Nuclear medicine offers unique insight into the pathophysiology of any system being imaged. Its use in the diagnosis of cardiac disease is becoming more widespread as its utility and cost-effectiveness is increasingly being realized. This article reviews the major classes of nuclear medicine's techniques, the features of its cardiac applications, and the future developments that may further its applicability.
In keeping with the prevalence and social impact of cardiac
disease, the role of diagnostic techniques in nuclear medicine is
rapidly growing in importance. These techniques have a proven
utility based on their ability to offer unique insight into the
pathophysiology of any system being imaged. More importantly, with
the trend toward managed healthcare and cost capitation, the
cost-effectiveness of nuclear medicine is increasingly being
realized. This article reviews the two major classes of nuclear
medicine techniques, namely, blood pool imaging, in which a
radiotracer in the blood is used for assessment of contractile
function, and perfusion imaging, in which the analysis of the
delivery of radiotracers to the myocardium is used to assess
myocardial perfusion. Other less widespread, but nonetheless
important, techniques such as imaging using positron emitters and
infarct avid imaging also are discussed. Finally, future
developments are described in view of their potential to further
the applicability of these techniques.
Blood pool imaging
First-pass studies-In this type of study, the information is
gained by tracking the initial transit of a radiotracer through the
heart. Thus, a proper injection technique is critical. The
antecubital vein must be cannulated with at least a 20-gauge
needle, properly secured, and attached to a three way stopcock and
two syringes, one containing the radiotracer in a small volume
(<1 ml) and the other containing a saline flush (10 ml to 20
ml). With the arm abducted and resting comfortably, the radiotracer
is then injected, immediately followed by the saline, flushed
strongly, as the tourniquet is released and the acquisition
Although any non-particulate radiotracer can be used, those that
rapidly clear from the blood such as Tc-99m-DTPA and Tc-99m-sulphur
colloid are preferred because they allow multiple studies to be
performed with little residual from any preceding study. The data
are recorded at a rate of at least 20 frames per second. The
passage of the bolus normally can be seen in the superior vena
cava, the right atrium and ventricle, the lungs, the left atrium
and ventricle, and finally out the aorta (figure 1). This sequence
is disrupted in right-to-left shunts by the appearance of the
tracer in the left side of the heart before passage through the
The magnitude may be estimated by comparing the counts in
appropriately drawn regions of interest. A left-to-right shunt may
be recognized as a reduction in the peak of the time-activity
curve, and the magnitude is best quantified by the
pulmonary-to-systemic flow (Qp:Qs) ratio. This ratio is determined
by a curve-fitting analysis of the pulmonary time-activity curve,
with a Qp:Qs ratio of greater than 1.2 indicating significant
left-to-right shunting.1 Reflux of activity into the jugular vein
may be seen in tricuspid valve disease. Other valvular diseases
manifest themselves by their effects on chamber size and function.
The ejection fractions of the right and left sides of the heart can
be measured separately using a composite curve for a region of
interest over each ventricle that is calculated by summing in phase
the six or seven beats with maximum activity (figure 2).
Rapid imaging and temporal separation of the two sides of the
heart with assessment of the transit times are two advantages of
first-pass studies. The disadvantage is that, with a single-headed
camera, only one projection can be recorded per injection.
Equilibrium studies-These studies involve imaging following the
radiolabelling of the blood pool with an agent such as an RBC or
albumin. Here, the goal is to obtain the "average" heart beat.
Using an R-wave trigger, the computer records an image of the heart
by splitting the R-R interval into 16 to 32 electronic bins. Only a
few events are recorded into each successive bin with each beat,
but repeating the process for 500 to 1000 beats yields sufficient
counts to form a representative time-activity curve for the left
ventricle (best seen in the left anterior oblique projection).
