201T1 DISTRIBUTION AND BLOOD FLOW/Nielsen et al.
to regional myocardial perfusion. Circulation 51: 641, 1975
12. Bradley-Moore PR, Lebowitz E, Greene MW, Atkins HL, Ansari AN: Thallium-201 for medical use. II. Biologic behavior. J
Nucl Med 16: 156, 1975
13. Beller GA, Watson DD, Pohost GM: Kinetics of thallium distribution and redistribution: clinical applications in sequential
797
myocardial imaging. In Cardiovascular Nuclear Medicine, 2nd
ed, edited by Strauss HW, Pitt B. St. Louis, CV Mosby, 1979,
pp 225-242
14. Schwartz JS, Ponto R, Carlyle P, Forstrom L, Cohn JN: Early
redistribution of thallium-201 after temporary ischemia. Circulation 57: 332, 1978
Linear Relationship Between the Distribution
of Thallium-201 and Blood Flow in Ischemic
and Nonischemic Myocardium During Exercise
ANTON P. NIELSEN, M.D., KENNETH G. MORRIS, M.D., ROBERT MURDOCK, B.S.,
FREDERICK P. BRUNO, M.S., AND FREDERICK R. COBB, M.D.
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SUMMARY The purpose of this study was to compare the myocardial distribution of thallium-201 and
regional myocardial blood flow during ischemia and the physiologic stress of exercise. Studies were carried out
in six dogs with chronically implanted catheters in the atrium and aorta and a snare on the circumflex coronary
artery distal to the first marginal branch. Regional myocardial blood flow was measured during quiet, resting
conditions using 7-10 , of radioisotope-labeled microspheres. Each dog was then exercised on a treadmill at
speeds of 5-9 mph at a 50 incline. After 1 minute of exercise the circumflex coronary artery was occluded and
thallium-201 and a second label of microspheres were injected. Exercise was continued for 5 minutes. The dogs
were then sacrificed and the left ventricle was sectioned into approximately 80 1-2-g samples to compare
thallium-201 activity and regional myocardial blood flow.
The maximum increase in blood flow ranged from 3.3-7.2 times resting control values. Each dog had
myocardial samples in which blood flow was markedly reduced, to less than 0.10 ml/min/g. In each dog there
was a close linear relationship between thallium-201 distribution and direct measurements of regional myocardial blood flow. Linear regression analyses demonstrated a correlation coefficient of 0.98 or greater in each
dog. These data indicate that during the physiologic stress of exercise, the myocardial distribution of thallium
activity is linearly related to regional myocardial blood flow in both the ischemic and nonischemic regions.
THALLIUM-201 is the most frequently used
radioisotope tracer to evaluate regional myocardial
perfusion. Although thallium-201 scintigrams of the
heart during rest and exercise stress testing have been
useful for diagnosing coronary artery disease, a
number of patients with significant coronary artery
disease by cardiac catheterization do not demonstrate
deficits on thallium scintigrams. -3 This apparent insensitivity to significant disease may be related to
several variables, including limitation of available imaging equipment,4 inability to resolve small perfusion
deficits,4 early redistribution of radioisotope,5 variable
interpretation of signlficant anatomic disease, variable
relationship between anatomic disease and clinical
From the Departments of Medicine, Division of Cardiology and
Radiology, Duke University Medical Center and the Veterans Administration Medical Center, Durham, North Carolina.
Supported in part by USPHS grant HL 18537, SCOR grant HL
17670 from the NHLBI, and the Medical Research Service of the
Veterans Administration Medical Center.
Address for correspondence: Frederick R. Cobb, M.D., Division
of Cardiology, Veterans Administration Medical Center, 508
Fulton Street, Durham, North Carolina 27705.
Received May 29, 1979; revision accepted October 10, 1979.
Circulation 61, No. 4, 1980.
manifestation of ischemia,6 and inconsistent relationship between thallium-201 distribution and myocardial blood flow.6, 8' Although experimental studies
have demonstrated a close linear relationship between
thallium-20 1 activity and direct measurements of
regional myocardial blood flow after acute coronary
artery occlusion,4 7 certain studies have indicated that
the thallium-20 1 distribution may not be linearly
related to myocardial perfusion when blood flow is increased above control values.6 8, 9 The relationship
between the myocardial distribution of thallium-201
and regional myocardial perfusion during ischemia
and the physiologic stress of exercise has not been
reported.
In this study we compared the myocardial distribution of thallium-201 and regional myocardial blood
flow during exercise and ischemia. Direct
measurements of regional myocardial blood flow were
made using the radioisotope-labeled microsphere
technique.10, X1
Methods
Six mongrel dogs were trained to run on a
motorized treadmill using positive reinforcement techniques. Each dog was anesthetized with thiamylal
798
VOL 61, No 4, APRIL 1980
CIRCULATION
sodium 30-40 mg/kg i.v. and mechanically ventilated.
