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Clinical Biochemistry
Volume 46, Issues
1
–
2
, January
2013, Pages 1
–
4
Third Universal Definition of
Myocardial Infarction
?
Allan S.
Jaffe
,
Introduction
The Third
Universal Definition of Myocardial Infarction (MI)
was recently published
conjointly by
the major cardiology organizations throughout the
world and in the
journals of the World
Health Organization (WHO). This definition builds
on two
previous two iterations which
were developed to make the diagnosis of myocardial
infarction (MI) more consistent.
The efforts started originally in 1999
in the conference in Nice stimulated by the
innovation of Dr. Kristian Thygesen and
Dr. Joseph Albert who had recognized this
problem and who developed a task force
jointly sponsored by the ACC (American
College of Cardiology) and the ESC
(European Society of Cardiology) to attempt to
standardize the definition of MI
[1]
. This major step led to
the first document which
moved the
field from the epidemiologically oriented
definition of MI which had been
developed by the WHO to track the
incidence of coronary disease and therefore was
oriented towards specificity to a more
clinically oriented definition which relied on
biomarkers as a key feature of the
diagnosis. This resulted in a paradigm shift where
the diagnosis required documentation of
myocardial necrosis with biomarkers and
especially cardiac troponin (cTn) which
was emerging at the time in the proper
clinical situation. A second iteration
in 2007
[2]
updated the
guidelines and the 2012
definition
refines the definition still further particularly
as it relates to biomarkers
[3]
which have in
the past decade become progressively more and more
sensitive.
Intrinsically, increases in
sensitivity of this sort tend to result in a
diminution of
specificity since
increasingly sensitive measurements often unmask
new etiologies
for in this instance,
elevations of these sensitive cTn biomarkers.
Areas of the 2012 definition that
remains
important but unchanged
The definition of MI from the
pathologic circumstance obviously is not going to
change. The definition mandates the
finding of cardiomyocyte necrosis defined
pathologically due to myocardial
ischemia. However, the clinical definition since
pathology is not readily available to
guide clinical care relies on a surrogate marker
for cardiac injury; i.e., cardiac
biomarkers and particularly, cTn. As in previous
iterations, cTn is the biomarker of
choice and strongly preferred for the overall
guidelines as well as for each specific
guideline. The definition of MI from the clinical
perspective has not changed
substantively. It requires detection of a rise
and/or a
fall of a cardiac biomarker,
preferably cTn, with at least one value above the
99th
percentile reference limit in the
appropriate clinical setting (see
Table
1
for criteria).
There are additional types of MI which
will be covered subsequently but the
guidelines rely heavily on clinical
signs or symptoms, a clinical situation where
ischemia is suspected even if signs and
symptoms are absent or imaging information
suggestive of ischemia in the presence
of a changing pattern of elevated biomarkers.
Table
1.
Criteria for acute myocardial
infarction (Third Universal Definition of
Myocardial
Infarction).
?
Detection of a rise and/or
a fall of cardiac biomarker values
(preferably
cardiac
troponin
(cTn))
with
at
least
one
value
above
the
99th
percentile
upper
reference
limit
(URL)
and
at
least
one
of
the
following:
?
Ischemic
symptoms
?
ECG
changes of new ischemia (new
ST
–
T changes or new
LBBB)
?
Development of pathologic Q waves in the
ECG
?
Imaging
evidence
of
new
loss
of
viable
myocardium
or
new
regional
wall
motion abnormality
?
Identification
of
an
intracoronary
thrombus
by
angiography
or
autopsy
Full-size
table
Table
options
The metrics for the
use of these biomarkers remain the same. One needs
a value
above the 99th percentile of
the upper reference limit with a rising and/or a
falling
pattern of values. However, as
cTn assay sensitivity has improved, the ability to
consistently operationalize these
criteria has become more problematic as will be
discussed below. The document also
recognizes a variety of special clinical
circumstances which require unique
handling. Some of these are related to cardiac
procedures such as percutaneous
interventions (PCI) or coronary artery bypass
graft
(CABG) surgery but others to
novel procedures that are being developed such as
transcutaneous aortic valve
interventions (TAVI). The document discusses as
well
subsets of patients who are
critically ill, those with heart failure, and
those
undergoing non-cardiac surgery as
well. These classifications are not new from the
2007 document but are considered in
greater detail.
