Acute Coronary Syndrome WorkupApproach ConsiderationsAs
previously mentioned, stable coronary artery disease (CAD) may result
in ACS in the absence of plaque rupture and thrombosis, when physiologic
stress (eg, trauma, blood loss, anemia, infection, tachyarrhythmias)
increases demands on the heart. In such cases, the diagnosis of acute
myocardial infarction can be made if workup reveals the typical rise and
fall of biochemical markers of myocardial necrosis along with either
the development of pathologic Q waves or the presence (on ECG or in the
setting of a coronary intervention) of ischemic ST-segment changes.
(However, the presence of ischemic symptoms can be substituted for the
Q-wave or ST-segment evidence.)
[1] Non–ST-segment
elevation myocardial infarction (NSTEMI) is distinguished from unstable
angina by elevated levels of cardiac enzymes and biomarkers of myocyte
necrosis. Differentiation is generally based on 3 sets of biomarkers
measured at 6- to 8-hour intervals after the patient's presentation to
the ED. The current definition of NSTEMI requires a typical clinical
syndrome plus elevated troponin (or creatine kinase isoenzyme MB
[CK-MB]) levels to over 99% of the normal reference (with a coefficient
of variation of < 10% for the assay). Given this definition, nearly
25% of patients who were previously classified as having unstable angina
now fulfill the criteria for NSTEMI. Measure cardiac enzyme
levels at regular intervals, starting at admission and continuing until
the peak is reached or until 3 sets of results are negative. Biochemical
biomarkers (demonstrated in the image below) are useful for diagnosis
and prognostication.
This
plot shows changes in cardiac markers over time after the onset of
symptoms. Peak A is the early release of myoglobin or creatine kinase
isoenzyme MB (CK-MB) after acute myocardial infarction (AMI). Peak B is
the cardiac troponin level after infarction. Peak C is the CK-MB level
after infarction. Peak D is the cardiac troponin level after unstable
angina. Data are plotted on a relative scale, where 1.0 is set at the
myocardial-infarction cutoff concentration. Courtesy of Wu et al (1999).
ROC = receiver operating characteristic. Of note,
cardiac-specific troponins are not detectable in the blood of healthy
individuals; therefore, they provide high specificity for detecting
injury to cardiac myocytes. These molecules are also more sensitive than
CK-MB for myocardial necrosis and therefore improve early detection of
small myocardial infarctions. Although blood troponin levels increase
simultaneously with CK-MB levels (about 6 h after the onset of
infarction), they remain elevated for as long as 2 weeks. As a result,
troponin values cannot be used to diagnose reinfarction. New methods of
detecting troponins in the blood can measure levels as low as 0.1-0.2
ng/mL. Minor elevations in these molecules can be detected in the
blood of patients without ACS in the setting of myocarditis
(pericarditis), sepsis, renal failure, acute congestive heart failure
(CHF), acute pulmonary embolism, or prolonged tachyarrhythmias.
ElectrocardiographyECGs should be reviewed promptly. Involve a cardiologist when in doubt. Recording
an ECG during an episode of the presenting symptoms is valuable.
Transient ST-segment changes (>0.05 mV) that develop during a
symptomatic period and that resolve when the symptoms do are strongly
predictive of underlying CAD and have prognostic value. Comparison with
previous ECGs is often helpful. Alternative causes of ST-segment
and T-wave changes are left ventricular aneurysm, pericarditis,
Prinzmetal angina, early repolarization, Wolff-Parkinson-White syndrome,
and drug therapy (eg, with tricyclic antidepressants, phenothiazines). In
the emergency setting, ECG is the most important ED diagnostic test for
angina. It may show changes during symptoms and in response to
treatment, confirm a cardiac basis for symptoms. It also may demonstrate
preexisting structural or ischemic heart disease (left ventricular
hypertrophy, Q waves). A normal ECG or one that remains unchanged from
the baseline does not exclude the possibility that chest pain is
ischemic in origin. Changes that may be seen during anginal episodes
include the following:
- Transient ST-segment elevations
- Dynamic T-wave changes - Inversions, normalizations, or hyperacute changes
- ST depressions - May be junctional, downsloping, or horizontal
In
patients with transient ST-segment elevations, consider LV aneurysm,
pericarditis, Prinzmetal angina, early repolarization, and
Wolff-Parkinson-White syndrome as possible diagnoses. Fixed changes
suggest acute myocardial infarction. When deep T-wave inversions
are present, consider the possibility of central nervous system (CNS)
events or drug therapy with tricyclic antidepressants or phenothiazines
as the cause. Diagnostic sensitivity may be increased by performing right-sided leads (V
4 R), posterior leads (V
8, V
9), and serial recordings.ECGs from 2 patients are shown below.
