The combined evaluation of myocardial perfusion and ventricular function can provide important diagnostic and prognostic information in the assessment of patients with coronary artery disease. Cardiovascular nuclear imaging represents an accurate and safe noninvasive imaging modality for assessment of both of these physiologic parameters, and the ability to do so using a single injection of tracer should result in its wider application and acceptance.
The evaluation of myocardial perfusion and ventricular function
provides important diagnostic and prognostic information in the
assessment of patients with known or suspected cardiovascular
disease. Cardiovascular nuclear imaging represents accurate, safe,
relatively inexpensive, and widely accepted noninvasive modalities
for assessing these physiologic parameters. The results of these
studies frequently influence clinical decisions in the medical care
of these patients.
Myocardial perfusion is assessed by the administration of
radiopharmaceuticals that are extracted from the blood pool and
distributed intracellularly within the myocardial tissue (e.g.
thallium-201 [Tl-201] or technetium-99m [Tc-99m] agents), whereas,
historically, ventricular function is assessed while the selected
radiopharmaceutical is still within the circulating blood pool.
Conventionally, ventricular function is evaluated by multigated
acquisition studies (MUGA) with either Tc-99m-labeled red blood
cells or human serum albumin that remains in the blood pool for a
prolonged period of time, or by first-pass radionuclide angiography
(RNA) that requires the administration of a high dose of a
radiopharmaceutical agent that needs to remain in the blood pool
for only a brief period of time. Several Tc-99m-labeled agents have
been used for first-pass RNA, including sodium pertechnetate,
diethylenetriamine penta-acetic acid (DTPA), and sulfur colloid, as
well as other radionuclides such as gold-195m and iridium-191m.
Historically, relative to the choices of radiopharmaceuticals, as
noted above, a decision had to be made prior to testing whether to
assess myocardial perfusion or ventricular function. In order to
fully assess both of these parameters, two separate studies had to
be performed at different times with the administration of two
Myocardial perfusion imaging has been used as an adjunct to
cardiovascular stress testing for many years and is a well
established imaging modality for the assessment of myocardial
ischemia. Myocardial perfusion studies can be acquired as planar
images, but the preferred imaging modality is single photon
emission computed tomography (SPECT). The two most commonly used
classes of radiopharmaceuticals for perfusion imaging are Tl-201
and Tc-99m agents.
Thallium-201, a cyclotron-produced radionuclide which acts as a
potassium analog and is extracted by the myocardium relative to
myocardial blood flow, has been used extensively for many years for
evaluating patients for myocardial ischemia and viability. All of
the early investigations, dating back to the 1970s, upon which the
foundation for myocardial perfusion imaging has been built, were
based on the pharmacokinetics of Tl-201. Some limitations of this
agent include its low photon energy of approximately 80 keV (the
characteristic x-ray of mercury-201) and its relatively long
half-life of 73 hours, which limits the average dose of this
myocardial perfusion tracer to approximately 4.0 mCi (148 MBq).
Technetium-99m agents also are distributed in the myocardium in
relationship to regional myocardial blood flow. These
radiopharmaceuticals offer several advantages over Tl-201. They are
available in a kit form and can be prepared on site, with Tc-99m
eluted from a standard molybdenum-99/Tc-99m gen-erator. The optimal
six-hour half-life of Tc-99m allows for a significantly higher dose
of radioactivity to be administered (as much as 30 mCi [1,110
MBq]), which results in better imaging statistics with higher count
rates than what is obtainable with Tl-201.
