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THE ELECTROCARDIOGRAM IN ACUTE CORONARY SYNDROMES
325
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Cardiovascular Problems in Emergency Medicine: A discussion-based review, First Edition.
Edited by Shamai A. Grossman and Peter Rosen.
© 2011 John Wiley & Sons, Ltd. Published 2011 by John Wiley & Sons, Ltd.
Cardiac markers
J. Stephen Bohan
Executive Vice Chair, Department of Emergency Medicine, Brigham and Women’s
Hospital, Assistant Professor of Medicine, Harvard Medical School, Boston,
Massachusetts, USA
23
Section I: Case presentation
A 45-year-old woman who complained of substernal
chest pain radiating to the left arm, neck, and back pre-
sented to the emergency department (ED). The pain
began about 12 hours before presentation. She had a
history of “microvascular angina,” and had been seen
and evaluated multiple times for similar symptoms by
the cardiology service at this hospital. There was a
recent cardiology note in the electronic record stating
that they have attempted to control her symptoms with
nitroglycerin on a prn basis. The patient had taken
15 nitroglycerin tables on the day of presentation,
and noted that she did have some relief, but it did not
completely resolve the pain, so she came in for further
evaluation. She also stated that she had right upper
quadrant pain that is chronic for her. She specifi cally
denied any diaphoresis, headache, or visual change.
She denied nausea, dizziness, syncope or near syncope,
weakness, dyspnea, ankle swelling, orthopnea, or par-
oxysmal nocturnal dyspnea. She did not have a cough.
The past medical history was signifi cant for long-
standing chest pain with a negative cardiac catheter-
ization 18 months ago, along with no hypertension,
diabetes, oral contraceptive use, or hyperlipidemia.
She had two pregnancies, and has two living children.
She had regular periods that ended two years prior.
There was no history of venous thrombosis or cancer.
Her only medication was a daily aspirin. The family
history was noteworthy for a father who died at age
66 of a heart attack; he had been a life-long smoker.
The patient was a nonsmoker. She drank 2–4 glasses
of wine per month.
On physical examination she was comfortable while
recumbent on a gurney. The vital signs were: pulse 74
beats/min and regular; blood pressure 180/103 mmHg;
respirations 15 breaths/min; temperature 98.6ºF; O
2
saturation 98%. There was no jugular venous disten-
tion at 30 degrees; the point of maximum impulse was
normal, and there was no thrill. The peripheral pulses
were normal. There was a normal S1S2 without mur-
mur, rub, or gallop. The chest cardiac sound was with-
out crackles or wheezes. The abdomen had no scars,
and was soft and nontender, despite the complaints of
chronic pain mentioned above. Laboratory evaluation
showed a normal complete blood count, metabolic
panel, and cardiac enzymes. The chest X-ray study
was normal with no infi ltrates and a normal hilum.
The EKG was normal in all respects.
The patient was given one dose of IV metoprolol,
and the blood pressure fell to 158/93 mmHg. The
patient’s cardiologist was inclined to discharge the
patient, but he and the emergency physician con-
cluded that it would be more prudent to ensure that
the patient’s blood pressure was better controlled
before discharge. The plan was as follows: “We have
decided to admit to the Observation Unit for both
blood pressure control with her oral antihypertensives,
CARDIAC MARKERS
327
a single set of enzymes may be useful, as we showed
in our study.
Dr Peter Rosen: The problem is often timing the onset
of the symptoms that relate to the present problem. It
is possible that this patient’s symptoms were stutter-
ing, and that the true ischemia did not start 12 hours
prior, but rather just before she came to the ED.
DB: Does a normal cardiac catheterization 18 months
previous help you in your confi dence that she does
not have an acute coronary syndrome at this point?
Dr Stephen Bohan: It would boost my confi dence, but
not to 100%. About 90% of people who have a normal
cardiac catheterization will, when repeated, even up to
7 or 8 years later, still have normal coronary arteries.
However, there is a recent phenomenon of women
who have a “chest pain syndrome,” and cardiac
catheterization shows normal or minimally-diseased
coronary arteries. The outcome in this patient popula-
tion 5 years later turns out to be worse than women
who are asymptomatic, so there’s probably something
different about women, particularly in the subset of
women who have a recurrent chest pain syndrome.