A
50-year-old man with type 1 diabetes mellitus and hypertension presents
after experiencing 1 hour of midsternal chest pain that began after
eating a large meal. Pain is now present but is minimal. Aspirin is the
single drug that will have the greatest potential impact on subsequent
morbidity. In the setting of ongoing symptoms and electrocardiogram
(ECG) changes, nitrates titrated to 10% reduction in blood pressure and
symptoms, beta blockers, and heparin are all indicated. If the patient
continues to have persistent signs and/or symptoms of ischemia, addition
of a glycoprotein IIb/IIIa inhibitor should be
considered.
A
62-year-old woman with a history of chronic stable angina and a "valve
problem" presents with new chest pain. She is symptomatic on arrival,
complaining of shortness of breath and precordial chest tightness. Her
initial vital signs are blood pressure = 140/90 mm Hg and heart rate =
98. Her electrocardiogram (ECG) is as shown. She is given nitroglycerin
sublingually, and her pressure decreases to 80/palpation. Right
ventricular ischemia should be considered in this patient. In
difficult cases with nondiagnostic ECGs, such as those involving a left
bundle-branch block, early imaging is useful to assess wall-motion
abnormalities. An important use of noninvasive imaging is to classify a patient has having NSTEMI or true STEMI.The
Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment
of Myocardial Infarction (OCCULT-MI) trial compared the 80-lead (80L)
mapping system to standard 12-lead (12L) ECG. The study concluded that
the 80L body surface mapping technology detected more patients with MI
or ACS than the 12L ECG, while still maintaining a high degree of
specificity.
[11] Measurement of CK-MB LevelsCK-MB,
the isoenzyme specific to the heart muscle, was the principal biomarker
of cardiac injury until troponin supplemented it. In the setting
of myocardial infarction, plasma CK-MB concentrations typically rise
about 4-6 hours after the onset of chest pain. They peak within 12-24
hours and return to baseline levels within 24-48 hours. Serial
measurements obtained every 6-8 hours (at least 3 times) are warranted
until peak values are determined. The area under the
concentration-time curve for CK-MB created with serial measurements of
blood enzyme levels provides a reliable estimate of the size of the
infarct. Clinical settings other than ACS, such as trauma, heavy
exertion, and skeletal muscle disease (eg, rhabdomyolysis), may elevate
CK-MB values. Determination of subforms of CK-MB (CK-MB2 that is more specific to heart muscle) may improve the sensitivity of this test.
Measurement of Troponin levelsThe
troponins are regulatory proteins found in skeletal and cardiac muscle.
The 3 subunits that have been identified include troponin I (TnI),
troponin T (TnT), and troponin C (TnC). The genes that code for the
skeletal and cardiac isoforms of TnC are identical; thus, no structural
difference exists between them. However, the skeletal and cardiac
subforms for TnI and TnT are distinct, and immunoassays have been
designed to differentiate between them. This explains the
cardiospecificity of the cardiac troponins. Skeletal TnI and TnT are
structurally different. No cross-reactivity occurs between skeletal and
cardiac TnI and TnT with the current assays. The cardiac
troponins are sensitive, cardiospecific, and provide prognostic
information for patients with ACS. They have become the cardiac markers
of choice for patients with ACS. Early studies on the release
kinetics of the cardiac troponins indicated that they were not early
markers of myocardial necrosis. The early generation troponin assays
yielded positive results within 4-8 hours after symptom onset, similar
in timing to the release of CK-MB; however, they remained elevated for
as long as 7-10 days post-myocardial infarction. Initial studies
on the cardiac troponins revealed a subset of patients with rest
unstable angina in whom CK-MB levels were normal but who had elevated
troponin levels. These patients had higher adverse cardiac event rates
(acute myocardial infarction, death) within the 30 days after the index
admission and a natural history that closely resembled patients with
NSTEMI. The table below outlines many of the initial studies on
troponins in ACS.