Myocardial perfusion scintigraphy with either Tl-201 or Tc-99m
agents is an accurate technique for the diagnosis of coronary
artery disease. Although these two perfusion tracers have different
characteristics and pharmacokinetics, they have comparable accuracy
in their diagnostic capabilities. Pooled data for exercise Tl-201
SPECT imaging has an average sensitivity of 92% and a specificity
of 68% for the diagnosis of coronary artery disease.1 Comparable
results are noted from pooled data for Tc-99m sestamibi SPECT
imaging, which has an average sensitivity of 89% and a slightly
higher specificity of 90% for the detection of coronary artery
In addition to demonstrating its value in the diagnosis of
coronary artery disease, myocardial perfusion imaging also has been
shown to be valuable in establishing patient prognosis and risk
stratification in a variety of clinical settings. In patients with
stable coronary artery disease, the number of ischemic myocardial
segments on perfusion imaging has been shown to be a powerful
predictor of future cardiac events.3,4 Multiple studies have
demonstrated that a normal myocardial perfusion imaging study
predicts a risk of only approximately 1% annual cardiac event
rate.5 Thus, the abnormal and the normal myocardial perfusion
imaging study have significant prognostic power for cardiac events
as related to the extent of perfusion abnormalities. In patients
who have had thrombolytic therapy, five-year mortality is
significantly higher in patients who demonstrate large perfusion
defects than in those with small perfusion defects.6 Finally, the
presence of reversible ischemia by myocardial perfusion
scintigraphy also has been found to be a significant predictor of
peri-operative cardiac events in patients undergoing non-cardiac
surgery.7 Therefore, the information provided to the clinical
services by myocardial perfusion imaging studies in patients with
known or suspected coronary artery disease has become an important
factor in the subsequent medical management of these patients.
Combined myocardial perfusion and ventricular functional
As early as 1984, using Tl-201 for perfusion and gold-195m for
first-pass RNA,8 and later in 1988, using Tl-201 for perfusion and
iridium-191m for first-pass RNA,9 assessment of myocardial
perfusion and ventricular function was performed simultaneously as
one test, but the injection of two separate radionuclides was still
required. Due to technical considerations, these techniques were
not popular or widely used.
The introduction of Tc-99m-labeled radiopharmaceuticals for
myocardial perfusion imaging ushered in a new era of enhanced
capabilities for performing the simultaneous assessment of
myocardial perfusion and ventricular function. Technetium-99m
agents have been shown to be reliable radiopharmaceuticals for the
assessment of myocardial perfusion,10-12 one of which, Tc-99m
sestamibi, also has been shown to be reliable in the assessment of
left ventricular function by first-pass RNA.13,14 The ability to
administer a higher dose of radioactivity and to perform
simultaneous assessment of myocardial perfusion and ventricular
function with a single injection of a Tc-99m-labeled
radiopharmaceutical13,15 has made these combined procedures more
widely available, and has led to the development of novel
techniques for acquiring this information with a single
radiopharmaceutical injection. The modalities for assessing
ventricular function that can be performed in conjunction with
myocardial perfusion, include first-pass RNA and gated SPECT
First-pass radionuclide angiography-First-pass RNA is a well
established nuclear imaging technique that has been used for many
years for the assessment of ventricular function. This technique
requires the delivery of a compact bolus of radiopharmaceutical
into the central circulation, and the ability to record high count
rates over a brief interval of time as the administered tracer
makes its first pass sequentially through the superior vena cava,
the right ventricle, the lungs, the left ventricle, and the aorta.
It is essential that the tracer administered for first pass RNA
studies be delivered as a compact bolus injection. Image quality is
directly related to the compactness of the bolus injection. The
temporal resolution required for processing the final data depends
upon a compact transit of the bolus of radioactive tracers.
Although this procedure can be performed with a large gauge
catheter in an antecubital vein in order to increase the likelihood
for a good compact bolus injection, the preferable sight for
injection of the first-pass RNA tracer is via a 20-gauge short
angiocath in an external jugular vein. In our experience, nuclear
medicine technologists have become proficient in the insertion of
external jugular venous catheters, and this approach has been
widely accepted by patients referred to nuclear cardiology for
these studies. Injection of tracer into a more peripheral vessel,
such as in the dorsum of the hand, cannot maintain a good bolus
effect, and this site generally is suboptimal for the performance
of these studies. First-pass RNA is optimally acquired by a
multi-crystal gamma camera that is specially designed for rapid
detection of high count rates such as those encountered during
first-pass RNA studies.