This curve can be Fourier analyzed to yield the end systolic and
diastolic volumes, the regional and global ejection fractions, the
peak emptying and filling rates, and the amplitude and phase of the
contraction (figure 3).2,3 While the parameters yielded by such an
analysis can be reported from a printout, the interpretation of
these studies must include viewing all the data on a computer
screen, especially in a cinematic loop. The serial assessment of
these parameters is important in the management of cardiomyopathy
and the use of cardiotoxic chemotherapeutic agents.
Nuclear probe studies-A non-imaging variant of equilibrium
studies uses a probe detector instead of a gamma camera. This
permits ambulatory measurements of the ejection fraction.4
Choice of stress-Many forms of stress have been shown to be
adequate for myocardial perfusion imaging. Recently, however,
pharmacological stress has been gaining acceptance because of its
ease, reproducibility, and freedom from patient motivation and/or
Physical stress-This remains the physiological standard. It may
be performed on an ergometer, starting at 25 watts per minute and
increasing by 25 watts per minute every three minutes thereafter,
or a calibrated treadmill with an increasing speed and gradient to
impose a similar workload.5 The endpoints are a) achievement of 70%
to 80% of the age-predicted maximum heart rate; b) the appearance
of serious symptoms such as progressive angina, a drop in blood
pressure or heart rate, severe dyspnea or faintness, or ventricular
arrhythmias; or c) symptoms such as marked ST segment depression,
atrial arrhythmias, AV blocks, marked elevation of blood pressure,
chest pain with no electrocardiographic changes, or fatigue.
Pharmacological stress-There are two main classes of drugs used
to cause cardiac stress for perfusion imaging purposes. The choice
depends primarily on whether or not the patient has significant
pulmonary disease, such as asthma, which would require the use of
inhalers. In this scenario, vasodilators would not be the agents of
Vasodilators-These agents are postulated to affect the
intracellular cyclic AMP and GMP levels, along with calcium, via
the A2 receptors, which results in coronary hyperemia that is
indirect in the case of dipyridamole and direct in the case of
adenosine. The use of caffeine and other methylxanthine compounds,
such as those in tea, chocolate, several types of cola drinks, and
certain over-the-counter medications, should be discontinued at
least 24 hours before the test to avoid a reduction in sensitivity,
which may require a 50% increase in the vasodilator dose used. It
is useful to give each patient a prepared list of the agents to be
Dipyridamole-The dose is 0.56 mg/kg infused over 4 minutes, with
infusion of the imaging agent 3 to 5 minutes later. Side effects of
dipyridamole are mostly flushing and nausea, but occasionally
bronchospasm requiring the use of aminophylline may be induced.6
The drug's duration of action is about 30 minutes, and the patient
will require some supervision after the test.
Adenosine-A six-minute infusion at the rate of 140 mcg/kg per
minute is given, with the injection of the radiotracer during the
third minute. The incidence of minor side effects such as flushing
is higher compared to dipyridamole, and the frequency of AV blocks,
usually mild and transient, mandates close supervision during the
infusion.7 Adenosine has a short duration of action: only 2 to 3
minutes. Two advantages arising from this, however, are that most
of the side effects or blocks that occur during the test can be
relieved by merely stopping the infusion, and prolonged supervision
after the test is not necessary.
Inotropes- The prime candidates for the use of these agents are
those with COPD, asthma, or allergy to the vasodilator agents.
These drugs exert their effects via beta-1 agonist activity to
increase myocardial contractility, thus increasing oxygen demand.
Hypertension, especially in severe cases, and atrial fibrillation
or flutter are important contraindications. If these agents are
used in patients who are not asthmatics, beta blocker
administration should be stopped at least 48 hours before the
Dobutamine-Depending on the patient's condition, the dose can be
started at 5 mcg/kg per minute for five minutes, and increased in
steps of 5 mcg/kg every five minutes, to a maximum infusion rate of
30 mcg/kg per minute. Alternatively, an infusion starting at 10
mcg/kg per minute, increased by the same every three minutes, to a
maximum of 40 mcg/kg per minute, also can be given.8 Both protocols
can be titrated according to the patient's response. The
radiotracer is injected at the onset of significant symptoms, ECG
changes, or achievement of the maximal rate of infusion or heart
rate, and the infusion is maintained for an additional two minutes,
with titration adjusted to the condition of the patient.
