Table of Contents
1. Indications for Radionuclide Myocardial Perfusion Imaging
(rMPI) with Stress Testing
2. Diagnostic Utility of rMPI
3. Exercise Stress Testing
a. Contraindications to Exercise Stress Testing
b. Indications for Terminating Exercise Stress Testing
c. Exercise Protocols
d. Monitoring During Exercise Stress Testing
4. Beyond ST Depression
5. Pharmacologic Stress Testing
a. Adenosine
b. Regadenoson
c. Dobutamine
6. The Basic Stress Testing Routine at the MUSC ART
7. Patients with LBBB or a Paced Ventricular Rhythm
8. Some Notes on SPECT
9.
Indications for rMPI with Stress Testing
The vast majority of “stress” testing (both exercise and pharmacologic) is performed on
adults with symptoms of known or probable ischemic heart disease. Candidates for
stress testing may have stable symptoms of chest pain, may be stabilized by medical
therapy following symptoms of unstable chest pain, or may have already had a
myocardial infarction or a revascularization procedure. The clinical suggestion of CAD
based on patient history findings, ECG tracings, and symptoms of chest pain must be
established and used as a guide to determine if stress testing may be useful according
to the Bayes theorem, which states that the diagnostic power of exercise stress testing
is maximal when the pretest probability of CAD is intermediate (30-70%) based on age,
sex, and the nature of the chest pain. When the diagnosis of CAD is certain, based on
age, sex, description of chest pain, and history of prior myocardial infarction, a clinical
need may arise for risk or prognostic assessment to reach a decision regarding possible
coronary angiography and further medical management. Myocardial infarction is a
common first presentation of ischemic heart disease. This subset of patients also may
require prognostic and/or risk or assessment.
Stable patients with an acute coronary syndrome (myocardial infarction or unstable
angina) may undergo a submaximal exercise test prior to discharge unless they have
undergone percutaneous coronary intervention or coronary artery bypass graft surgery
and been fully revascularized (eg, single vessel disease successfully treated with PCI).
The submaximal exercise test uses one of the following end points:
 A peak heart rate of 120 to 130 beats per minute or 70 % (not 85%) of the
maximal predicted heart rate for age
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A peak work level of 5 METs
Mild angina or dyspnea
≥2 mm of ST segment depression
Exertional hypotension
Three or more consecutive ventricular premature beats
Diagnostic Utility of rMPI
A meta-analysis compared the performance of the following tests in patients with an
intermediate pretest risk of CHD (25 to 75 percent): exercise ECG testing, planar
thallium imaging, SPECT perfusion imaging, stress echocardiography, and positron
emission tomography (PET), each of which was followed by coronary angiography if the
test was positive. The following values for sensitivity and specificity were noted:
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Exercise ECG testing — 68 and 77 percent in 132 studies of over 24,000
patients
Planar thallium rMPI (including both exercise and pharmacologic testing) —
79 and 73 percent in six studies of 510 patients.
Thallium SPECT rMPI (including both exercise and pharmacologic testing) —
88 and 77 percent in 10 studies of 1174 patients
Stress echocardiography — 76 and 88 percent in six studies of 510 patients
PET scanning — 91 and 82 percent in three studies of 206 patients.
In a second meta-analysis, 44 articles met criteria for determining the sensitivity and
specificity (compared to coronary angiography) of exercise SPECT rMPI and exercise
echocardiography for the diagnosis of CHD. The two tests had similar sensitivity (85
and 87 percent), but the specificity was significantly lower (ie, more false positives)
with exercise rMPI (77 versus 64 percent).
Exercise Stress Testing
All treadmill stress tests should by symptoms limited. In patients who are able to
exercise and can…
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achieve an adequate heart rate (defined as ≥85 % of their age-predicted
maximum where the maximal HR = 220 - age in years) and
achieve an adequate workload (defined as ≥80 percent functional aerobic
capacity). Adequate Functional capacity is >10 METs or normal for age:
Women 13.7-(0.13 x age) = METs.
Men 18 – (0.15 x age) = METs or 14.7 – (0.11 x age) = METs.
A less accurate and less desirable estimate of ‘adequate stress’ is provided by the
“double product” (ie the product of peak systolic blood pressure and heart rate
with adequate usually defined as ≥20,000).
The treadmill or bicycle (Europe) exercise is the preferred form of stress, because it
provides the most information concerning patient symptoms, cardiovascular function,
and prognosis.
Contraindications to Exercise Stress Testing
Some reasonable contraindications to exercise that are not specifically listed above:
 Marked ST segment depression (= to or >3 mmm)
 Ischemic ST segment elevation of >1 mm in leads without pathological Q waves
 Frequent appearance of non-sustained ventricular tachyarrythmia
 CNS symptoms
 Peripheral hypoperfusion
 Any factors that will impair the ability to monitor the EKG (ex. LBBB) or BP
 Severe pulmonary hypertension
Indications for Terminating Exercise Stress Testing
The optimal duration of an individual exercise test is one that is carried out until the
patient feels that he/she cannot exercise further. This is called a symptom-limited
maximal exercise test. However, the decision to stop an exercise test can be patientdetermined, protocol-determined, or physician-determined.
Some reasons to stop a stress test that aren’t listed above:
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Ischemic ST segment elevation of >1 mm in leads without pathological Q
waves.