When Tc-99m sestamibi is injected for perfusion imaging, whether
the study is being performed as a one-day or a two-day protocol,16
there is adequate activity (minimal injected dose averages 10 mCi
[370 MBq]) to obtain a first-pass RNA study. When rest and stress
first-pass RNA studies are done in conjunction with perfusion
imaging using a Tc-99m agent, the resting study is performed in the
anterior projection with the patient standing or recumbent,
depending upon whether the stress portion of the study is done with
bicycle or treadmill exercise or with intravenous dobutamine. The
stress first-pass study is acquired at the peak effect of
intravenous dobutamine or at peak exercise on the bicycle or
treadmill. Patient motion at peak exercise may present somewhat of
a problem. However, motion can be corrected by a computer software
program that can track an isolated source of a second radionuclide
which is attached to one of the electrocardiographic chest leads
and has a different photon energy than Tc-99m (e.g. iodine-125 or
americium-241). The first-pass RNA study is acquired in such a
brief interval that it represents almost a snapshot of left
ventricular function at the true peak of stress.
Various measurements can be derived from the first-pass data,
including global and/or regional ventricular ejection fractions,
ventricular wall motion, left ventricular end systolic and end
diastolic volumes, and cardiac output. The ante-rior projection
allows for segmental wall motion analysis of the anterior wall,
inferior wall, and apex of the left ventricle. Rest and exercise
studies can be compared in order to evaluate for changes that may
occur in any of these parameters (figure 1). The left ventricular
ejection fraction (LVEF) at peak exercise has been shown to be a
powerful prognostic indicator in patients with coronary artery
disease.17 Therefore, this study has become an important adjunct to
the standard perfusion examination in the clinical assessment of
many of these patients.
Gated SPECT myocardial perfusion-Gated SPECT myocardial
perfusion imaging with Tc-99m sestamibi is a relatively new
modality in cardiovascular nuclear medicine.18 The success of this
adjunctive functional technique is also related to the higher count
rates provided by the Tc-99m-labeled radiopharmaceuticals for
myocardial perfusion. Many current SPECT imaging systems have the
capability of acquiring gated perfusion studies. As with a MUGA
study, the acquisition of the perfusion study is synchronized with
the patient's electrocardiogram, with the image acquisition divided
into eight frames per R-R interval and subsequently reviewed in a
cine format. The time for image acquisition is not significantly
lengthened by acquiring a perfusion study in a gated format, and
the data does provide additional functional information that allows
for the assessment of left ventricular wall motion (best evaluated
on a black-and-white monitor); left ventricular wall thickening, as
manifested by the degree of the increase in regional intensity of
the left ventricular myocardium during the cardiac cycle (best
evaluated on a color monitor); and calculation of an LVEF (figure
2).19-21 Chua et al20 have correlated gated SPECT assessment of
regional wall motion and wall thickening with echocardiography.
They found exact agreement in 91% of studies for wall motion and in
90% of studies for wall thickening. The stress gated SPECT study,
in contrast to a stress first-pass RNA, is acquired approximately
30 minutes after peak stress and, therefore, does not provide the
snapshot of left ventricular function at peak stress as does the
first-pass RNA study.
Benefits of simultaneous perfusion and functional imaging-The
left ventricular ejection fraction probably is the single most
important measurement of cardiac performance. It is a major
indicator of patient prognosis and is an important factor in risk
stratification. The LVEF has been shown to be a powerful prognostic
indicator of survival in patients with coronary artery disease.
Analysis of data from the Coronary Artery Surgery Study (CASS)
Registry has demonstrated progressively increasing mortality rates
as the resting LVEF decreases in patients on medical therapy.22 In
this study, four-year survival was 92% in patients with an LVEF of
50% or more, 83% in patients with an LVEF of 35 to 49%, and only
57% in patients with a LVEF of less than 35%. Prognostic data also
have been reported from results of LVEF determined during exercise
in patients with coronary artery disease. Data reported by Lee et
al17 demonstrated that the LVEF during exercise, which relates to
the extent of myocardial ischemia, provides significant incremental
prognostic information relative to coronary angiography and proved
to be a powerful predictor of patient survival. With a mean
follow-up of 5.4 years, patient survival progressively declined in
proportion to a decline in the exercise LVEF below 50%.