A left thoracotomy was performed in the fourth left
intercostal space. The circumflex coronary artery was
dissected free just beyond the first marginal branch. A
pneumatic cuff occluder was positioned around the
vessel. Polyvinyl chloride catheters, 3 mm o.d., were
filled with heparin and inserted into the left atrium via
the left atrial appendage and in the aortic arch via the
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left internal thoracic artery. The occluder and
catheters were tunneled to a subcutaneous pouch at
the base of the neck.
At least 6 days were allowed to assure that the dogs
had recovered from the surgery. The day before the
study, the dogs were sedated with thiamylal sodium 10
mg/kg i.v., the pouch was infiltrated with lidocaine
and the catheters and snare were exteriorized. Each
dog was placed in a protective vest to prevent damage
to the catheters and snare. A period of 14-24 hours
was allowed for recovery from this procedure.
Each dog was given lidocaine 2 mg/kg i.v., and
quinidine gluconate 6 mg/kg i.m. 15 minutes and 1
hour before the exercise study. Before exercise
myocardial blood flow was measured using "'Nblabeled 7-10-g microspheres during quiet, resting conditions as previously described.'0' The dogs were
then placed on a motorized treadmill and run at
speeds of 5-9 mph at a 50 incline. After 1 minute of
running time, the circumflex coronary occluder was
inflated. Thallium-201, 0.5 mCi, was injected into the
left atrium 30 seconds after complete occlusion.
Scandium-46-labeled microspheres were injected into
the left atrium immediately after the thallium-201 injection, approximately 45 seconds after occlusion.
Beginning with the injection of radioisotope, serial
blood samples were withdrawn from the aortic
catheter at a measured flow rate as previously
described to facilitate calculation of regional blood
flow,'"11 and to measure serial changes in arterial
thallium activity. The dogs were run for a total of 5
minutes after coronary artery occlusion. Immediately
after the exercise period, each dog was anesthetized
with 40 mg/kg thiamylal sodium and the heart was
fibrillated with potassium chloride solution. The heart
was immediately removed and cooled to approximately 5-10°C.
The hearts were then prepared for sectioning by
removing the right ventricle, atria, aorta and pericardial fat. The left ventricle was then sectioned into 4
transverse layers of approximately equal thickness as
previously described.10' 11 The apical ring was sectioned into anterior and posterior regions. The other
rings were sectioned into anterior, anterior papillary,
lateral, posterior papillary, posterior and septal
regions. Each region was further sectioned into four
transmural layers of approximately equal thickness.
This procedure produced approximately 80 1-2-g
tissue samples for comparison of blood flow and
thallium-201 distribution.
Thallium-201 activity in each tissue and blood sample was counted in a gamma spectrometer, 50-100keV window. The samples were held for 1 week to
allow for high-energy contaminate isotopes of
thallium-201 to decay. The tissue samples and
reference blood samples were then counted for 95Nb
and 46Sc radioactivity in a gamma spectrometer at optimum window settings selected to correspond to the
peak energies of each nuclide. The counts per minute
recorded in each window from the myocardial and
reference blood samples were corrected for
background activity and spillover activity contributed
by the accompanying isotope by an appropriate computer program.'0 11 Flow to each region of the
myocardium was calculated in ml/min using the formula:
Qrn
=
Qr
X
Cm/Cr
where Qm - myocardial blood flow (ml/min), Qr =
reference blood flow (ml/min), Cm = counts activity
in the myocardium, and Cr = count activity in
reference blood samples. Myocardial blood flow
(ml/min) was divided by the sample weight and expressed as ml/min/g.
The relationship between thallium-201 distribution
and regional myocardial blood flow was analyzed by
linear regression analyses.
Results
Table 1 lists mean blood flow during quiet resting
conditions and the maximum blood flow during exercise in each dog. The maximum increase in blood flow
in individual dogs ranged from 3.3-7.2 times values
during resting conditions. In each dog there were
myocardial samples in which blood flow was markedly
reduced, to less than 0.10 ml/min/g. It was thus possible to compare the distribution of thallium-201 activity and myocardial blood flow over a wide range of
ischemic and nonischemic blood flow measurements.
The relationship between the regional distribution
of thallium-201 and myocardial blood flow during
ischemia and treadmill exercise in each dog is illustrated in figure 1. In each dog there was a close
linear relationship between thallium-201 distribution
and direct measurements of regional myocardial
blood flow; linear regression analyses demonstrated a
correlation coefficient of 0.98 or greater in each dog.
