.g.: an antithrombotic therapy impacting on plaque rupture, and to include only patients who have had a previous type 1 MI. The effects of the therapy can also be determined on each of the types of MI as was shown in the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) trial. ⁽¹⁰⁾

A new category of MI type 4c has been created for the not uncommon situation where a patient presents with an MI (rise and/or fall in troponin values in the setting of ischaemia) with ECG changes in the territory of previous setting and the only angiographic finding on angiography is restenosis ≥50% following previous successful stent deployment or balloon angioplasty. This designation will be very useful for adjudication committees in clinical trials where an event is clearly not a type 1 MI (plaque rupture in a native coronary artery segment) nor is it a type 4b MI related to stent thrombosis.

Global implications

The rates of cardiovascular events are exploding worldwide and a standardized definition will be useful for epidemiological comparisons. It is recognised that in countries with limited economic resources that biomarkers and imaging modalities (and sometimes ECGs) may not be available and hence more flexible standards are required. ⁽¹¹⁾

The new 2012 definition has important changes which have been achieved by consensus. It is hoped that the new definition will be embraced worldwide and be used to improve patient care.

References

Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Eur Heart J 2007;28:2525-2538.
Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J 2012;Epub ahead of print:
Wong CK, White HD. Patients with circumflex occlusions miss out on reperfusion: How to recognize and manage them. Curr Opin Cardiol 2012;327-330.
Jaffe AS, Apple FS, Morrow DA, Lindahl B, Katus HA. Being rational about (Im)precision: A statement from the Biochemistry Subcommittee of the Joint European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/planet Heart Federation Tas force for the Definition of myocardial infarction. Clin Chem 2010 Jun; 56(6):941-943.
Damman P, Wallentin L, Fox KA, et al. Long-term cardiovascular mortality after procedure-related or spontaneous myocardial infarction in patients with non-ST-segment elevation acute coronary syndrome: a collaborative analysis of individual patient data from the FRISC II, ICTUS, and RITA-3 trials (FIR). Circulation 2012;125:568-576.
Jaffe AS, Apple FS, Lindahl B, et al. Why all the struggle about CK-MB and PCI? Eur Heart J 2012;33:1046-1048.
Miller WL, Garratt KN, Burritt MF, et al. Baseline troponin level: key to understanding the importance of post-PCI troponin elevations. Eur Heart J 2006;27:1061-1069.
Gustavsson CG, Hansen O, Frennby B. Troponin must be measured before and after PCI to diagnose procedure-related myocardial injury. Scand Cardiovasc J 2004;38:75-79.
White HD. Pathobiology of troponin elevations: do elevations occur with myocardial ischemia as well as necrosis? J Am Coll Cardiol 2011;57:2406-2408.
Morrow DA, Wiviott SD, White HD, et al. Effect of the Novel Thienopyridine Prasugrel Compared With Clopidogrel on Spontaneous and Procedural Myocardial Infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation 2009;119:2758-2764.
Mendis S, Thygesen K, Kuulasmaa K, et al. World Health Organization definition of myocardial infarction: 2008-09 revision. Int J Epidemiol 2011;40:139-146.

Various clinical entities that can be associated with myocardial injury with cell death and troponin elevation. If this occurs in the setting of clinical ischaemia with rise and/or fall of troponins the diagnosis becomes myocardial infarction. ⁽²⁾

Figure 2

Differentiation between myocardial infarction (MI) types 1 and 2 according to the condition of the coronary arteries. ⁽²⁾

Table 1: ECG manifestations of acute myocardial ischemia (in absence of LVH and LBBB) ⁽²⁾ [Request permission – Thygesen et al. EHJ 2012 – Table 3]

ST elevation

New ST elevation at the J point in two contiguous leads with the cut-points:

≥0.1 mV in all leads other than leads V₂–V₃ where the following cut-points apply: ≥0.2 mV in men ≥40 years; ≥0.25 mV in men

ST depression and T wave changes

New horizontal or down-sloping ST depression ≥0.05 mV in two contiguous leads and/or T inversion ≥0.1 mV in two contiguous leads with prominent R wave or R/S ratio >1.

Table 2: Universal classification of Myocardial Infarction ⁽²⁾ [Request permission – Thygesen et al. EHJ. 2012 – Table 2]

Type 1: Spontaneous myocardial infarction

Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, Assuring, 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 related to percutaneous coronary intervention (PCI)

Myocardial infarction associated with PCI is arbitrarily defined by elevation of cTn values >5 x 99th percentile URL in patients with normal baseline 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 x 99th percentile URL in patients with normal baseline cTn values (

Table 3: Injury related to supply/demand imbalance of myocardial ischemia ⁽²⁾ [Request permission – Thygesen et al. EHJ. 2012 – Table 1]

Injury related to supply/demand imbalance of myocardial ischemia

Tachy-/brady-arrhythmias

Aortic dissection or severe aortic valve disease

Hypertrophic cardiomyopathy

Cardiogenic, hypovolemic, or septic shock

Severe respiratory failure

Severe anemia

Hypertension with or without LVH

Coronary spasm

Coronary embolism or vasculitis

Coronary endothelial dysfunction without significant CAD

Injury not related to myocardial ischaemia

Cardiac contusion, surgery, ablation, pacing or defibrillator shocks

Rhabdomyolysis with cardiac involvement

Myocarditis

Cardiotoxic agents, e.g., anthracyclines, herceptin

Multifactorial or indeterminate myocardial injury

Heart failure

Stress (Takotsubo) cardiomyopathy

Severe pulmonary embolism or pulmonary hypertension

Sepsis and critically ill patients

Renal failure

Severe acute neurological diseases, e.g., stroke, subarachnoid haemorrhage

Infiltrative diseases, e.g., amyloidosis, sarcoidosis

Strenuous exercise

Table 4: Pathobiological classification of types of mechanisms causing troponin elevations ⁽⁸⁾ [Request permission – White. JACC. 2011: 57: 2406 – Table 1]

Type 1.	Myocyte necrosis
Type 2.	Apoptosis
Type 3.	Normal myocyte turnover
Type 4.	Cellular release of proteolytic troponin degradation products
Type 5.	Increased cellular wall permeability
Type 6.	Formation and release of membranous blebs

Figure 1 – [Request permission – Thygesen et al. EHJ. 2012 – Fig 1]