It has been demonstrated that regional myocardial perfusion with
Tc-99m sestamibi SPECT provides significant incremental information
over that provided by the exercise EKG alone, and assessment of
regional myocardial function from the exercise first-pass RNA
provides further significant incremental information over that
provided by the perfusion study in predicting the anatomical extent
of coronary artery disease.23 Borges-Neto et al, from our
laboratory, also have demonstrated that combined studies of
myocardial perfusion and left ventricular function by first-pass
RNA can significantly improve the prediction of the extent of
coronary artery disease, adding 31% of predictive information
beyond that of electrocardiographic and clinical data.24
Fixed myocardial perfusion defects that result from artifact due
to diaphragmatic attenuation or overlying soft-tissue attenuation
(breast, obesity, pectoralis muscles) are common occurrences in
myocardial perfusion imaging. These artifacts can decrease test
specificity when they are incorrectly interpreted as regions of
prior myocardial infarctions. Normal myocardium that demonstrates
attenuation artifact on perfusion imaging also should demonstrate
normal wall thickening and wall motion, whereas regions of
myocardial infarction should demonstrate significantly
diminished-to-absent wall thickening and wall motion. Thus,
correlation of fixed perfusion defects with corresponding segmental
functional analysis by first-pass RNA (wall motion) (figure 3) or
gated SPECT perfusion (wall motion and wall thickening) can
increase the level of confidence in the analysis of the perfusion
defects on the static myocardial perfusion images. Using gated
SPECT evaluation of fixed myocardial perfusion defects, DePuey and
Rozanski have reported an improvement in their false positive rate
for regional myocardial infarction from 14% to 3%.25
The combination of ventricular functional imaging with
myocardial perfusion imaging provides additional incremental
information that can assist in the diagnosis and prognostic
determination of patients with known or suspected coronary artery
disease. The ability to acquire perfusion and functional images
with a single injection of tracer should result in wider
application and acceptance of simultaneous first-pass RNA and/or
gated SPECT imaging with myocardial perfusion imaging. AR
1. Beller GA: Current status of nuclear cardiology techniques.
Curr Probl Cardiol 16:451-535, 1991.
2. Verani MS: Thallium-201 and technetium-99m perfusion agents:
Where are we in 1992? In: Zaret BL, Beller GA (eds): Nuclear
Cardiology - State of the Art and Future Directions, pp
St. Louis, Mosby, 1993.
3. Brown KA, Boucher CA, Okada RD, et al: Prognostic value of
exercise thallium-201 imaging in patients presenting for evaluation
of chest pain. J Am Coll Cardiol 1:994-1001, 1983.
4. Ladenheim ML, Pollock BH, Rozanski A, et al: Extent and
severity of myocardial hypoperfusion as predictors of prognosis in
patients with suspected coronary artery disease. J Am Coll Cardiol
5. Brown KA: Prognostic value of myocardial perfusion imaging:
State of the art and new developments. J Nucl Cardiol 3:516-537,
6. Cerqueira MD, Maynard C, Ritchie JL, et al: Long-term
survival in 618 patients from the Western Washington Streptokinase
in Myocardial Infarction trials. J Am Coll Cardiol 20:1452-1459,
7. Leppo J, Plaja J, Gionet M, et al: Noninvasive evaluation of
cardiac risk before elective vascular surgery. J Am Coll Cardiol
8. Narahara KA, Mena I, Maublant JC, et al: Simultaneous maximal
exercise radionuclide angiography and thallium stress perfusion
imaging. Am J Cardiol 53:812-817, 1984.
9. Verani MS, Lacy JL, Ball ME, et al: Simultaneous assessment
of regional ventricular function and perfusion utilizing
iridium-191m and thallium-201 during a single exercise test. Am J
Cardiac Imaging 2:206-213, 1988.