PR: About 30 years ago, there was a description of
women who had chest pain but no EKG changes, and
who on coronary angiography had right coronary artery
spasm. This was prior to troponin measurements, so it
is not possible to know if the lack of fl ow during spasm
was producing necrosis, although some of the patients
did evolve an inferior wall myocardial infarction.
DB: Does the combination of the normal coronary
artery angiogram 18 months ago, coupled with the
normal initial set of cardiac markers, make you feel
comfortable sending this patient home without fur-
ther treatment or evaluation?
SB: This is an interesting phenomenon. Here, we’re
unable to tell when ischemia ended and infarction
began. Almost all people short of an unequivocal
ST-segment elevation myocardial infarction (STEMI)
and a complete occlusion have some degree of isch-
emia before the heart shows evidence of an infarct.
We don’t know when that transition occurs. In addi-
tion, there’s a fundamental question we must ask
when practicing emergency medicine, which is why
did she come now, why did she not come at hour four,
hour seven, or hour nine? Why did she wait 12 hours?
What happened at 12 hours to make her come?
in addition to the one dose of IV metoprolol that we
gave her, and also pain control so that we hope to get
her pain free. Once this is accomplished, and after
she has two sets of negative markers, we will discharge
her home. The pain has been going on for approxi-
mately 13 hours, and given this, I feel that two sets
of markers are appropriate. Disposition: Admit to
Observation Unit for pain control . . .”
Subsequently an addendum was dictated: “This
is an addendum to the note I dictated earlier on this
patient. The patient initially had a set of negative
cardiac markers, and had remained chest pain free
throughout her entire stay in the observation unit;
however, her B set of cardiac markers shows a tro-
ponin of 64 and a repeat to ascertain whether or not
this was a true value showed a troponin level of 114.
EKGs throughout this interval have not shown any
ST-segment changes, and the patient remains pain
free. We discussed this with her cardiologist, and she
will be admitted.”
Section II: Case discussion
Dr David Brown: How much stock do you place in
the initial set of cardiac biomarkers being normal,
particularly in the context of her symptoms persisting
for 12 hours?
Dr Shamai Grossman: The issue of a single set of car-
diac markers is a controversial one, and unfortunately
there is little data that look specifi cally at a single set
of cardiac markers as a reliable test to demonstrate a
patient has not had an acute myocardial infarction.
There is one study, by a group of us at Massachusetts
General Hospital, in which we fi nd that a single set
of cardiac markers drawn about 8 hours from the
onset of symptoms is very sensitive, in a range of
about 95%, a number quite similar to serial cardiac
markers.
1
This data makes sense logically given that
the sensitivity of serial troponins drawn 3 and 9 hours
from the onset of symptoms is about 95%. The prob-
lem with a single set of cardiac markers is that the
average patient arrives about 3 hours from the onset
of symptoms, and at 3 hours a single set of markers
has a very low sensitivity. In this particular case, the
patient came approximately 12 hours after the onset
of symptoms, which places her outside the norm,
and because she was no longer the average patient,
CHAPTER 23
328
thought that once this was accomplished, and after a
second set of negative markers, they would be able to
discharge her home.
SG: Can you identify patients who you think are the
appropriate population for an ED observation unit?
Are there certain patients who you think belong
there?
SB: In our ED, if you have a normal initial set of
markers and a normal EKG, you’re suitable for the
observation unit, and if we think that it’s important to
control mildly elevated blood pressure, the observa-
tion unit would also be suitable.
SG: What would it take to make that patient ineligible
for the observation unit? Who would you not put in
there?
SB: Our exclusion criteria are an abnormal set of
biomarkers, particularly troponin, because that’s a
myocardial infarction by defi nition, and new EKG
changes or an abnormal EKG, not known to be old.
DB: As many patients come in with a story that is
atypical and abnormal EKGs with no access to their
old tracings, we tend to be a little less restrictive in
our observation unit, and place patients there whom
we believe to be low likelihood to have positive test-
ing, and have a high likelihood of going home in
18–24 hours.