CNS symptoms
Peripheral hypoperfusion
Technical difficulties in monitoring EKG or BP (a kind of equipment failure)
Exercise Protocols
The Bruce protocol is generally preferred for office-based exercise testing largely
because it has been carefully validated. The protocol is divided into successive three
minute stages, each of which requires the patient to walk faster and at a steeper grade.
Stage I is at an incline of 10 percent and a speed of 1.7 miles per hour; stage II
progresses to an incline of 12 percent and a speed of 2.5 miles per hour. The modified
Bruce protocol can be used for risk stratification of patients after an acute coronary
syndrome (myocardial infarction or unstable angina) and in sedentary patients in whom
the standard Bruce protocol may be too strenuous. The modified protocol adds two
low-workload stages, both of which require less effort than Stage 1, to the beginning of
the standard Bruce protocol.
The Cornell protocol was developed for use with computerized ST/HR slope
determination, a possibly improved method of quantitative exercise
electrocardiography. The ACC/AHA guidelines concluded that the ST/HR slope (the
rate-related change in exercise-induced ST segment depression) has not yet been
validated, but that it could prove useful in patients with borderline or equivocal ST
responses, such as ST segment depression associated with a very high exercise heart
rate. In the Cornell protocol, each stage of the Bruce protocol is divided into two
smaller and shorter stages. Although this was done to provide more data points for the
computerized ECG analyses, the protocol is also more applicable to patients with limited
exercise tolerance because of the smaller workload increments.
The Naughton protocol is often used in post-MI exercise testing to classify patients into
high-risk and low-risk categories and to determine optimal treatment strategies. This
protocol is also used for functional exercise testing with gas analysis techniques to
measure oxygen uptake and VO2max.
Regardless of the protocol used, patients should be instructed not to eat, drink, or
smoke for at least three hours prior to the examination, as this permits the patient to
achieve a higher workload. A brief interview by a physician or qualified health
professional should be performed prior to testing to rule out contraindications and to
gather information that will facilitate interpreting the test. All patient medications must
be identified since certain drugs will reduce the maximal heart rate that is achieved (eg,
beta-blockers, verapamil, diltiazem, and amiodarone), while other drugs, particularly
digoxin, are associated with a false-positive ECG response to exercise. In addition,
diuretic-induced hypokalemia can interfere with the interpretation of the ST segment
and T waves, and recent use of nitrates can minimize the ischemic response to exercise
in patients with coronary disease. In general, patients undergoing exercise testing for
diagnostic purposes should not take anti-ischemic medications or drugs that slow the
heart rate. However, anti-ischemic medications should be continued if the purpose of
the test is to establish prognosis or adequacy of anti-ischemic therapy. A limited
cardiac examination should be performed, with attention given to detecting heart
murmurs (particularly aortic stenosis), evidence of heart failure, and pulmonary findings
such as wheezing. Detecting mitral valve prolapse is also important, since this valve
lesion may be associated with a false positive ECG response to exercise.
Monitoring During Exercise Stress Testing
The most popular lead system for exercise ECG testing is a simple modification of the
standard 12-lead ECG with the arm and leg electrodes moved to the torso. It is
important that the arm electrodes be placed at the base of the shoulder just inside the
border of the deltoid muscles and 1 to 2 cm below the clavicles. More medially placed
electrodes are associated with false positive and false negative diagnostic errors for
myocardial infarction. The leg electrodes should be positioned below the umbilicus and
above the anterior superior iliac crest.
The resting ECG is sometimes obtained both supine and standing, since patient position
can influence the QRS and T wave axes. ECGs obtained during exercise should be
compared with the resting standing ECG, while ECGs obtained during recovery should
be compared with the resting ECG in the same position. The presence of an
arrhythmia, confirmed by the resting ECG, should be documented since it may have an
impact on exercise. Important examples are atrial fibrillation or atrial flutter which, if
not appropriately treated with an AV nodal blocking agent, may result in excessively
high heart rates during exercise.
During the exercise test, data should be obtained at the end of each stage and at any
time an abnormality is detected clinically (eg, chest pain) or on the monitor. Similarly,
during recovery from exercise, the ECG should be recorded every two minutes for 7 to
10 minutes until the heart rate slows below 100 beats per minute or the ECG waveform
returns to the control baseline pattern. In addition, continuous monitoring of the ECG
waveform in selected leads should be performed throughout the exercise period and
during recovery to assess cardiac rate, rhythm, and ST segment responses. During the
test, you can change the leads that are continuously displayed by clicking on their
labels. For example, rather than monitoring leads I, II, and III, you can monitor leads
aVR, II, and V5. By doing so, you’ll be very unlikely to miss any evolving St segment
changes. Ventricular arrhythmias can occur during the recovery period, and their
occurrence during recovery is associated with an increased risk of death during followup.