10. Taillefer R, Dupras G, Sporn V, et al: Myocardial perfusion
imaging with a new radiotracer, technetium-99m-hexamibi (methoxy
isobutyl isonitrile): Comparison with thallium-201 imaging. Clin
Nucl Med 14:89-96, 1989.
11. Iskandrian AS, Heo J, Kong B, et al: Use of technetium-99m
isonitrile (RP-30A) in assessing left ventricular perfusion and
function at rest and during exercise in coronary artery disease,
and comparison with coronary arteriography and exercise
thallium-201 SPECT imaging. Am J Cardiol 64:270-275, 1989.
12. Berman DS, Kiat H, Maddahi J: The new 99m-Tc myocardial
perfusion imaging agents: 99m-Tc-sestamibi and 99m-Tc-teboroxime.
Circulation 84(suppl 1):I-7-I-21, 1991.
13. Baillet GY, Mena IG, Kuperus JH, et al: Simultaneous
technetium-99m MIBI angiography and myocardial perfusion imaging. J
Nucl Med 30:38-44, 1989.
14. Williams KA, Taillon LA, Draho JM, et al: First-pass
radionuclide angiographic studies of left ventricular function with
technetium-99m-teboroxime, technetium-99m-sestamibi and
technetium-99m-DTPA. J Nucl Med 34:394-399, 1993.
15. Borges-Neto S, Coleman RE, Potts JM, et al: Combined
exercise radionuclide angiocardiography and single photon emission
computed tomography perfusion studies for assessment of coronary
artery disease. Semin Nucl Med 21:223-229, 1991.
16. Borges-Neto S, Coleman RE, Jones RH: Perfusion and function
at rest and treadmill exercise using technetium-99m-sestamibi:
Comparison of one- and two-day protocols in normal volunteers.
J Nucl Med 31:1128-1132, 1990.
17. Lee KL, Pryor DB, Pieper KS, et al: Prognostic value of
radionuclide angiography in medically treated patients with
coronary artery disease. Circulation 82:1705-1717, 1990.
18. Mannting F, Mannting MGM: Gated SPECT with
technetium-99m-sestamibi for assessment of myocardial perfusion
abnormalities. J Nucl Med 34:601-608, 1993.
19. DePuey EG, Nichols K, Dobrinsky C: Left ventricular ejection
fraction assessed from gated technetium-99m-sestamibi SPECT. J Nucl
Med 34:1871-1876, 1993.
20. Chua T, Kiat H, Germano G, et al: Gated technetium-99m
sestamibi for simultaneous assessment of stress myocardial
perfusion, post-exercise regional ventricular function and
myocardial viability. J Am Coll Cardiol 23:1107-1114, 1994.
21. Germano G, Kiat H, Kavanagh PB, et al: Automatic
quantification of ejection fraction from gated myocardial perfusion
SPECT. J Nucl Med 36:2138-2147, 1995.
22. Mock MB, Ringvist I, Fisher LD, et al, and Participants of
CASS: Survival of medically treated patients in the Coronary Artery
Surgery Study (CASS) Registry. Circulation 66:562-568, 1982.
23. Palmas W, Friedman JD, Diamond GA, et al: Incremental value
of simultaneous assessment of myocardial function and perfusion
with technetium-99m-sestamibi for prediction of extent of coronary
artery disease. J Am Coll Cardiol 25:1024-1031, 1995.
24. Borges-Neto S, Shaw LJ, Kesler KL, et al: Prediction of
severe coronary artery disease by combined rest and exercise
radionuclide angiocardiography and tomographic perfusion imaging
with technetium 99m-labeled sestamibi: A comparison with clinical
and electrocardiographic data. J Nucl Cardiol 4:189-194, 1997.
25. DePuey EG, Rozanski A: Using gated technetium-99m-sestamibi
SPECT to characterize fixed myocardial defects as infarct or
artifact. J Nucl Med 36:952-955, 1995.
Dr. Hanson is Chief of Nuclear Cardiology, Assistant Professor
of Radiology, and Assistant Professor of Internal Medicine at Duke
University Medical Center in Durham, NC.