Arbutamine-This newer agent is more potent than dobutamine.
Additionally, it is available in the market with its own
computerized delivery system that titrates the dose rate
automatically, thereby reducing the workload of the supervising
Choice of imaging agent-The two major radionuclides used for
perfusion imaging are thallium-201 (T1-201) as a solution of its
chloride salt, and technetium-99m (Tc-99m), coupled to one of three
classes of agents: isonitriles (e.g. MIBI), boronic acid oximes
(e.g. teboroxime), or phosphines (e.g. tetrofosmin). While the
properties of each are further described below, it is important to
recognize their major differences. Tl-201 is a low energy emitter;
its administration dosage is limited by its relatively higher
radiation level as compared to the optimal physical characteristics
of Tc-99m. However, Tl-201 has a higher total accumulation in the
myocardium, and can provide redistribution information which is
relevant in assessing viability.
Depending mainly on the logistics at a particular center,
combined protocols, such as rest Tl-201 followed by stress
Tc-99m-MIBI imaging, can be chosen.10,11 This is made possible by
the fact that while there is considerable downscatter from the
Tc-99m into the Tl-201 energy window (about 30%), there is very
little crosstalk between the Tl-201 and Tc-99m windows (about 3%),
so that a lower activity, lower energy Tl-201 imaging scan can be
performed first. However, the performance characteristics must be
carefully evaluated with extensive phantom studies before comparing
clinical images, due to the differences in processing (especially
filtering) necessitated by the different energies.
Regardless of which agent is used, it is important to remember
that, as a rough estimate, the half-value thickness in tissue is
only about 3 cm for the Tl-201, and only about 4.5 cm for Tc-99m.
This means that the deeper parts of the heart, such as the inferior
wall, or those overlain with dense/large tissue (i.e. breast
tissue), such as the anterolateral wall, will appear less avid on
images in spite of equal uptake. Techniques such as attenuation
correction, which may reduce but not totally eliminate this
disparity, may be employed to counteract this limitation.
Thallium-201-This radionuclide is produced from the conversion
of stable thallium-203 into lead-201 by the (p,3n) reaction in a
cyclotron. It has a half-life of 9.4 hours, after which it decays
into thallium-201, which in turn decays with a half-life of 74
hours into stable mercury-201; both transformations occur by
electron capture. The 69-83 KeV mercury-201 x-rays, along with a
smaller abundance of 135 KeV (2%) and 167 KeV (8%) gamma photons,
are available for imaging. The low energy x-rays and the relatively
long half-life make for less than ideal imaging characteristics,
and limit the total administered activity per procedure to 3 mCi to
4 mCi, either as a single dose with imaging immediately post-stress
and at 3 hours, or split into 2 mCi for the stress study, followed
3 hours later by a 1 mCi re-injection and a rest study 30 minutes
later. Either protocol can include delayed imaging at 24 hours for
a viability study (figure 4).
The myocardium takes up the administered activity by the Na-K
ATPase system with a first-pass extraction of 80% to 90%. The
overall amount taken up varies from about 3% to 4% at rest up to
about 8% to 10% with dipyridamole stress. The initial uptake is
proportional to regional perfusion (figure 5), and differences may
be displayed as polar plots, also called bull's eye views (figure
6). The distribution of Tl-201 is not static after this initial
uptake. Clearance from the myocardium is proportional to the
regional perfusion, so that areas with normal perfusion that took
up relatively greater amounts initially also lose this activity at
a rate greater than that from less well-perfused areas.12
Additionally, areas with greatly reduced perfusion continue to
increase their accumulation slowly, so that by 24 hours they may
show uptake, thus indicating their viability as compared to
nonviable areas that persist as defects in uptake. It is this
dynamic pattern of distribution that makes Tl-201 the current agent
of choice in assessing viability. Additional information such as
the calculation of the heart-to-lung ratios is of value in
assessing triple-vessel disease. In this, increased activity in the
lungs, seen despite a relatively normal pattern of distribution
within the myocardium itself, may belie the severity of the
Technetium-99m-This workhorse radionuclide of nuclear medicine
is popular because of its low cost, low radiation dose, easy
availability, and excellent imaging characteristics (figure 7).