SG: I would tend to concur with you, as did the
Faroukh et al. study a number of years ago. This
study demonstrates the safety of an intermediate-risk
patient population in an observation unit.
2
The idea
is that if you’re not sending the patient home, then
you have most of the same monitoring capacities
in the observation unit that you have anywhere else
in the hospital, and if the patient evolves evidence of
an infarction or more evidence of an acute coronary
syndrome, then you can always transfer the patient
to a higher acuity bed.
SB: It’s just that we happen to be quicker and cheaper
in the observation unit than upstairs.
PR: I wonder whether approaching this patient as
having cardiac ischemia is the right approach at all.
This is a patient who is described as having ongoing
abdominal discomfort as well as chest discomfort, and
we need to be concerned that perhaps this is not car-
diac ischemia at all, and maybe what is being missed
SG: What you’re really saying is that you cannot trust
the patient who tells you that it’s been the same for
12 hours. Maybe it’s not really the same.
SB: In addition, a joint statement from the American
College of Cardiology and the European Society of
Cardiology recommends a set of biomarkers on pre-
sentation and another 6 hours later. It does admit that
the symptoms may exist a while before that.
SG: Is there a way in your mind to identify which of
those women are more likely to actually have micro-
vascular disease, and which are less likely to have this
process?
SB: I don’t know that there’s any way to really detect
them, other than that they’re symptomatic. Although
the overall event rate is low, it is still substantially
higher than the rate in a group of asymptomatic
women who were the control group.
DB: Does that leave us in the position of having to
admit and rule out that cadre of patients—young
women with normal EKGs and atypical stories?
SB: I think that sometimes it is a gut feeling or a clini-
cal judgment. Remember, the prevalence of coronary
heart disease in pre-menopausal women is extremely
low, but at the same time we know that symptom-
atic women, even with normal coronary arteries, do
have a higher rate of incidence than asymptomatic
women.
SG: If you look at the various studies that have stud-
ied the patients inadvertently discharged home from
the ED with an unrecognized myocardial infarction,
one of the more common misses is the young woman.
Clearly, we do need to be more discerning and pay
closer attention to these patients.
DB: Why don’t we go ahead and discuss the emergency
department course?
SB: Her cardiologist was consulted on the basis of the
initial biomarkers and EKG. The cardiologist felt that
she could probably be safely discharged, given the
negative catheterization, but the emergency physician
concluded that the blood pressure was substantially
high on presentation, and was still abnormal after
treatment. He suggested that they put her in the obser-
vation unit for both blood pressure control, and to see
if they could control her pain, and rule out a very
unlikely myocardial infarction (MI). The physician
CARDIAC MARKERS
329
troponin was 114 µg/L. The EKGs throughout this
interval did not show ST-segment changes and the
patient remained painfree. At this point she is admitted
to cardiology. I’m very troubled by this case. At times,
I have decided that a single set of cardiac markers in a
low-risk patient with continuous chest pain, particu-
larly when they have had prior testing, is adequate to
exclude the presence of a myocardial infarction, and
been satisfi ed that the chest pain was noncardiac. In
this case, a cardiac catheterization, the most defi nitive
of tests, was done within the last 18 months, which
I think is a reasonable time interval. Now, despite the
negative coronary angiogram and what sounds like
multiple evaluations, she’s ruling in for some myo-
cardial necrosis or a non-ST-segment elevation MI,
without any signifi cant clues other than a prolonged
episode of chest pain.
SB: No matter what we think about, there’s always
one person, out of the entire population we see, who
is going to upset our theories. Judd Hollander has
tried to look for a group of people who he felt could
safely be discharged from the ED after presenting with
chest pain; the criteria were no risk factors, age less
than 40 years, a normal EKG, and one set of normal
enzymes. He found no bad outcomes at 30 days.
3
This
patient doesn’t fulfi ll these criteria exactly because
she’s over 40. Secondly, it comes back to what I men-
tioned earlier, which is that there’s something about
this patient that brought her to the ED this time.