Issues related to
biomarkers
As in the past, cTn is the
marker of choice and a rise and/or a fall in
values is
necessary to define an acute
event such as MI. It is recognized that there is
some
tension about how one defines the
99th percentile. It is assay dependent and is
often defined based on convenience
samples. Therefore, there is concern that
perhaps they are not as reliable as if
the sample populations were more intensively
studied
[4]
. The
values for these assays should be expressed in
ng/L so that they are
whole numbers
because as assays become more complicated and more
sensitive,
the number of zeros could
lead to clinical dysfunction. The assays should be
precise
and the document prefers assays
that have excellent precision with a CV of 10% or
less of the 99th percentile to allow
detection of changing values. However, the
document allows for assays with CVs up
to 20% to be used
[5]
. It
also is noted that
analytic and pre-
analytic problems can be problematic and lead to
false-positive and
false-negative
values especially with more sensitive assays. It
is also recommended
that sex dependent
values may be used with high sensitivity assays.
Sampling should be done at 0, 3, and 6
h and later if additional episodes occur or if
the timing of the initial symptoms is
unclear. The diagnosis requires a rising and a
falling pattern which is essential to
differentiate elevations that are acute from those
that are chronic and associated with
structural heart disease such as patients with
renal failure, heart failure, left
ventricular hypertrophy, and the like. It is
recognized
that one needs to be careful
because at times one could present sufficiently
late as
to miss an elevated value or
could be near the time of peak values at which
point in
time one could believe that a
change had not occurred when simply the values
were
similar on both sides of the peak.
It is recognized and allowed that there
may be circumstances in which cardiac injury
could be present but not meet the
diagnosis of MI because it is not in the
appropriate setting or does not
manifest a rise and a fall and there are a large
number of such situations in which a
diagnosis of cardiac injury may be more
appropriate than the diagnosis of acute
MI (see
Table
2
).
Table
2.
Elevations of cardiac troponin values
because of myocardial injury (Third Universal
Definition of Myocardial Infarction).
?
Injury related
to primary myocardial ischemia (MI type 1; i.e.,
plague rupture, intraluminal coronary
artery thrombus formation)
?
Injury related to
supply/demand imbalance of myocardial ischemia (MI
type2;i.e., tachy-/brady-arrhythmias,
aortic dissection, or severe
aortic
valve
disease,
hypertrophic
cardiomyopathy,
cardiogenic
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 ischemia (i.e., cardiac contusion,
surgery, ablation, pacing,
defibrillator shocks, rhabdomyolysis with
cardiac involvement, myocarditis,
cardiotoxic agents)
?
Multifactorial or
indeterminate myocardial injury (i.e., heart
failure,
stress
(takotsubo)
cardiomyopathy,
severe
pulmonary
embolism
or
pulmonary hypertension, sepsis and
critically ill patients, renal
failure,
severe
acute
neurological
(e.g.,
stroke)
infiltrative
diseases
(e.g.,
amyloidosis), strenuous exercise)
Operationalizing change in cTn values
is complex and assay dependent. It should be
clear that given previous ways of
diagnosing infarction have often not required
changes over time that as one starts to
implement these changes, one will have
differences in both sensitivity and
specificity
[6]
. In fact,
most of the data in this area
suggests
that the use of delta change criteria improves
specificity but at the cost of
sensitivity. There are multiple reasons
why this could be the case. The first is that it
may be that there are patients being
diagnosed with acute infarction who do not
have a rising and a falling pattern
based on clinical judgment since one can have
acute looking plaques even in patients
with stable coronary artery disease
[7]
. A
second
potential issue relates to the situation where
there is variation in coronary
artery
perfusion. Biomarker release is flow dependent and
the consequence of that
is that there
may well be circumstances with closed vessels
where it takes much
longer for the
egress of marker to reach the circulation than in
others. Thus, the idea
of short periods
of one or two hour sampling times looking for
change may be
inadequate. There also
are issues related to the spontaneous change that
can occur.
This has been termed
biological variation and clearly is much more
substantial than
just the variability
associated with the imprecision of the assays
[8]
. Nonetheless, it is
clear there is some overlap between the
values that one believes are associated with
patients with MI and the values that
are considered part of the spontaneous
biological variation
[9]
. In addition, the
optimal values to use with each assay are not
clear. One could calculate an ROC curve
which many laboratorians are enamored of
doing and pick the value that
classifies the most patients correctly. However,
this
may not be what clinicians need.
Cardiologists want relatively high specificity to
avoid unnecessary procedures in
patients who are not at risk, whereas emergency
department physicians often want more
sensitive criteria so that they do not
inadvertently discharge patients who
are at risk
[10]
. The
balance between these
two needs to be
found at each institutional level. Thus, the
complexity of this issue,
with high-
sensitivity assays, needs to be discussed at each
local site and adjudicated
on a case by
case by assay basis.