Other advantages include flexible scheduling and increased patient
throughput; however, these advantages are somewhat offset by the
characteristics of the agents it is coupled to for myocardial
perfusion imaging. While gated SPECT, which can correlate perfusion
with regional contractile dysfunction (figure 8), is possible with
these agents, overall, they are less well suited to assess
viability, and they have demonstrated a lower defect reversibility.
More development and evaluation will be required before these
agents, or their successors, can replace Tl-201. Some of the more
important derivatives amongst these are described briefly:
Tc-99m-MIBI-The uptake of this cationic lipophilic isonitrile
complex, which associates intracellularly with myocyte
mitochondria, is proportional to the regional perfusion of the
myocardium, albeit nonlinearly, with a fall-off in extraction at
higher rates of flow. Both the first-pass extraction (about 40%)
and overall accumulation (about 4%) of Tc-99m-MIBI are only half
that of Tl-201 at stress, with significant amounts of hepatic
activity that can cause artifacts and problems in interpretation.13
The subsequent washout is also much slower, necessitating the use
of separate injections for the stress and rest studies. A
particular advantage of this slow washout is that an injection can
be made in the emergency room at admission for a suspected cardiac
event that reflects the perfusion at initial presentation, with
imaging possible for several hours after stabilization of the
Tc-99m-teboroxime-This neutral bor- onic acid oxime complex has
first-pass extraction and total accumulation levels comparable to
that of Tl-201, and also exhibits a biexponential washout from the
myocardium.14 However, there is higher background from lung and
liver activity in contrast to Tl-201, negating some of this agent's
advantages. Thus, the imaging protocol represents a compromise
between the conflicting requirements of high background requiring a
delay for clearance and the rapid component of redistribution
requiring early onset of imaging. This component also causes
reconstruction artifacts, which require the use of triple-headed
cameras or rapid, repeated acquisitions on older machines for
Tc-99m-tetrofosmin-This diphosphine complex, as well as its
related compounds Q12 (furifosmin) and Q3, have lower first-pass
extraction and overall accumulation levels compared to Tl-201,15
but offer what is, perhaps, a better compromise, due to their slow
myocardial washout with rapid background clearance. However, rapid
redistribution studies for viability are not possible.
Infarct avid imaging
The fact that acute myocardial infarction may be silent in up to
one-fourth of patients, and the ability to use reperfusion therapy
to improve outcomes, if given early in the course of the disease,
make the detection of myocardial necrosis increasingly important.
While several agents have been used for this purpose, the most
widely used are Tc-99m-pyrophosphate (PYP) and Tc-99m-antimyosin
Tc-99m-pyrophosphate-PYP is thought to localize in damaged
myocardial tissue by combining with the calcium that is known to
accumulate in these areas. The largest levels of accumulation occur
with a 60% to 70% reduction in flow, with a reduction in
accumulation from this peak seen with greater levels of occlusion.
This may lead to a doughnut-shaped pattern of uptake, which
indicates a worse prognosis. The accumulation can be detected as
early as 6 hours after an infarction, but is usually better seen at
24 hours, with the peak occurring at around 48 to 72 hours and
persisting for several days thereafter.16
Problems with the use of PYP include overlying activity in the
ribs, significantly reduced sensitivity for nontransmural infarcts
compared to transmural infarcts (which are usually detectable by
conventional modalities anyway), and a false-positive incidence of
10%; these have a wide variety of causes, the more important
being blood pool activity, recent cardioversion, cardiac contusion,
previous infarcts, valvular calcifications, and cardiomyopathy.