The intercept on the y-axis, thallium-201 activity, was
significantly greater than zero, mean intercepts 0.10 X
106, range 0.061-0.178 X 106 counts/min/g (p <
0.05).
Figure 2 is a representative illustration of thallium
TABLE 1. Mean Myocardial Blood Flow During Resting Conditions Before Exercise and Maximum Blood Flow Daring
Exercise
Myocardial blood flow (ml/min/g)
Basal
Maximum exercise
Dog
1
0.85
2.80
2
0.80
3.30
3
4
5
6
0.62
0.68
0.71
0.90
2.90
4.90
2.80
3.80
]~ 0
201T1 DISTRIBUTION AND BLOOD FLOW/Nielsen et al.
799
4
000 * 0
3.0
2.5
00
0
00
2.0
00
0
1.5p
W
0
0
i.0
0.5
0
2.5
0
*
n8
00
00
0,
000 00
0
0
0
r=0.99
000
*
2
00 0
n=80
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1.5
i.0
c:
(-)
H
0r 0.99
0.5
0
3.0
0
-
000
0
*".@0
0
0
0
0
r = 0.98
*
*
Basal MBF =0.80
3
Basal MBF = 0.68 ml/min/9
5
0
-j
00
00
00
*:
Basal MBF = 0.85 ml/min/g
2.0
-J
.0
*.:*,0
_
0
0 0
0
* 00.
00
*00
0
0
E
C
n =85
n=76
0*
r =0.99
0
ml/min/g
.000
Basal MBF- 0.71 ml/min/g
6
n =80
n =84
.0.0
2.5
*00:0
..0 0
2.0
Basa
'-"
1.5
0
* 0*00
00
MBF0.62m*
i0
~Basal MBF = 0.62 ml/min/g
I.0
0
0.5
0
Bsa
r=0.99
,. Basal MBF =10.90 ml/min/g
0.5
1.0 1.5 2.0 2.5 3.0 3.5
1.0
2.0
MYOCARDIAL BLOOD FLOW mi/min/gm
FIGURE 1. The relationship between thallium-201 activity and myocardial blood.flow
dogs during exercise and ischemia. n = number of samples analyzed.
activity in the arterial blood as a function of time after
injection. Thallium activity in the arterial blood
decreased as an exponential function. Five minutes
after thallium injection and immediately before
sacrifice, thallium activity in the arterial blood
decreased approximately tenfold.
3.0
4.0
5.0
(ml/minlg) in six
Discussion
Previous studies have demonstrated a close linear
relationship between the myocardial distribution of
thallium-201 and the distribution of myocardial blood
flow after acute coronary artery occlusion.4 7 Other
800
VOL 61, No 4, APRIL 1980
CIRCULATION
75
0
c:
FIGURE 2. Serial measurement of arterial
thallium-201 activity after left atrial in-
E
jection.
X
50 -
C
D
:3
U
25
I
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04
-
30
60
90
120
s
150 180
time - seconds
210
240
studies have concluded that when blood flow is increased above control values the distribution of
thallium-201 and blood flow may not be linear.6' 8, 9
This apparent dissociation between the myocardial
distribution of thallium-201 and blood flow during
conditions of increased flow must be interpreted in
terms of whether the augmentation in blood flow
results from direct vasomotor effects on the coronary
vasculature, increased metabolic demands of the
myocardium, or a combination of the two factors.
Adenosine and dipyridamole are potent coronary
vasodilators that have direct vasomotor effects on the
coronary vasculature. Adenosine infusion may increase myocardial blood flow four- to sixfold.'0' " The
increase in myocardial blood flow during adenosine infusion is associated with no change or a decrease in
myocardial oxygen utilization and a marked decrease
in coronary arteriovenous oxygen differences.'2
Transient myocardial ischemia may also effect
maximum increase in myocardial blood flow."