The ECG should be recorded after a brief cool-down, while the patient is still on the
treadmill or sitting on the bicycle. If significant ECG abnormalities did not develop
during exercise, and the test is being done to diagnose ischemia, the patient should
return to the supine position for the remainder of the recovery period. The increased
venous return in the supine position may precipitate ischemic abnormalities not seen
when upright on the treadmill. ST segment changes limited to the recovery period are
as predictive of underlying coronary disease as changes seen during exercise. If,
however, the patient develops ischemic ECG abnormalities during exercise, it may be
safer to have the patient sit during recovery to minimize the risk of increasing ischemia
and ventricular arrhythmias. Other abnormalities that occur during recovery also have
prognostic importance:
 A slower than expected fall in heart rate at one minute (≤12 to ≤18
beats/min; see below)
 A delayed fall in systolic pressure
 The development of frequent ventricular ectopy
The blood pressure should be measured at rest (supine and standing) and during the
last minute of each exercise stage. For ease of measurement, the arm should be
straightened and the hand placed on the shoulder or in the axilla of the person taking
the pressure. The systolic blood pressure should rise with each stage of exercise until
peak is achieved, while the diastolic pressure falls or remains unchanged.
In addition to monitoring and recording the presence of chest discomfort or dyspnea,
the American Heart Association recommends recording the patient's perceived level of
exertion during the last five seconds of each exercise minute using defined scales, such
as the rating of perceived exertion (RPE or Borg) scale.
Report exercise capacity in estimated metabolic equivalents (METs) of exercise. A MET
refers to the resting volume oxygen consumption per minute (VO2) for a 70-kg, 40year-old man. One MET is equivalent to 3.5 mL/min/kg of body weight.
Once you’ve reviewed the ECGs, write your interpretation somewhere on them. On the
resting ECG at the top right corner (adjacent to the resting ECG interpretation) is a
reasonable place. Be sure to report the rhythm and rate (eg, sinus tachy. To 167), any
arrhythmia, and any ischemic or other noteworthy changes. Some attendings may be
interested in additional indices that can be calculated from the exercise stress data (see
below), but others are not.
Beyond ST Depression
Exercise-induced ST segment elevation is uncommon except in leads showing previous
Q wave infarctions, but it does occur during stress testing in two groups of patients.
 Patients with severe and often multivessel CHD may develop transmural ischemia
because of a marked decrease in coronary blood flow to a segment of
myocardium during exercise. In contrast to ST depression, the leads showing ST
elevation in these patients localize the coronary artery responsible for the
ischemia. This difference was demonstrated in a study of 452 patients with
single vessel coronary disease undergoing exercise testing. ST depression
occurred most commonly in leads V5 or V6 regardless of which coronary artery
was involved. In contrast, anterior ST elevation indicated left anterior
descending coronary disease in 93 percent of cases, and inferior ST elevation
indicated a lesion in or proximal to the posterior descending artery in 86 percent
of cases.
 Variant or Prinzmetal's angina is characterized by episodic chest pain occurring
mostly at rest, ST segment elevation during pain, and coronary artery spasm.
Exercise-induced ST elevation occurs in 10 to 30 percent of patients with variant
angina.
In patients with single vessel disease (eg, an occluded artery with Q waves on the EKG)
in which ST segment elevation is associated with reciprocal depression in the
noninfarcted area, the reciprocal changes are indicative of residual viability in the
infarct-related area.
Exercise-induced ventricular ectopy occurs in 7 to 20 percent of patients undergoing
exercise ECG testing for known or suspected CHD. Most studies have noted an
association between exercise-induced ventricular arrhythmia and increased mortality
risk that may be limited to frequent ventricular ectopy during recovery. Atrial ectopy is
also frequent during exercise testing, but it does not appear to be an independent
predictor of adverse outcome.
Pharmacologic Stress Testing
Pharmacologic stress testing is generally used when contraindications to routine
exercise stress exist or when the patient is unable to exercise adequately for any reason
(eg, functional decline, limiting orthopedic problems, ataxia with risk for falls).
It should be noted that ST segment depression occurring during pharmacologic stress
has a high positive predictive value (90 percent); however, 70 percent of patients with
CHD who undergo pharmacologic stress testing show no ECG changes but positive
imaging results. Predictors of ST segment depression during vasodilator stress were
assessed in a report of 65 patients with CHD and reversible thallium defects after
adenosine infusion. Independent predictors of ST segment depression, which occurred
in one-third of patients, included the presence of collaterals at angiography (which may
predispose to coronary steal), higher baseline systolic blood pressure, and the
development of typical angina during infusion; in comparison, the size of the perfusion
defects and the extent of CHD were not predictors of ST segment depression. Thus, a
positive ECG response to vasodilator stress is a marker of significant coronary artery
disease and probably warrants further evaluation even in the presence of normal rMPI.
In comparison, the development of nonspecific chest pain during adenosine or
dipyridamole stress is not clearly associated with CHD and can occur in healthy
volunteers.
Coronary “steal” during vasodilation refers to an absolute decrease in flow distal to a
coronary stenosis in response to coronary vasodilation occurring either within the
coronary artery territory (endocardial to epicardial) or between coronary artery
territories.
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Intracoronary steal (from endocardium to subepicardial territory) occurs when
the coronary bed distal to a severe stenosis is perfused with collaterals from
another coronary artery territory. During vasodilatation, resistance in the normal
coronary artery falls, resulting in increased flow in areas without stenosis and
reduced collateral flow to stenotic artery segment.
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A perfusion defect and/or ST segment depression or elevation can occur if
coronary steal produces significant myocardial ischemia. In a report of 18
patients with steal, myocardial blood flow fell from 90 to 68 mL/100 g per min
after dipyridamole in the segments with steal, and increased from 87 to 138
mL/100 g per min in the segments without steal. Steal was associated with
either ST segment changes and angina.