Tc-99m-antimyosin Fab fragments-In order to provide a specific
marker of irreversible myocyte damage, Fab fragments of an
antibody, raised against the water-insoluble heavy chains of
cardiac myosin that are exposed due to necrosis, have been used
with some success.17 (Radioisotopes of iodine, and indium-111 have
also been used as radiolabels.) Localization occurs only in acute
infarcts, and the intensity decreases as the infarcts heal. The
sensitivity achievable with this agent is around 95%.
Positron emission tomography (PET)
The use of positron emitters to assess damage to the heart
offers the advantages of 1000-fold improvement in sensitivity of
event detection, and a two-fold improvement in resolution, albeit
at greater cost and more limited availability. PET can provide
information both about perfusion and metabolism.
Perfusion-Regional perfusion can be imaged with
nitrogen-13-ammmonia, oxygen-15-water, and rubidium-82. This last
agent has the advantage of being available from a strontium-82
generator, enabling it to be used without an on-site cyclotron.
Overall, while the accuracy of perfusion for detecting fixed
lesions is similar to that of Tl-201, it is reportedly higher for
Metabolism-Several agents, each looking at a particular
metabolic pathway, have been evaluated with good results.
Fluorine-18-deoxyglucose correlates with the rate of glycolysis and
shows a focal increase in areas of mild reduction in perfusion.
This mismatch, that is, an area of reduced perfusion as seen on a
Tl-201 scan (or with a Tc99m agent) showing a focal increase in
F-18-DG uptake, is an important predictor of improvement in
regional function after surgical intervention, with over 90% of
matching defects on perfusion and F-18-DG images not improving
Carbon-11-palmitate assesses beta-oxidation, and reduction of
uptake correlates with the severity of ischemia. Carbon-11-acetate
has been suggested to evaluate tricarboxylic acid cycle activity,
with delayed clearance indicating impairment, and may offer the
ability to estimate regional oxygen consumption.
Receptor and inflammation imaging
Receptor imaging-Various receptors play a role in the regulation
of cardiac activity and the pathogenesis of important diseases of
the heart. While these can be imaged with use of appropriate
agents, such as iodine-123-MIBG, carbon-11-propanolol,
carbon-11-prazosin, flourine-18 metaraminol, and
hydrogen-3-methylscopolamine, it is iodine-123-MIBG that has been
evaluated the most due to its single-photon emission and wider
availability. Reductions in MIBG uptake correlate with the severity
of heart failure and idiopathic cardiomyopathy, with the
heart-to-mediastinum activity ratios serving as better predictors
of survival than ejection fraction and echocardiography.20 This
agent also has been used to assess neuronal damage after
infarction, which correlates with wall motion abnormalities and
Inflammation-In addition to the use of PYP and antimyosin
fragments for the asessment of myocarditis, non-specific agents
such as gallium-67-citrate and Tc99m-antigranulocyte antibodies may
have a limited role in assessment of pericarditis and subacute
infective endocarditis, respectively.
The role of nuclear medicine presented here is likely to be
in the future due to the recent progress in equipment and
reconstruction techniques. Of particular interest is the ability to
perform attenuation correction, which employs a transmission source
(for example, gadolinium-153) to estimate the distribution of
attenuation within each patient, and then uses this information to
correct the emission data. Another interesting development is the
use of F-18-DG as a single-photon emitter with specially adapted
gamma cameras in an attempt to obviate the need for expensive
dedicated PET scanners. The use of iterative reconstruction
techniques, with their improvement in image quality, is also
increasing due to the affordability of powerful computers. Initial
results for these are encouraging, but further experience is
required before they are incorporated into mainstream technologies.
The authors thank Dr. Ronald G. Schwarz and Ms. Marie Mackin for
providing some of the figures used in this article.
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