SG: Perhaps we don’t understand what microvascu-
lar angina is on a pathophysiologic basis. She does
carry this strange diagnosis, and perhaps that actually
should have raised some red fl ags, and that’s the key
to this case. There’s reassuring data using a protocol
consisting of a single set of enzymes and rapid stress
testing in the ED. Looking at this patient, do you
think this might have been an appropriate approach?
DB: I would not have chosen that protocol in this par-
ticular patient because my pretest probability that she
has epicardial coronary artery disease with a negative
catheterization 18 months ago is so low that I feel it
wouldn’t be necessary. Frankly, if she weren’t hyper-
tensive, I would have sent her home based on a single
negative marker, the history of the normal coronary
angiogram, the normal EKG, and the normal set of
markers. The hypertension seemed to help in this case,
in a way, because it got her admitted. I might still have
here is gall bladder disease. We do know there is over-
lap of symptoms between cardiac and gall bladder
diseases, and sometimes we become so focused upon
the cardiac diagnosis that we forget the possibility of
alternative concomitant diseases.
DB: The way that this case is described, the pain is
unchanged from her baseline right upper quadrant
pain. I think that it becomes more of an issue if the
pain in the right upper quadrant is different or if
the examination is concerning.
SB: I agree. Her principal complaint is unequivocally
chest pain. She notes the abdominal pain as being
chronic, but what brought her to the ED was persis-
tent chest pain. Someone once said that a lot of people
have had coronary bypasses for gall bladder disease,
and a lot of people have had their gall bladder out for
coronary heart disease.
DB: You’re right that gallbladder disease can present
with chest pain, back pain, or fl ank pain in addition
to, or instead of, right upper quadrant pain, but in my
experience, the discomfort can be elicited on physical
examination, either in the right upper quadrant or in
the fl ank when the gallbladder is infl amed. In addition,
in this particular case, the woman is able to make a
distinction between her chest pain, which is different
and new in onset, from her abdominal pain, which is
chronic and unchanged. Couple that with a physical
examination that elicits no right upper quadrant or
fl ank tenderness, gallbladder disease has considerably
lower probability, and should not require any further
evaluation in the ED in the absence of vomiting, fever,
or other concerning fi ndings on examination.
PR: Nevertheless, given the increasing capacity of the
emergency physician to utilize bedside ultrasound
imaging, it wouldn’t take much time to examine
the gall bladder with an ultrasound in the ED, and
order a formal study only if something abnormal is
discovered.
DB: This patient was admitted to the observation unit,
was given an intravenous beta-blocker, and I presume
started on an oral antihypertensive agent, since previ-
ously she had not been on one. She was then observed
for a period of several hours, and had a second set of
cardiac markers. The second set of cardiac markers
showed a troponin of 64 µg/L, and when repeated to
ascertain whether or not this was a true value, the
CHAPTER 23
330
the cause of a disease that did not cause infarction?”
The answer to that has to be a separate question, with
a separate testing mode, and that is where CT angiog-
raphy and provocative testing may come in. Although
the CT scan is a very attractive test, there’s only one
ED study, containing 568 patients, that says that if
you have a TIMI score of one or less, with one set of
enzymes and a CT angiography that is normal (by defi -
nition less than a 40% obstruction), then those patients
can go home and will have no adverse events within
30 days.
5
SG: I might look at this case a little differently. People
often mistakenly call normal coronary angiography a
catheterization where there was no signifi cant disease,
and it’s likely this patient really did have coronary dis-
ease, but it was insignifi cant. The patient may have had
30 or 50% stenoses 18 months ago, and, therefore, it
was a relevant study 18 months ago, but not as relevant
today.
SB: When we say normal, obviously every study has a dif-
ferent defi nition of normal. There’s “perfectly normal,”
meaning no disease at all, then there is some disease. In
2009, in an article termed “Adverse cardiac outcomes in
women with non-obstructive coronary artery disease,”
Gulati and Cooper-DeHoff divided the patients into
those who had 1–50% obstruction and those who had
zero obstruction, followed them for 5 years, and com-
pared them to asymptomatic women.