Use of cardiac markers in the ED. Studies on troponins in ACS. As
previously mentioned, an elevated troponin level also enables risk
stratification of patients with ACS and identifies patients at high risk
for adverse cardiac events (ie, myocardial infarction, death) up to 6
months after the index event.
[3, 4] In
a study by Antman et al, the initial TnI level on admission in patients
with ACS correlated with mortality at 6 weeks. CK-MB levels, although
sensitive and specific for the diagnosis of acute myocardial infarction,
were not predictive of adverse cardiac events and had no prognostic
value.
[3] The relationship between TnI levels and risk of cardiac events and mortality is demonstrated in the graphs below.
Use of cardiac markers in the ED. Troponin I levels and cardiac mortality in ACS.
Use
of cardiac markers in the ED. Cardiac event rates in the platelet
receptor inhibition for ischemic syndrome (PRISM) study based on
troponin I results. Data from a meta-analysis indicated that
an elevated troponin level in patients without ST-segment elevation is
associated with a nearly 4-fold increase in cardiac mortality rate. For
the composite end point of acute myocardial infarction or death, an
elevated troponin level was associated with an odds ratio of 3.3.
[12] The
TIMI IIIB, GUSTO IIa, GUSTO IV ACS, and Fragmin During Instability in
Coronary Artery Disease (FRISC) trial all demonstrated a direct
correlation between the level of TnI or TnT and the adverse cardiac
event rate and mortality rate in ACS.
[3, 13, 14, 15, 16] These studies confirmed the use of the cardiac troponins TnI and TnT in risk stratification and therapeutic decision making. Studies
by Ohman et al and Stubbs et al revealed that an elevated troponin
level at baseline was an independent predictor of mortality even in
patients with chest pain and acute myocardial infarction with ST-segment
elevation who were eligible for reperfusion therapy.
[13, 17] With
the introduction of increasingly sensitive and precise troponin assays,
up to 80% of patients with acute myocardial infarction will be found to
have an elevated troponin within 2-3 hours of ED arrival. With this
improved clinical performance in cardiac troponin assays, the so-called
rapidly rising cardiac biomarkers, such as myoglobin or CK-MB isoforms,
have little clinical utility.
[18, 19, 20, 21] As a result, some authorities have called for a troponin standard alone and recommend eliminating CK-MB.
[22] The
2007 American College of Cardiology (ACC) guidelines for NSTEMI
recommend that serial troponins be obtained for a definitive rule out at
baseline and 6-9 hours later. To establish the diagnosis of acute
myocardial infarction, only 1 elevated level above the established
cutoff is required. The demonstration of a rising or falling level is
needed to distinguish persistently elevated troponin levels (eg, in some
patients with renal failure) from those patients with acute myocardial
infarction.
[23] If
myocardial injury is suspected despite negative cardiac-specific
troponin findings, additional, sensitive laboratory assays are
indicated.
[24] Measurement of Myoglobin LevelsMyoglobin
is not cardiac specific, but it may be detected as early as 2 hours
after myocardial necrosis starts. However, myoglobin results should be
supplemented with other, more specific cardiac biomarkers, such as CK-MB
or troponin. Myoglobin values have a high negative predictive value when blood is sampled in the first 4-8 hours after onset.
Complete Blood Count DeterminationThe
CBC count helps in ruling out anemia as a secondary cause of ACS.
Leukocytosis has prognostic value in the setting of acute myocardial
infarction.