Adenosine – Some Notes
Mechanism of action
Adenosine functions to regulate blood flow in many vascular beds, including the
myocardium. Adenosine activates the A1 and A2 cell surface receptors. In vascular
smooth muscle, adenosine primarily acts by activation of the A2 receptor, which
stimulates adenylate cyclase, leading to an increase in cyclic adenosine monophosphate
(cAMP) production. Increased cAMP levels inhibit calcium uptake by the sarcolemma,
causing smooth muscle relaxation and vasodilation. Activation of the vascular A1
receptor also occurs, which stimulates
guanylate cyclase, inducing cyclic guanosine monophosphate production, leading to
vasodilation. This direct coronary artery vasodilation induced by adenosine is
attenuated in diseased coronary arteries, which have a reduced coronary flow reserve
and cannot further dilate in response to adenosine. This is not the case in healthy or
less-diseased coronary arteries in the same patient, which produces relative flow
heterogeneity throughout the coronary arteries, resulting in relatively more coronary
blood flow in the healthy or less-diseased coronary arteries compared with the more
diseased coronary artery. In most cases, coronary blood flow in the diseased coronary
arteries does
not decrease. In cases of severe vessel stenosis or total occlusions with compensatory
collateral circulation, a decrease in coronary blood flow may occur in the diseased
coronary artery, thus inducing ischemia via a coronary steal phenomenon. This
regional flow abnormality also induces a perfusion defect during radionuclide imaging.
Indications
Any physical limitation that prevents a patient from exercising maximally is an indication
for vasodilator stress testing. Patients taking beta-blockers or other negative
chronotropic agents that would inhibit the ability to achieve an adequate heart rate
response to exercise are also appropriate candidates for vasodilator stress. Patients
with left bundle branch block or ventricular pacemaker (particularly those with severely
diseased AV nodes or status post-AV node ablation who are unable to override their
ventricular pacing rate) should undergo pharmacologic vasodilator stress because
exercise stress often produces a false-positive perfusion defect in the interventricular
septum. These defects are probably related to decreased septal contractility, which is
accompanied by an autoregulated fall in coronary blood flow to the interventricular
septum. Exercise stress or any other cause of tachycardia tends to enhance this
heterogeneous perfusion by increasing the flow proportionately more in the normally
contracting myocardium, resulting in a falsely underperfused interventricular septum on
perfusion imaging. Vasodilator stress has been shown to overcome this coronary blood
flow autoregulation, resulting in a more homogeneous perfusion pattern.
Contraindications
Adenosine and dipyridamole are contraindicated in patients with hypotension (since
both drugs lower the blood pressure), sick sinus syndrome or high degree
atrioventricular (AV) block without a functional PPM, and in patients receiving oral
dipyridamole therapy. Another concern is bronchospastic airway disease since both
drugs stimulate A2B receptors, which cause bronchospasm. Thus, adenosine and
dipyridamole should generally not be used in patients with pronounced bronchospastic
airway disease, even though this side effect may be promptly reversed by
aminophylline.
Absolute
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Patients with active bronchospasm or patients being treated for reactive airway
disease should not be administered adenosine because this can lead to
prolonged bronchospasm, which can be difficult to treat or can remain refractory.
Patients with more than first-degree heart block (without a ventricular-demand
pacemaker) should not undergo adenosine infusion because this may lead to
worsening of the heart block. While this is usually transient, due to the
extremely short half-life of adenosine (approximately 6 s), cases of prolonged
heart block (and asystole) have been reported.
Patients with an SBP less than 90 mm Hg should not undergo adenosine stress
testing because of the potential for further lowering of the blood pressure.
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Patients using dipyridamole or methylxanthines (eg, caffeine and aminophylline)
should not undergo an adenosine stress test because these substances act as
competitive inhibitors of adenosine at the receptor level, potentially decreasing
or completely attenuating the vasodilatory effect of adenosine. In general,
patients should refrain from ingesting caffeine for at least 24 hours prior to
adenosine administration. Patients should avoid decaffeinated products, which
typically contain some caffeine, as opposed to caffeine-free products, which do
not. More on this appears below.
Relative
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Patients with a remote history of reactive airway disease (COPD/asthma) that
has been quiescent for a long time (approximately 1 year) may be candidates for
adenosine. However, if a question exists concerning the status of the patients'
airway disease, a dobutamine stress test may be the safer choice.
Patients with a history of sick sinus syndrome (without a ventricular-demand
pacemaker) should undergo adenosine stress testing with caution. These
patients are prone to significant bradycardia with adenosine; therefore, use
caution if they are to undergo adenosine stress. Similarly, those patients with
severe bradycardia (heart rate of <45 bpm) should undergo adenosine stress
with caution.
Significant adverse events are uncommon with adenosine. In a registry report of 9,256
consecutive patients, the most frequent were second degree AV block (4.1 percent),
hypotension (1.8 percent), third degree AV block (0.8 percent), and bronchospasm (0.1
percent); there were no deaths. All these side effects resolved spontaneously and
rapidly with a reduction in the adenosine dose. Minor side effects are much more
common. In this same registry report, they occurred in 81 percent of patients, with the
most common being flushing, nausea, chest pain, dyspnea, and headache. These side
effects are rapidly reversed by terminating the infusion or by administering
aminophylline, which was required in 0.8 percent of patients.