6
Of the women
who did have some disease, they had a higher incidence
of adverse events compared to those who had no
demonstrable anatomic disease. Nevertheless, patients
who had no demonstrable anatomic disease still had a
higher event rate than the asymptomatic patients. This
case does emphasize the utility of two sets of enzymes,
as somewhere in those 12 hours, this patient infarcted,
and we otherwise couldn’t tell that.
SG: I might make the argument that perhaps that we
are all at fault for being unable to get enough history
from this patient about what happened in the course of
those 12 hours. Clearly, if she’s bumping her enzymes
now, there was something that did change over the
course of those 12 hours. Unless she’s truly, truly an
outlier, the inciting event was probably somewhere
around hour six or so.
SB: In our department we can exercise people based on
their history, without evidence of enzyme elevations,
when we think that the history that they are giving us
sent her home if her blood pressure fell on its own,
without much treatment, and I would have ascribed
the hypertension to anxiety or pain or fear.
I have occasionally used a single set of markers and
a stress test. For example, if the duration of pain was
suffi ciently long enough ago in onset that the fi rst set
of markers should have been accurate, and if she was
pain free after 12 hours of symptoms in the ED and
had a negative set of markers, she could have gotten
a stress test in our institution. If she were still hav-
ing pain, or if her pain were only within 2–3 hours
of symptom onset, then she would not have gotten a
stress test. A low-risk patient like this, with no known
coronary disease, a normal EKG, and symptoms that
are somewhat atypical, is a good candidate for a coro-
nary CT scan. If the test is completely normal, you
can feel comfortable with the patient not having coro-
nary artery disease.
SB: In this case I would argue as Goldman and Kirtane
did in 2003, in the Annals of Internal Medicine, “If
you think enough to do the fi rst set, then you are
obliged to do the second set.”
4
DB: Is that 6 hours after the fi rst set or 6 hours after
the resolution of pain?
SB: People used to talk about the resolution of pain,
but the ACC guidelines for myocardial infarction in
2007 talk about after the fi rst set.
DB: What then would you recommend to the practic-
ing emergency physician who walks into a patient’s
room, hears the story, feels that it is atypical, with an
EKG that is normal, but as part of the standard chest
pain protocol, the fi rst set of markers has already
been sent off?
SB: I think that the emergency physician needs to ask
himself four questions sequentially for any patient who
could be having cardiac ischemia or infarction, and the
fi rst question is, “Is this patient having an ST-segment
elevation MI, and do I need to do anything about it
right now?” If the answer to that is no, then the next
question is, “Could this patient be having a myocardial
infarction of the type that I don’t need to deal with
right now, but a myocardial infarction nonetheless?”
That question, in my mind, is only answerable by
enzymes, and the current literature supports two sets
taken 6 hours apart. Then there is a third question: “If
those are negative, does this patient have ischemia as
CARDIAC MARKERS
331
spasm does to enzyme elevation, perhaps the clue to
this case is a woman with persistent, but increasing,
pain. Rather than trying to decide with a single set
of enzymes, serial enzymes would then make a lot
of sense. Moreover, while most patients may have a
slower rate of progression than 18 months, that surely
can’t fi t all patients. I would have been much happier
about the normal angiogram if it were 3–6 months
ago. Finally, as was already mentioned, we don’t know
what negative meant in that study.
Case resolution
During admission, the patient was sent for a cardiac
catheterization that showed a totally occluded obtuse
marginal branch of the left circumfl ex artery. This was
successfully opened, and a stent was placed. On review
of the prior catheterization, a 40–50% occlusion of
that artery was evident. The patient had an uneventful
recovery, and was symptom free at 30 days.
Section III: Concepts
“The sobering bottom line is that two decades of
research has taught us that without compelling evi-
dence of a noncardiac cause, there is no absolutely
fail-safe way to exclude myocardial ischemia or
infarction at the time of a patient’s initial presenta-
tion.” The emergency physician, when faced with a
patient whose symptoms suggest cardiac ischemia or
infarction, needs to answer four questions:
Is this patient having a myocardial infarction?1
If not, does this patient have unstable angina?2
If not, does this patient have cardiac ischemia as 3
the cause for his/her symptoms?