Classification of
MIs
There are multiple reasons why cTn
could be elevated that need to be distinguished
from MI. One could have a rising and a
falling pattern of cTn due to sepsis or
pulmonary embolism, or acute heart
failure with myocardial stretch; none of which
would be associated, nor should be
considered the same as MI. In addition, there are
types of MIs as well and it may well be
of some importance to distinguish the types
as the care of these individuals may be
different. The task force recognized multiple
types of acute MI
[3]
. They define type 1
which many have called the so called “wild”
type as an episode associated with
plaque rupture and spontaneous in nature. Thus,
these patients most often present after
an episode of chest discomfort often with
ECG changes, elevated biomarkers, and
in the studies of such patients it is clear that
having an elevated cTn indicates a
beneficial response to an aggressive strategy with
anticoagulation and the use of IIb/IIIa
agents and early invasive strategy
[11]
. So
called
type 2 MIs are less typical. They often occur in
patients who have fixed
atherosclerotic
disease who developed tachycardia, hyper- or
hypotension, or in
individuals who have
abnormalities in coronary vasomotion such that
they do not
improve increased coronary
blood flow in response to stress or have overt
vasospasm. Such events can even occur
in some individuals whose coronary arteries
are totally normal but who have such
severe supply demand imbalance due to
extreme tachycardia, hyper- or
hypotension. These scenarios can become complex.
One could suggest that there is a
continuum between myocardial injury which might
be diagnosed, for example, in a young
person with tachycardia who had an elevated
cTn than who was totally asymptomatic,
to a similar patient who might have more
typical chest pain who might be called
a type 1 MI, to an individual who might have
vague symptoms that are difficult to
classify in whom a diagnosis of type 2 MI might
be made. This is an area where clinical
judgment will be important for clinicians but
it should be clear that solitary
elevation of cTn even with a rising and a falling
pattern
does not mandate a diagnosis of
MI. These distinctions are made more difficult by
the fact that in certain circumstances
such as the elderly, the diabetic, and patients
who are postoperative classic findings
may not be observed.
Type 3 MI subsumes
that circumstance where there is a patient with a
classic MI
documented either by
electrocardiography or angiography where the
biomarkers
have not been obtained or
have not had sufficient time to be elevated. This
is rarely
a problem except in those
patients who succumb at a very early time during
the
process.
There also are
myocardial infarctions associated with
revascularization procedures
such as
PCI or CABG. These are complex and will be covered
below.
Electrocardiographic changes
The electrocardiographic changes that
should be observed for did not change
markedly but looking for evidence of
circumflex coronary artery ischemia is
emphasized. Posterior leads (V
7
–
V
9
) should be recorded in patients who may have
circumflex involvement. This may be
suspected if there is ST segment depression in
V
1
–
V
3
. The ECG criteria for acute MI
and common ECG pitfalls in diagnosing
infarction are detailed in the Third
Universal Definition of Myocardial Infarction
[3]
.
Periprocedural myocardial infarctions
This is an area of intense controversy.
It is clear that myocardial injury can occur
after percutaneous procedures. This can
be due to emboli, whether they are a clot of
atherosclerotic, occlusion of a side
branch, or simply prolonged ischemia. What has
been problematic has been the ability
to know for sure that these events are
associated with an adverse prognosis
[12]
. The criteria provided
do not attempt to
make that distinction
since such a distinction requires outcome data.
The thought
with that is that for many
such elevations, elevations prior to the procedure
are
present but have been ignored
[12]
. Indeed in recent meta-
analysis, not one study
that claimed to
have a normal baseline had such a baseline.
Therefore, the
proponents of this
particular point of view would argue that there is
rarely
prognostic significance. If so,
the question arises as to whether or not
diagnosing
these patients with acute MI
is of value. The opposing view is that prior
studies,
particularly done with less
sensitive markers where one could ignore the
baseline
changes because markers like
CK-MB were insensitive and did not detect very
many
such elevations suggested that
there was prognostic significance to these events.
Given the task force has moved strongly
toward a cTn oriented structure and did not
have to, nor did, dwell on the issue of
prognostic significance, the question then was
viewed as how to define a distinction
between the cardiac injury that might have led
to the procedure and some sort of
additional insult caused by the procedure itself.
The task force then decided to mandate
the need for a normal cTn value or
documentation of a stable or a falling
pattern at baseline and then to rely on a 5 fold
elevation of cTn when there was a clear
cut abnormality induced by the procedure
itself or marked symptoms occurred. The
criteria uses previously of a threefold was
increased to fivefold along with these
ancillary criteria given the increase in assay
sensitivity that has occurred since
2007 but it should be clear that given the
heterogeneity of present day cardiac
troponin assays that this will be a moving
target depending upon the assay that
one utilizes in any given situation.