Practical considerations
Adenosine is administered via an infusion pump at a dose of 140 µg/kg/min for six
minutes. The patient should have an intravenous line with a 3-way stopcock or should
have 2 intravenous lines. If one intravenous line is used, take care to inject the
radiopharmaceutical slowly because a bolus or any forceful injection will cause an
abrupt increase in the infusion rate of the adenosine running through the same line.
This can lead to significant AV nodal block. ECG monitoring of the vital signs is
necessary as with exercise stress testing. At the 3-minute mark, the stress
radiopharmaceutical is injected, and the infusion is continued for 3 more minutes.
Some have suggested that patients determined to be at high risk for complications (eg,
questionable history of asthma, hypotension, recent ischemic event, severe
bradycardia) should undergo an incremental 7-minute adenosine protocol. This
protocol starts at 50 mcg/kg/min and increases to 75, 100, and 140 mcg/kg/min at 1minute intervals followed by injection of the stress radiopharmaceutical at 1 minute
after the highest tolerated dose. The test continues for 3 minutes following injection of
the radiopharmaceutical, although some investigators have suggested discontinuation
of the infusion two minutes after the radionuclide injection. Some centers are now
using a 4-minute protocol in which the radiotracer is injected two minutes into the
infusion.
It has been suggested that the administration of aminophylline (50 mg by slow
intravenous injection) three minutes or more after the technetium is injected should not
interfere with imaging results since technetium-based tracers have minimal
redistribution. So, injecting aminophylline (to treat side effects of adenosine) three
minutes after the tracer is injected should not confound the MPI as long as the tracer is
technetium.
The 2003 ACC/AHA guidelines recommended that patients not use theophylline or
caffeine containing products for 24 hours prior to adenosine or dipyridamole stress.
This is based on studies of dipyridamole testing that suggest that caffeinated food,
beverages, or medications can reduce hyperemic blood flow, coronary flow reserve, the
increase in heart rate, and dipyridamole-induced defect size. However, caffeine, taken
as one cup of coffee one hour prior to the procedure, does not appear to interfere with
adenosine SPECT perfusion imaging. Similarly, caffeine does not appear to interfere
with the hyperemic response to regadenoson. The 2003 ACC/AHA guidelines were
published before the above observation suggesting that at least one cup of coffee does
not interfere with adenosine imaging. Until further data are available, instructing
patients to avoid caffeine for 24 hours prior to vasodilator stress testing is reasonable.
However, if a patient has consumed no more than one cup of coffee on the morning of
an adenosine or regadenoson SPECT, it seems reasonable to perform the test the same
day, preferably three to four hours after ingestion, and not to reschedule.
Early termination
The following are indications for early termination of adenosine infusion:
 Severe hypotension (SBP <90 mm Hg)
 Symptomatic Mobitz-I second-degree heart block
 Mobitz-II or third-degree heart block
 Bronchospasm
 Severe chest pain associated with ECG changes (>2 mm ST depression or any ST
elevation in a non–Q-wave lead)
In most cases, discontinuation of the adenosine infusion is followed by a prompt (<1
min) resolution or improvement of the adverse effect. In rare cases, aminophylline may
be required.
Adverse effects
Approximately 80% of patients experience minor adverse effects from adenosine
infusion. However, an absence of these effects does not imply a lack of efficacy of the
adenosine with respect to coronary vasodilation. The chest pain experienced during
adenosine infusion is very nonspecific and does not indicate the presence of CAD.
Three categories of adverse effects exist, including systemic effects (dizziness [7%],
headache [21%], symptomatic hypotension [3%], dyspnea [19%], flushing [35%]),
gastrointestinal effects (nausea
[5.1%]), and cardiac effects (chest pain [34%] and ST-segment changes [13%]).
Adenosine-walk protocol
For patients who are able, combined low-level treadmill exercise during adenosine
infusion has been demonstrated in several reports to be associated with a significant
decrease in the frequency of adverse effects (eg, flushing, nausea, headache). In
addition, less symptomatic hypotension and bradycardia occur. These studies have also
uniformly reported improved image quality, as demonstrated by an increased target-tobackground ratio. An additional advantage is that simultaneous low-level exercise
allows for immediate imaging, as would be performed with exercise stress testing. This
is due to the peripheral vasodilation and splanchnic vasoconstriction induced by
exercise.
Regadenoson (Lexiscan) – Some Notes
Regadenoson (Lexiscan) is a selective A2A receptor agonist that was FDA-approved for
use in rMPI in April of 2008. It produces hyperemia with rapid onset (30 seconds) for a
longer period (approximately two to five minutes) than adenosine, which permits more
convenient administration (injection of 400 mcg over 10 seconds). Straightforward
dosing (no weight adjustment) is likely to facilitate use and reduce errors due to dose
calculations. Small randomized double-blind studies of patients with mild or moderate
asthma who had bronchial reactivity to adenosine monophosphate and in patients with
moderate or severe chronic obstructive pulmonary disease found that regadenoson was
well tolerated with no significant differences in FEV1 compared to placebo. A study in
41 volunteers examined the effects of caffeine on resting and hyperemic myocardial
blood flow measured by PET in response to regadenoson. The results showed that
hyperemic flow and coronary flow reserve were not blunted by caffeine.
Mechanism of action
Coronary vasodilation and an increase in coronary blood flow (CBF) results from
activation of the A2A adenosine receptor by regadenoson.