Is it safe to send this patient home?4
Answering these questions sequentially enables
risk stratifi cation, as the three entities that form the
basis of these questions have sequentially less risk of
adverse outcomes. We can never achieve a zero risk
because of the vagaries of human diseases, our abili-
ties to interpret the histories, and the reality that we
can never practice perfect medicine, but at some level
of risk it is safe to send a patient home.
In 1979 the World Health Organization defi ned
acute myocardial infarction with three parts: charac-
teristic chest pain of greater than 10 minutes duration,
evolutionary EKG changes (ST-segment elevation
is very much like what you would get in an offi ce visit.
“Oh yes, doctor, when I go up to get my mail in the
morning up the hill, I get pain, but it doesn’t happen
in the summer, but in the winter it comes, and my wife
sent me here . . .” and that’s an offi ce visit. In that kind
of situation, you’re not wondering if this patient has
an infarction; you just want to know if this patient has
obstructive coronary heart disease, and we can send
patients for exercise testing on this basis.
SG: I would argue that despite Goldman and Kirtane’s
concerns, simply because someone sent a test in error
doesn’t mean that you need to make a second error.
We don’t always have control over every test in the
ED, but that shouldn’t change what our thinking was
in the fi rst place. We don’t need to say that we base
all of our thinking and all of our clinical judgment on
testing; rather, our thinking is based on our clinical
judgment.
SB: Are we, as a group or as an industry, trying to
push for one enzyme because we are being forced by
overcrowding rather than the literature supporting
this decision making, or do we feel deprived in our
judgment? A doctor’s clinical judgment in assigning a
diagnosis of noncardiac chest pain is clearly fallible.
About 3% of people who have been determined, by
physicians from six academic centers, to have non-
cardiac chest pain experience cardiac events within
30 days.
SG: I think the argument is a logical one. We know
the pharmacokinetics of troponin, and we know that
troponin peaks 6–8 hours from the onset of symp-
toms. If we can clearly defi ne when the symptoms
were, then we should know when the enzymes should
be elevated, and have an idea that when enzymes are
negative, they are negative. I think that this is the argu-
ment that people have used, and although it’s true that
logic doesn’t always work in medicine, it’s always the
way we try and practice.
SB: Two newer, more-sensitive troponin assays have
recently been described. These assays allow earlier
detection of MI; however, whether they improve
patient outcomes remains to be seen. With the new
assays, as with current assays, sensitivity for unstable
angina is inadequate, and discharging a patient after a
single troponin test may still be imprudent.
7–9
PR: Since we don’t know if the patient has been having
coronary artery spasm, and since we don’t know what
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332
The chemical diagnosis of myocardial infarction
There are three markers used in contemporary testing:
myoglobin, creatine kinase, and troponin. Myoglobin
is present at about 2.5 hours after cardiac injury, and
while highly sensitive, it is notably nonspecifi c. It
does, however, have a high negative predictive value
(99%) when the degree of rise is considered in the
decision.
13
Creatine kinase and its subunits have been the
workhorse markers of the past 40 years; however,
they have been replaced by troponin testing as the
preferred marker, as noted in the 2007 defi nition
document.
12
There are two cardiac troponins: troponin T and
troponin I; they are proteins that control the interac-
tion between actin and myosin during muscle contrac-
tion. A form of troponin T exists in skeletal muscle as
well (though is not detected by the latest generation
troponin T testing), while the troponin I is not found
outside the heart.
The methodology for troponin T testing is a pat-
ented process, and therefore the same irrespective of
the location of testing. As a result, the range of nor-
mal values is also the same. Conversely, there are
multiple patented methods for testing for troponin I,
and each has its own range of normal values, which
are not comparable to other methods or institutions.
The ESC/ACC consensus document recommends that
each institution establish its own 99th percentile of the
normal population.