A
similar statement can be made for CABG.
Unfortunately, given the heterogeneity
of assays, there is no single cutoff
value that can be utilized. However, it is clear
that
individuals who start with an
elevated cTn preoperatively elaborate more cTn
[3]
.
Thus, a
normal baseline value is important for comparative
information. It is also
clear that the
more cTn that is elaborated, the more adverse the
prognosis; thus,
making many more
comfortable with this diagnosis than with the
post-PCI diagnosis
[13]
.
However, there also is an obligatory amount of
injury that is indigenous to the
cardiac surgical procedure and the
question is how much should be or should not be
included. An arbitrary decision was
made to suggest that above a tenfold increase
from the URL value for any given cTn
assay should be considered abnormal and lead
to investigation looking to see if the
additional criteria were present. These could be
provided by imaging or by the
electrocardiogram.
Novel circumstances
Several other circumstances are
recognized in the guidelines that are of
relevance.
For example, any procedure
done on the heart is likely to cause elevations of
cTn.
Therefore, transcatheter aortic
valve implantations, the so called TAVI or mitral
clip
procedures are likely to cause
such cardiac injury. The task force suggested that
the
criteria for CABG be applied in
that circumstance. In non-cardiac surgical
procedures,
there often are cTn
elevations. Many of these appear to be the so
called type 2
events although
definitive information in this area is lacking and
it is not clear that
we have defined
well enough the appropriate clinical criteria to
distinguish type 1
and type 2 MI
[3]
. Nonetheless, it appears
that at least based on an earlier data and
vascular surgery patients that patients
often have abnormalities in the supply and
demand that can be documented. It has
been shown
[14]
that
tachycardia,
hypotension, or
hypertension post operatively is often associated
with ST
–
T wave
changes and subsequent elevation in cTn
and the adverse prognosis are known to be
associated to such elevations. However,
the pathologic literature would suggest, and
this is why one needs to be cautious in
this area, that those events that lead to
mortality often are associated with
plaque rupture and may be more type 1 events
[15]
. Thus, there is still
ambiguity about exactly what types of infarctions
might exist
and therefore the criteria
are highly nuanced in that regard. Similar
statements can
be made about patients
who are critically ill who may have elevations for
a variety of
reasons, some of which
have nothing to do with the supply demand
imbalance and
some of which do. Some of
the elevations in cTn could be related to the
toxic effects
of the disease (sepsis
and heat shock proteins and/or TNF) or of
medications that are
being used
therapeutically
[16]
. What
is suggested by the task force is that the
clinician needs to develop his or her
own sense of when these elevations are due to
ischemia and an imbalance between
myocardial oxygen supply and demand and
then one can diagnose that episode as a
type 2 MI. In the absence of such a
diagnosis, one would suggest the
presence of cardiac injury due to whatever
pathophysiology is thought to be
present. Heart failure perhaps is one of those
more
common situations where this issue
may arise. Many patients have heart failure due
to ischemic heart disease. However,
there also are non-ischemic mechanisms for the
cTn release including acute myocardial
stretch
[17]
so the task
force took a very
careful look and
suggested that although some elevations could be
due to acute
ischemia, that the vast
majority might well be considered not to be due to
acute
infarction. Again, this is an
area where clinical judgment is likely to be
essential.
Clinical trials and societal
issues
It was acknowledged in the
guidelines that the implementation of the criteria
suggested for the diagnosis of MI could
cause substantial difficulties both for
patients and for those who are doing
clinical trials. The diagnosis of MI carries with
it
substantial negative consequences
and clinicians should be aware and sensitive to
that issue when they are making this
diagnosis. In addition, clinical trial groups may
have difficulty at times collecting the
ideal information to employ the criteria
proposed. Their ability to come as
close as possible however to more clearly mimic
the real world of clinical cardiology
will be important if those trials are to have real
applicability to the everyday patient.
Nonetheless, it is clear that there may be times
when resource limitations and/or
circumstance make total adherence impossible.
Conclusion
The 2012
guidelines expand on the criteria previously
established and amplify on the
criteria. However, it is clear that as
additional data are developed, these guidelines
are apt to change still further.
Disclosures
Dr. Jaffe has or
presently consults for most of the major
diagnostic companies.
References
1.
o
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o
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o
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K. Thygesen, J.S. Alpert, A.S. Jaffe,
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Third Universal Definition of
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