Dosing and administration
The recommended intravenous dose of regadenoson is 5 mL (0.4 mg regadenoson)
administered as a rapid (approximately 10 seconds) injection into a peripheral vein
using a 22 gauge or larger catheter or needle. This should be followed by a saline flush
immediately after the injection of regadenoson. The radionuclide myocardial perfusion
imaging agent is given 10–20 seconds after the saline flush. The radionuclide may be
injected directly into the same catheter as regadenoson.
Indications
Same as adenosine.
Hemodynamic effects
A rapid increase in coronary blow flow of a short duration occurs with regadenoson.
Clinical studies showed that most patients manifested a decrease in blood pressure and
an increase in heart rate after administration of regadenoson.
Contraindications
Regadenoson should not be administered to patients with sinus node dysfunction,
Mobitz type II second-degree atrioventricular block, or complete heart block (unless
these patients have a functioning ventricular pacemaker). Also, active wheezing (but
not a history of reactive airway disease) is a contraindication.
Practical considerations
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit. Do not
administer regadenoson if it contains particulate matter or is discolored.
Adverse effects
During clinical development, of 1,337 patients in whom regadenoson was administered,
adverse effects occurred in 80% as follows: dyspnea (28%), headache (26%), flushing
(16%), chest discomfort (13%), angina pectoris or ST-segment depression (12%),
dizziness (8%), chest pain (7%), nausea (6%), abdominal discomfort (5%), dysgeusia
(5%), and feeling hot (5%).
Dobutamine – Some Notes
Mechanism of action
Dobutamine is a synthetic catecholamine, which directly stimulates both beta-1 and
beta-2 receptors. A dose-related increase in heart rate, blood pressure, and myocardial
contractility occurs. As with physical exertion, dobutamine increases regional
myocardial blood flow based on physiological principles of coronary flow reserve. A
dissimilar dose-related increase in subepicardial and subendocardial blood flow occurs
within vascular beds supplied by significantly stenosed arteries, with most of the
increase occurring within the subepicardium rather than the subendocardium. Thus,
perfusion abnormalities are induced by the development of regional myocardial
ischemia.
Indications
Consider dobutamine as a second-line pharmacologic stressor to be used in patients
who cannot perform exercise stress and have a contraindication to vasodilator stress.
Dobutamine is specifically indicated in the following groups of patients:
 Patients who have contraindications to vasodilators, including patients who have
chronic obstructive pulmonary disease or asthma (adenosine and, indirectly,
dipyridamole promote bronchospasm)
 Patients who are taking theophylline or have ingested caffeine within the past 24
hours (both are adenosine receptor antagonists and can interfere with imaging
results)
Hemodynamic effects
A dose-related increase in both heart rate and SBP occurs with dobutamine. However,
diastolic pressure falls as the dose of dobutamine increases. These hemodynamic
changes are similar to those of exercise stress.
Contraindications
Patients with recent (1 week) myocardial infarction; unstable angina; significant aortic
stenosis or obstructive cardiomyopathy; atrial tachyarrhythmias with uncontrolled
ventricular response; history of ventricular tachycardia, uncontrolled hypertension, or
thoracic aortic aneurysm; left bundle branch block; or a V-paced rhythm should not
undergo dobutamine stress testing.
Practical considerations
In general, the diagnostic accuracy of dobutamine rMPI is comparable to exercise or
vasodilator rMPI. Dobutamine is administered in graded doses, beginning with 5 to 10
µg/kg per minute, up to a maximum dose of 30 to 40 µg/kg per minute; three minute
stages are adequate, with radionuclide injection at peak stress. Atropine or arm/leg
exercise should be added before the radionuclide if 85 percent of the maximum
predicted heart rate is not achieved at the peak dose of dobutamine; otherwise, the
presence and severity of CHD may be underestimated.
Dobutamine must be infused using an infusion pump. The patient should have an
intravenous line with a 3-way stopcock or should have 2 intravenous lines. If 1
intravenous line is used, take care to infuse the radiopharmaceutical slowly because a
bolus or forceful injection will cause an abrupt increase in the infusion rate of the
dobutamine running through the same line, which can lead to significant
tachycardia, hypotension, and myocardial ischemia. Perform standard ECG and blood
pressure monitoring as with exercise stress testing.
Once the target heart rate is achieved, the radiopharmaceutical is injected and the
dobutamine infusion is discontinued. The indications for early termination of
dobutamine stress testing are similar to those of exercise stress testing.
ST elevation and ventricular tachycardia are more likely with dobutamine stress testing
than any other type of stress testing. Typically, adverse effects requiring early
termination subside within 5-10 minutes of discontinuation of the infusion (the half-life
of dobutamine is 2 minutes). The effect of dobutamine can be reversed with betablockers; typically, an intravenous agent with an ultrashort half-life, such as esmolol, is
used. Because most patients who undergo dobutamine stress testing have
bronchospastic lung disease, beta-blockers should be used with caution.
Adverse effects
In a review of 1118 patients who underwent dobutamine stress echocardiography, the
main reasons for test termination were achievement of target heart rate (52 percent),
administration of maximum dobutamine dose (23 percent), and development of angina
(13 percent). Adverse effects occur in approximately 75% of patients undergoing
dobutamine stress testing: effects include ST changes (50%), chest pain (31%),
palpitations (29%), and significant supraventricular or ventricular arrhythmias (8-10%).