12
The ESC/ACC also states that
there is a binary classifi cation for troponin I levels:
normal and abnormal, with no intermediate levels in
between. There is evidence to support this convention
(Figure 23-1), as even the lowest levels of abnormal-
ity are associated with worse cardiac outcomes in
patients with acute coronary syndromes than those
with subsequent normalization and the development
of Q waves), and a rise in the total creatine kinase
(CK), with greater than 5% identifi ed as the MB
band.
2,3,7–10
Subsequently, it became apparent that
there were individuals who incurred myocardial cell
death who did not manifest the defi ned EKG changes,
(and in some cases had no EKG changes). This group
of non-ST-segment MIs had heterogeneous EKG
changes, and were initially termed non-Q wave MIs;
these patients were found to have a worse prognosis
than the archtypical ST elevation MI. These hetero-
geneous variants came to be grouped together as non-
STEMIs, or NSTEMI.
Twenty-one years later, and about 10 years after
the introduction of troponin testing (which had
proven to be both more sensitive and more specifi c
than CK-MB and had a much greater prognostic
accuracy), the American College of Cardiology and
the European Society of Cardiology developed a new
defi nition based almost exclusively on troponins.
11
This defi nition requires a rise and fall in the troponin
level in a patient who has presenting features that
could be consistent with myocardial ischemia. This
defi nition was revised in 2007 to refl ect the growing
awareness of the phenomenon of small rises in the
troponin level resulting from procedures, as well to
include those patients who die before any testing can
be done.
12
EKG changes are no longer a necessary ele-
ment of the diagnosis of acute myocardial infarction
(Table 23-1).
By this defi nition, all patients with symptoms com-
patible with ischemia who are troponin positive at
any level of abnormality (higher than the 99th per-
centile of a healthy cohort) have had a myocardial
infarction. A further classifi cation was done to orga-
nize clinical events according to pathophysiology
(Table 23-2).
Table 23-1. Criteria for acute myocardial infarction.
The term myocardial infarction should be used when there is evidence of myocardial necrosis in a clinical setting consistent with
myocardial ischemia. Under these conditions any one of the following criteria meets the diagnosis for myocardial infarction:
Detection of rise and fall of cardiac biomarkers (preferably troponin) with at least one value about the 99th percentile of
the upper reference limit (URL) together with evidence of myocardial ischemia with at least one of the following:
Symptoms of ischemia•
EKG changes indicative of new ischemia (new ST-T or new left bundle branch block [LBBB])•
Development of pathological Q waves in the ECG•
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality•
Source: Eur Heart J. 2007;28:2525–2538.
CARDIAC MARKERS
333
The release of small amounts of intracellular tro-
ponin from the injured cell is not immediately detect-
able by assays in current use. Nevertheless, these
assays can detect larger amounts resulting from
degradation of structural troponin within 3 hours
of release in 80% of patients. This interval is not
much different than that achieved by the inclusion of
myoglobin in the testing scheme, and troponin also
provides a much higher specifi city.
16
Serial testing of
troponin levels, beginning at 6 hours, captures the
remainder of cases, and testing for peak troponin
with normal levels; this phenomenon continues across
all levels of abnormality (the higher the abnormality,
the worse the prognosis). Moreover, there is some
evidence that the presence of any detectable troponin
(by current methods) is abnormal, and is associated
with a worse natural history. Studies have shown that
individuals who have detectable but normal troponin
levels often have heart failure, diabetes, or left ven-
tricular hypertrophy.
14,15
The full clinical implications
of this phenomenon are as yet unknown, and should
not enter into the decision making in the ED.
Table 23-2. Clinical classifi cation of different types of myocardial infarction.
Type 1
Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as plaque erosion or
rupture, fi ssuring, or dissection.
Type 2
Myocardial infarction secondary to ischemia due to either increased oxygen demand or decreased supply, e.g., coronary
artery spasm, coronary embolism, anemia, dysrhythmias, hypertension, or hypotension.
Type 3
Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischemia,
accompanied by presumably new ST elevation, or new LBBB, or evidence of fresh thrombus in a coronary artery by
angiography or at autopsy, but death occurring before blood samples could be obtained, or at a time before the
appearance of cardiac biomarkers in the blood.
Source: Eur Heart J. 2007;28:2525–253.