Although the reactive hyperemic response that follows
transient ischemic stimulation is related to the
metabolic state of the myocardium,"3 the oxygen debt
incurred during transient ischemia is overpaid threeto sixfold during the reactive hyperemic response and
coronary arteriovenous oxygen difference decreases.14
Coffman and Gregg14 have suggested that transient
ischemia is a greater stimulus to coronary blood flow
than to myocardial oxygen utilization. Treadmill exercise, on the other hand, is a potent stimulus to
myocardial metabolism; myocardial oxygen utilization and coronary arteriovenous oxygen difference increase during exercise.'5 Myocardial blood flow may
increase more than fourfold in dogs during heavy exercise on a treadmill."' 16 Increasing the heart rate by artificial pacing is a relatively less potent stimulus to
blood flow and myocardial oxygen demands; ventricular pacing at rates of 120-240 beats/min
augmented coronary blood flow only approximately
270
300
50%."" 18 Coronary arteriovenous oxygen difference
increases during rapid ventricular pacing.'8
Strauss et al.,6 using acute animal preparations,
observed that thallium activity increased approximately 60% of that measured directly by
microsphere techniques when blood flow was increased by transient myocardial ischemia. Weich et
al., using acute animal preparations,8 measured the
myocardial extraction of thallium-201. They found
that 87% of thallium-201 was extracted from the blood
during the first pass through the heart and that the extraction fraction decreased when blood flow was increased above control values by transient ischemic
stimulation or adenosine and minoxidal, but did not
change when blood flow was increased by atrial pacing. The extraction fraction was not changed by insulin, propranolol, alkalosis, or acetyl strophanthan,
but was reduced by hypoxia. These investigators
reasoned that when blood flow increases in proportion to myocardial demands, the extraction fraction
remained constant, but when blood flow exceeds
myocardial demands, the extraction fraction decreases logarithmically. This hypothesis was not
tested over a wide range of physiologic increases in
blood flow and oxygen demands because atrial pacing
increased coronary blood flow only approximately
88% above control values. Gould9 determined the ratio
of myocardial/background counts of thallium-201
and technetium-99m-macroaggregated albumin
microspheres in dogs in response to dipyridamole and
treadmill exercise. He observed that during
dipyridamole infusion the ratio of technetium-99mmacroaggregated albumin was 4.5, compared with a
thallium-201 ratio of 2.4. In the studies by Gould,
treadmill exercise resulted in smaller increases in the
myocardial/background ratio of technetium-99mmacroaggregated albumin microspheres; the mean
ratio during exercise was 2.3. In a representative study
the myocardial/background ratio of thallium-201 was
20"T1 DISTRIBUTION AND BLOOD FLOW/Nielsen et al.
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1.5 at rest and 2.0 at exercise. These studies support
the view that when myocardial blood flow is increased
in excess of oxygen demands, the myocardial distribution of thallium-201 is not proportional to
myocardial blood flow. Previous studies have not
directly assessed the myocardial distribution of
thallium-201 and regional blood flow over the wide
range of physiologic flows that may occur during
treadmill exercise.
In the present study the combination of ischemia
and the physiologic stress of exercise provided a wide
range of measurements for comparison of the myocardial distribution of thallium-201 and blood flow.
Blood flow increased three- to sevenfold with the
above control values; there were regions of severe
ischemia with blood flow less than 0.10 ml/min/g in
each dog. There was a close linear relationship
between the myocardial distribution of thallium-201
and regional myocardial blood flow; regression
analysis between thallium activity and regional
myocardial blood flow demonstrated correlation
coefficients of 0.98 or greater in each dog.
In the present study the animals were sacrificed 5
minutes after injection of thallium-201. Schwartz et
al.19 observed that the myocardial extraction of
thallium-201 may become negative approximately 10
minutes after i.v. injection, suggesting relatively early
loss of thallium activity from the normal myocardium.
Schwartz et al.'9 and Pohost et al.5 have described
early redistribution of thallium-201 activity to the
ischemic region after restoration of blood flow.
Therefore, when myocardial thallium-201 activity is
assessed at longer intervals after i.v. injection, the
myocardial thallium-201 activity may not accurately
reflect regional myocardial blood flow at the time of
injection in either the nonischemic or ischemic
regions.
The results of the present study indicate that during
physiologic exercise sufficient to increase coronary
blood flow three- to sevenfold, the initial myocardial
distribution of thallium activity is linearly related to
regional myocardial blood flow in both the ischemic
and nonischemic regions.
Acknowledgment
The authors acknowledge the following persons who rendered
valuable assistance in carrying out the study: Dr. Joseph C.
Greenfield, Jr. for continuing support; Dr. Judith Rembert, Maggie
Wilson and Dr. Philip A. McHale for assistance with the
radioisotope procedures and statistical analysis of the data; Kirby
Cooper and Eric Fields for expert technical assistance; Michael
Taylor and his staff of the Durham Veterans Administration
Medical Center Animal Care Facility; Donald G. Powell of the
Durham Veterans Administration Medical Center Medical Media
Department; and Cathie Collins for secretarial assistance.
801
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Linear relationship between the distribution of thallium-201 and blood flow in ischemic
and nonischemic myocardium during exercise.
A P Nielsen, K G Morris, R Murdock, F P Bruno and F R Cobb
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Circulation. 1980;61:797-801
doi: 10.1161/01.CIR.61.4.797
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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