The Basic Stress Testing Routine at the MUSC
ART
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The nurses usually do this part…
At the home page, click "NEW TEST” to bring up a list of all previously
studied patients.
o If the current patient is listed, highlight his/her name and click "SELECT.”
o If the current patient is not listed, click "NEW PATIENT" and enter the
requested information.
The nurses will also…
o Clean and shave (if necessary) the patient's chest to ensure good
conductivity of electrodes.
o Properly place the 10 electrodes on the patients chest.
o Ensure the IV site is patent by flushing 5-10cc of normal saline.
o Place the blood pressure cuff on the patient's arm that doesn’t have the
IV access and take a resting BP reading and document on database sheet.
o Call or Page the Cardiology Fellow or NP to supervise the test.
Perform a brief H & P to identify the indication for the test as well as any
contraindications to exercise or pharmacologic agents.
Tell the patient what to inspect on the treadmill and/or from the adenosine or
regadenoson. Obtain informed consent. Note the 1/10,000 risk of MI, stroke,
life-threatening arrhythmia, or death.
Go to the computer. Confirm the nurse-entered patient selection/data. Click
“ACCEPT” (if needed), then click “SELECT.”
Choose the protocol you’ll be using. There is no regadenoson protocol, so
choose adenosine if you plan to use regadenoson.
Instruct the patient to keep very still and relaxed, and press the “12SL” button to
get a baseline EKG complete with calculated intervals and a computer
interpretation. You can also get a plain EKG by pressing the other EKG button.
Get the patient onto the treadmill, provide some anticipatory guidance, and press
the “EXERCISE” button. This will bring the treadmill up (Bruce protocol), but the
treadmill won’t start until you press the “START TREADMILL” button. Know
where the “STOP EXERCISE” and emergency stop (on the treadmill itself)
buttons are before starting the treadmill. If you’re using the adenosine protocol,
pressing the “EXERCISE” button will start the timer. The treadmill will not move.
The physician will monitor the EKG strips for arrhythmia or ischemic changes
constantly. Leads I, II, and III are displayed by default. The displayed leads
can be changed by clicking on the label. Changing the display to include leads
avR, II, and V5 is reasonable since you’ll be very unlikely to miss any significant
ST deviation when monitoring these 3 leads.
The RN will monitor the patients BP and overall physical condition during
exercise.
Once the patient is at their target HR, the physician will notify the NM
Technologist to inject the RP into the established IV site followed by 10 cc of
normal saline. After injection, the physician will encourage the patient to
continue to walk for at least one more minute to ensure good uptake of the RP
into the myocardium.
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At the end of exercise, press the “RECOVERY” button. Note that’s adjacent to
the “EXERCISE” button and that the labels are positioned poorly. If the
“EXERCISE” button is pressed instead of the “RECOVERY” button by accident,
the treadmill will progress to the next stage of exercise instead of stopping.
Continue monitoring of the patient’s EKG, HR, BP, and general condition until the
HR returns to <100 and the patient feels pretty much back to normal (usually 35 minutes).
Press the “END TEST” button. Enter the requested information. If you include
the Duke Treadmill Score, be sure to confirm the data that the computer is using
and to click “CALCULATE” after any adjustments. Otherwise, you’ll get a
misleading DTS.
Print the test report before clicking “NEW TEST.”
The computer will ask if you want to save the ECG data. If there was any
significant arrhythmia, doing so is probably reasonable.
Patients with LBBB or a Paced Ventricular
Rhythm
In patients with ventricular pacing, use adenosine (or regadenoson) myocardial
perfusion imaging. In patients with LBBB, use adenosine (or regadenoson) myocardial
perfusion imaging or dobutamine stress echocardiography.
Left bundle branch block can interfere with exercise rMPI. Among patients who
undergo exercise rMPI, LBBB is associated with transient positive defects in the
anteroseptal and septal regions in the absence of a lesion within the left anterior
descending coronary artery (LAD) in approximately 10 to 20 percent of cases. Thus,
there is a high rate of false positive tests when exercise rMPI is performed in patients
with LBBB. In the largest study of 383 patients with LBBB, perfusion rMPI was
performed in conjunction with exercise in 206, adenosine in 127, and dobutamine in 50;
coronary angiography was performed in 154. Among the 77 patients undergoing
exercise rMPI in whom angiography was performed, 57 had a septal defect during
exercise that was falsely positive in 26 (46 percent). As a result, the specificity for LAD
disease was much lower with exercise rMPI (36 versus 81 and 80 percent with
adenosine and dobutamine) and the false positive rate for septal defects was much
higher with exercise compared to pharmacologic studies (46 versus 10 percent). A
similarly low specificity with exercise rMPI for disease in the coronary arteries supplying
the septum was noted in another report (42 versus 82 percent with adenosine rMPI).
Because of the low specificity for septal defects, exercise was associated with a
significantly lower positive predictive value than adenosine or dobutamine (64 versus 90
and 96 percent).
A paced right ventricular rhythm produces LBBB on the ECG. Like LBBB, a paced
ventricular rhythm produces false positive defects on exercise rMPI if pacing continues
during exercise. Studies in humans suggest that the inferoposterior, inferior, and apical
walls are the most common sites of false positive perfusion defects with right
ventricular pacing in contrast to the septum in patients with “natural” LBBB.