Figure 23.1 Kaplan-
Meier curves of six-
month cardiac mortality
for the different cardiac
troponin I (cTnI) values.
The trend toward
increased mortality and
increased cTnI is highly
signifi cant (p ⬍ 0.001).
In addition, mortality
is signifi cantly different
(p ⬍ 0.01) between the
negative (neg) cTnI and
low, intermediate (inter),
and high cTnI groups.
CHAPTER 23
334
usually have visible thrombosis and depressed left
ventricular function. Conversely, in patients whose
symptoms are not predominately of cardiac ischemia,
but who are seriously ill with other syndromes (e.g.,
sepsis, pulmonary edema), troponin levels may only
be 3–4 times normal levels, known colloquially as a
“troponin leak.” These microinfarctions are thought
to result more from demand/supply mismatch (type
2 infarction) (Table 23-2) than active vessel wall
disease.
11
However, because of the inherent serious-
ness of the active pathophysiology, the prognosis of
these patients is as poor as or worse than those with
higher troponin levels resulting from active vessel
wall disease.
3,19
Patients with renal failure often have particularly
high baseline troponin levels, more often when tro-
ponin T is measured than with troponin I. Usually
these patients also have substantial vascular disease,
and thus are prone to acute coronary syndrome,
resulting in a confounding situation for the clinician.
Nevertheless, in a group of more than 7,000 selected
patients, “troponin T elevation is an independent pre-
dictor of death or myocardial infarction within 30
days across the entire spectrum of renal function.”
20
Additionally, in a study of more than 800 patients
(including some on dialysis) troponin I levels are
independent of renal function, and no false positive
elevations of troponin I occur.
21
In contrast, CK-MB
and myoglobin elevations in this study are related to
renal function.
Low but abnormal levels of troponin are also
detectable in patients with trauma, and in marathon
runners, but this does not appear to mark a deleteri-
ous effect.
22
The current hypothesis is that in other-
wise healthy individuals, repair takes place. Because
these patients do not have symptoms of ischemia, or
evidence of supply/demand mismatch, they do not
fi t the operative defi nition of myocardial infarction.
Additionally, the elevated troponin in these otherwise
well, nonacute coronary syndrome cases is cleared
within 24 hours, in marked distinction to those with
an acute coronary syndrome.
23
Patients who are troponin negative after serial
testing have not had a myocardial infarction, and
question one of the four questions above has been
answered. However, this does not mean that they do
not have ischemia as the cause of their symptoms, and
except for a small segment of the patient population
who are less than 40 years old and have certain other
aids in prognostication and choice of therapy, as tro-
ponin-positive NSTEMI patients experience distinct,
well-proven benefi t from anticoagulants and invasive
therapy.
17
Because troponin stays in the serum for as long as
14 days, it can be diffi cult to detect a later reinfarction,
this long half-life is the only reason in contemporary
practice for ordering a CK, as CK is cleared rapidly
within 36–48 hours, and thus, allows for detection
of reinfarction if used after this time period. CK does
not provide earlier detection of MI than current tro-
ponin assays, and has shown to be normal when the
troponin is positive. The prognosis of patients with
discordant markers is related solely to troponin posi-
tivity, as troponin positive and CK negative patients
have a worse prognosis than those patients who are
troponin negative and CK positive.
18
The latter group
has a relative risk very close to baseline (Figure 23-2).
It is because of these test characteristics that troponin
is now the preferred maker in current guidelines,
and has come to form the defi nition of myocardial
infarction.
12
The degree of troponin elevation is of interest, in
that it appears to refl ect two separate pathophysi-
ologic processes. Coronary artery plaque rupture,
either on a macro level resulting in a STEMI, or on
a micro level resulting in a shower of microemboli,
yields troponin elevations at high multiples of nor-
mal, and patients with the highest troponin levels
0
1
2
3
4
Mortaility 42 days (%)
3.8 3.0Relative Risk
All patients CK-MB negative
patients
3.7
P <0.001
P <0.05
1.01
2.5
0.8
Figure 23.2 Relative risk of death at 42 days in troponin
positive vs. troponinnegative patients related to CK MB status