Basic Metabolic PanelObtain
a basic metabolic profile, including a check of blood glucose level,
renal function, and electrolytes levels, for patients with new-onset
angina. Close monitoring of potassium and magnesium levels is important
in patients with ACS because low levels may predispose them to
ventricular arrhythmias. Routine measurement of serum potassium levels
and prompt correction are recommended. Creatinine levels must be
considered before using an angiotensin-converting enzyme (ACE) inhibitor
and particularly if cardiac catheterization is considered. Use of
N -acetylcysteine and adequate hydration can help prevent contrast material–induced nephropathy.
[25] Other useful metabolic profiles include amylase and lipase.
New Biomarkerslevels
of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP)
are elevated in acute MI and provide predictive information for risk
stratification across the spectrum of ACS.
[26, 27] However,
a single, low BNP level obtained within 4 hours of a patient presenting
to the ED does not identify the patient as low-risk for 30-day acute
myocardial infarction or death.
[28] In
the future, a combination of levels of troponin (a biomarker for
myocardial necrosis), NT-pro-BNP (an indicator of elevated LV
end-diastolic pressure and wall stress), and C-reactive protein (CRP, an
estimate of the extent of systemic inflammation) may prove useful for
predicting the outcome of patients with ACS. Routine measurement of BNP and CRP levels in patients with ACS is not warranted at this time.Interleukin-6
is the major determinant of acute-phase reactant proteins in the liver,
and serum amyloid A is another acute-phase reactant. Elevations of
either of these can be predictive in determining increased risk of
adverse outcomes in patients with unstable angina. Several other
biomarkers with variable sensitivity and specificity have been
investigated, including sCD40 ligand, myeloperoxidase,
pregnancy-associated plasma protein-A, choline, placental growth factor,
cystatin C, fatty acid binding protein, ischemia modified albumin,
chemokines ligand-5 and -18 (mediators of monocyte recruitment induced
by ischemia), angiogenin, SCUBE1 (a novel platelet protein), and others.
[29, 30] In
a study that included 107 patients presenting to an emergency
department with chest pain, ischemia modified albumin was not found to
have superior sensitivity and specificity over traditional biomarkers,
with a sensitivity of 0.86 and specificity of 0.49.
[31] Chest RadiographyChest
radiography helps in assessing cardiomegaly and pulmonary edema, or it
may reveal complications of ischemia, such as pulmonary edema. It may
also provide clues to alternative causes of symptoms, such as thoracic
aneurysm or pneumonia (which can be a precipitating cause of ACS).
EchocardiographyEchocardiograms
may play an important role in the setting of ACS. Regional wall-motion
abnormalities can be identified with this modality, and echocardiograms
are especially helpful if the diagnosis is questionable. An
echocardiogram can also help in defining the extent of an infarction and
in assessing overall function of the left and right ventricles. In
addition, an echocardiogram can help to identify complications, such as
acute mitral regurgitation, LV rupture, and pericardial effusion. Absence
of segmental wall-motion abnormality on echocardiography during active
chest discomfort is a highly reliable indicator of a nonischemic origin
of symptoms, although echocardiography is of limited value in patients
whose symptoms have resolved or who have pre-existing wall-motion
abnormalities.
Myocardial Perfusion ImagingRadionuclide
myocardial perfusion imaging has been shown to have favorable
diagnostic and prognostic value in the emergent setting, with an
excellent early sensitivity in the detection of acute myocardial
infarction not found in other testing modalities. A normal
resting perfusion imaging study has been shown to have a negative
predictive value of more than 99% in excluding myocardial infarction.
Observational and randomized trials of rest and stress imaging in the ED
evaluation of patients with chest pain have demonstrated reductions in
unnecessary hospitalizations and cost savings compared with routine
care. Perfusion imaging has also been used in risk stratification
after myocardial infarction and for measurement of infarct size to
evaluate reperfusion therapies. Novel "hot spot" imaging
radiopharmaceuticals that visualize infarction or ischemia are currently
undergoing evaluation and hold promise for future imaging of ACS.