There is evidence and/or general agreement that cardiac stress imaging as the initial
test for risk stratification of patients with angina who are able to exercise is not useful
in the presence of left bundle branch block (ACC/AHA class III).
Some Notes on SPECT
SPECT stands for Single Photon Emission Computed Tomography, a nuclear medicine
procedure in which a gamma camera rotates around the patient and takes pictures
from many angles, which a computer then uses to form a tomographic (cross-sectional)
image.
Perfusion defects during vasodilator stress rMPI reflect the heterogeneity in coronary
flow reserve between normal and diseased coronary artery territories. Blood flow in
normal coronary arteries may increase up to fourfold in response to increased demand
via adenosine-mediated autoregulation (coronary flow reserve): endogenously produced
adenosine causes direct relaxation of the coronary arterioles (resistance vessels), which
results in increased blood flow. In the presence of coronary stenosis, part of the
coronary flow reserve is already in action in order to maintain resting blood flow.
Consequently, in a moderately-narrowed artery the blunted coronary flow reserve can
be detected if a perfusion tracer is injected during adenosine-induced hyperemia. The
tracer uptake in the myocardium supplied by the narrowed artery will be reduced
compared to the myocardium supplied by arteries without significant stenosis.
Coronary flow reserve is exhausted in severely-stenosed arteries, and even resting
blood flow is diminished. Both SPECT and PET imaging can detect these regional
differences in tracer uptake. Absolute quantification of coronary blood flow is possible
only with PET imaging.
A normal 201-Tl or 99m-Tc-sestamibi scan is generally associated with low risk of future
cardiac events (less than 1 percent per year). One report, for example, evaluated
5,183 consecutive patients with known or suspected CHD who underwent resting
thallium SPECT and an exercise or pharmacologic stress sestamibi SPECT. At 1.8 years
of follow-up, the 2,946 patients with a normal scan had a low risk for cardiac death or
myocardial infarction (≤0.5 and ≤0.3 percent per year, respectively). Among patients
with a normal scan, the prognosis is worse in those with known CHD or diabetes and in
males and older patients. The magnitude of these relationships was illustrated in a
review of 7,376 consecutive patients with a normal exercise or adenosine rMPI. An 80year-old man with diabetes and known CHD had a relatively high rate of cardiac death
or MI at two years (4.9 percent), while a 50-year-old woman without diabetes or known
CHD was at minimal risk (0.1 percent).
High-risk features on rMPI predicting an increased risk of cardiac events include
extensive ischemia involving more than 20 percent of the left ventricle, defects or
reversible ischemia in more than one coronary vascular supply region, transient or
persistent left ventricular cavity dilatation, and increased lung uptake of thallium or
sestamibi, a marker of exercise-induced left ventricular dysfunction that is best
assessed by obtaining a five minute post-stress and four hour redistribution or rest
anterior planar scan before the initiation of SPECT imaging.
Transient left ventricular dilation can occur (37 percent of cases in one series) during
pharmacologic stress testing. It is probably due to an absolute or relative decrease in
subendocardial blood flow, has a strong association with electrocardiographic signs of
ischemia, correlates with the severity and extent of the perfusion abnormality, is a
marker of high risk, and is a strong independent predictor of cardiac events.
Attenuation artifacts decrease the specificity of SPECT imaging. Attenuation correction
based on standard computed tomography can help eliminate attenuation artifacts. This
was illustrated in a prospective multicenter clinical trial. The normalcy rate was used as
a surrogate for specificity; it was defined as the rate of normal perfusion scans in
patients with <5 percent likelihood of CHD on the basis of clinical and ECG stress data.
The application of attenuation/scatter correction and resolution compensation
significantly improved the normalcy rate compared to uncorrected perfusion data using
either the corrected images (96 versus 86 percent) or the corrected data and
quantitative analysis (97 percent versus 86 percent). There was no reduction in overall
sensitivity (75 to 78 percent), although the detection of multivessel disease was
reduced.
99m-Tc gated SPECT imaging permits the assessment of systolic wall thickening at enddiastole and end-systole on multiple SPECT tomograms. Normal systolic thickening in a
fixed defect on both rest and stress images represents an attenuation artifact rather
than a myocardial scar, which is associated with reduced systolic thickening.
One limitation to gated SPECT measurement of LVEF after stress is that moderate to
severe stress-induced ischemia can cause myocardial stunning. As a result, the poststress LVEF may not reflect true left ventricular function at rest if only a post-stress
scan is obtained. In one report, the post-stress LVEF was more than 5 percent lower
than resting values in 36 percent of patients with reversible perfusion defects.
Calcium channel blockers, nitrates, and beta blockers can significantly alter the extent
and severity of perfusion defects as seen by dipyridamole or adenosine imaging. As a
result, the extent of coronary disease may be underestimated when these drugs are
given. The following approach to testing in patients taking calcium channel blockers,
nitrates, or beta blockers is reasonable:
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If the purpose of the test is for follow-up after an intervention (either medical or
surgical), these medications should be continued.
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If the purpose of the study is for diagnosis, these medications should be
discontinued if this can be accomplished safely. Calcium channel blockers and
nitrates should be discontinued for 24 hours, while beta blockers should be
discontinued for 48 hours.
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Patients should be advised to bring their medications with them to take after the
stress test.