Cardiac AngiographyCardiac catheterization helps in defining coronary anatomy and the extent of a patient’s disease. Patients
with cardiogenic shock, intractable angina (despite medication), severe
pulmonary congestion, or right ventricular (RV) infarction should
immediately undergo cardiac catheterization. (Cardiogenic shock is
defined as a systolic BP of less than 90 mm Hg in the presence of organ
hypoperfusion.) For high-risk patients with ACS without
persistent ST elevation, angiography with glycoprotein IIb/IIIa
inhibition has been recommended. The earlier that coronary angiography
is performed, the lower the risk of recurrent ischaemia.
[32] This also shortens the hospital stay for those patients. Most
patients benefit from angiography when they have a TIMI (Thrombolysis
in Myocardial Infarction) risk score of less than 3 points (see the
Table below). Table. TIMI Risk Score for Unstable Angina and NSTEMI
[33] (Open Table in a new window)Characteristic | Risk Score |
History |
Age ≥65 years | 1 |
At least 3 risk factors for coronary heart disease | 1 |
Previous coronary stenosis ≥50% | 1 |
Use of aspirin in previous 7 days | 1 |
Presentation |
At least 2 anginal episodes in the previous 24 hours | 1 |
ST-segment elevation on admission ECG | 1 |
Elevated levels of serum biomarkers | 1 |
Total Score | 0-7 |
Note: Event rates significantly increased as the TIMI risk score increased in the test cohort in the TIMI IIB study. Rates were 4.7% for a score of 0/1, 8.3% for 2, 13.2% for 3, 19.9% for 4, 26.2% for 5, and 40.9% for 6/7 (P < .001, χ2 test for the trend). The pattern of increasing event rates with increasing TIMI risk score was confirmed in all 3 validation groups (P < .001). |
Computed Tomography Coronary Angiography and CT Coronary Artery Calcium ScoringDual-source
64-slice CT scanners can do a full scan in 10 seconds and produce
high-resolution images that allow fine details of the patient's coronary
arteries to be seen. This technology allows for noninvasive and early
diagnosis of CAD and thus earlier treatment before the coronary arteries
become more or completely occluded. It permits direct visualization of
not only the lumen of the coronary arteries but also plaque within the
artery. Dual-source 64-slice CT scanning is being used with intravenous
(IV) contrast to determine if a stent or graft is open or closed. CT
coronary artery scoring is emerging as an attractive risk
stratification tool in patients who are low risk for ACS. This imaging
modality exposes the patient to very little radiation (1-2 msV). No
contrast is needed, and the study does not have a requirement for heart
rate.
[34] The
CAPTURE study, a randomized diagnostic trial, compared the efficacy a
comprehensive cardiothoracic CT examination in the evaluation of
patients presenting to the emergency department with undifferentiated
acute chest discomfort or dyspnea.
[35] Comprehensive
cardiothoracic CT scanning was reasonable, with a similar diagnostic
yield to dedicated protocols, but it did not reduce the length of stay,
rate of subsequent testing, or costs. The “triple rule out” protocol
might be helpful in the evaluation of select patients, but these
findings suggest that it should not be routinely used with the
expectation that it will improve efficiency or reduce resource use.
Other TechniquesOptical
coherence tomography (OCT), palpography, and virtual histology are
being studied for use in identifying vulnerable plaques.Noninvasive
whole-blood test prior to coronary angioplasty may be useful for
assessing obstructive CAD in patients without diabetes.
[36] Stress
cardiac magnetic resonance imaging (MRI) in an observation unit setting
has shown to reduce the medical costs, compared with inpatient care,
for patients who present with emergent, non-low-risk chest pain, without
missing acute coronary syndrome.
[37] The
CAPTURE study, a randomized diagnostic trial, compared the efficacy a
comprehensive cardiothoracic CT examination in the evaluation of
patients presenting to the emergency department with undifferentiated
acute chest discomfort or dyspnea.
[38] Comprehensive
cardiothoracic CT scanning was reasonable, with a similar diagnostic
yield to dedicated protocols, but it did not reduce the length of stay,
rate of subsequent testing, or costs. The “triple rule out” protocol
might be helpful in the evaluation of select patients, but these
findings suggest that it should not be routinely used with the
expectation that it will improve efficiency or reduce resource use.
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