Download Total and Regional Coronary Blood Flow Measured by Radioactive

Total and Regional Coronary Blood Flow
Measured by Radioactive Microspheres in
Conscious and Anesthetized Dogs
By Raul J. Domenech, M.D., Julien I. E. Hoffman, M.D.,
Mark I. M. Noble, M.B., Ph.D., Kenneth B. Sounders, M.D.,
James R. Henson, B.A., and Sujanto Subijanto, M.D.
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ABSTRACT
Total and regional coronary blood flow were measured in dogs by left atrial
injection of carbonized microspheres labeled with different radioactive isotopes
(mean diameter 14 to 6lfi). Simultaneously blood was collected at 20 ml/min
from a catheter tied into a peripheral artery. The ratios of flow to radioactivity
in myocardium and arterial blood should be equal if microspheres are well
mixed in the aortic root and are distributed regionally in proportion to flow.
This was proved in seven right heart by-pass experiments where coronary
venous drainage was measured directly. Also, less than 0.1% of total myocardial
radioactivity appeared in coronary venous blood, even with hypoxemia and
small microspheres.
Total coronary flow in seven conscious dogs averaged 95 to 150 ml/min/100
g heart; and flow to the left ventricle was 111 to 169 ml/100 g. Although
not validated independently, there was evidence that values for flow to each
ventricle, the atria and the septum were correct.
The radioactivity per gram of left ventricular subendocardial muscle was 2.5
times that of subepicardial muscle using microspheres 51 to 61yx in diameter,
but the ratios were 1.4 and 1.3 using microspheres of mean diameters 20 to 23/i,
and 14/i, respectively. It is unlikely that any of these microspheres measure
blood flow to small portions of the ventricle.
ADDITIONAL KEY WORDS
left ventricular muscle flow
coronary venous drainage
right heart by-pass
arteriovenous shunts
right ventricular muscle flow
arterioluminal shunts
particle streaming
• Coronary blood flow to the whole heart or
to specific portions of it is difficult to measure
From the Cardiovascular Research Institute and the
Department of Pediatrics, University of California San
Francisco Medical Center, San Francisco, California
94122.
This work was supported in part by U. S. Public
Health Service Program Project Grant HE-06285 from
the National Heart Institute. Dr. Domenech was a
U. S. Public Health Service International Postdoctoral
Research Fellow (F05 TW 1181). Dr. Hoffman was
formerly an Established Investigator of the American
Heart Association. Dr. Noble was a senior Fellow and
Dr. Saunders a Junior Fellow of the San Francisco
Bay Area Heart Research Committee. Mr. Henson was
supported by U. S. Public Health Service Ceneral
Research Support Crant (University of Cincinnati
College of Medicine). Dr. Subijanto was supported by
the Agency for International Development.
Received June 30, 1969. Accepted for publication
September 15, 1969.
Circulation Research, Vol. XXV, November 1969
in conscious dogs. Only electromagnetic or
ultrasonic flowmeters or indicator dilution
techniques might be applicable for total flow;
however, flowmeter transducers can seldom be
implanted successfully on both right and left
main coronary arteries, and indicator dilution
curves are difficult to perform and evaluate
because of the small size of the right coronary
artery and early branching of the left coronary
artery. None of these techniques can measure
flow to a ventricle or any specific portion of it.
All other methods—nitrous oxide washout (1,
2), washout of indicators injected into the
myocardium (3, 4) or coronary arteries (5,
6), rubidium clearance techniques (7, 8) —
either measure flow per unit weight of
myocardium without referring it to a welldefined region of the heart, refer it only to the
581
582
DOMENECH, HOFFMAN, NOBLE, SAUNDERS, HENSON, SUBIJANTO
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left ventricle or else require sacrifice of the
animal within a few minutes of the injection
of the indicator. These methods are often
difficult to apply in either conscious or
unconscious intact dogs.
Rudolph and Heymann (9) developed a
method for measuring the distribution of the
total cardiac output to different organs by the
injection of carbonized microspheres labeled
with gamma-emitter nuclides. The principle of
the method is that if the microspheres are well
mixed at the root of the aorta, are distributed
in proportion to blood flow, and do not escape
from the organs, their fractional distribution
in the organs will be in proportion to the
fraction of cardiac output going to the organs.
Then, if the flow to any organ (reference
flow) is known, the flow to any other organ
can be determined. This principle has been
validated for many organs (9, 10), but
because the coronary arteries arise close to the
site of injection of microspheres in the left
atrium or ventricle, we could not assume that
the microspheres would be mixed well enough
in the root of the aorta to permit the correct
measurement of coronary blood flow. Therefore we checked the accuracy of this method
in right heart by-pass preparations in which
almost all the coronary venous drainage could
be measured, and then applied it to measure
total coronary flow in conscious dogs.
In these studies we also estimated the
distribution of flow to atria, ventricular
septum, and ventricular free walls as well as
to portions of the ventricular walls, for
example, subendocardial and subepicardial
regions. These measurements could not be
checked directly, so we obtained indirect
evidence in support of our conclusions by
using microspheres of different sizes and
altering the mechanical and metabolic functions of the heart by preparations with
nonworking left ventricles.
Methods
The microspheres1 were labeled
with six
iFrom Nuclear Products Division of Minnesota
Mining & Manufacturing Company. These spheres
have a specific gravity of 1.3 to 1.6; they contain Ql%
different radioactive nuclides; the mean diameters
and standard deviations in microns of the large
microspheres were: 125 I, 56.0 ± 3.8; 141Ce,
60.0 ± 6.8; 51Cr, 60.9 ± 6.4; 85Sr, 55.8 ± 6.3;
91
Nb, 50.9 ± 3.6; «Sc, 55.0 ± 4.8. The smaller
microspheres used in some experiments had
diameters: 125 I, 22.4 ± 3.08 or 83Sr, 14.1 ± 2.52
and 20.5 ± 2.53. The total number of microspheres given with each injection usually varied
from 7,000 to 160,000, depending on the activity
of each radioisotope, but twice about 800,000
microspheres with low activity were injected;
with each injection about 1 to 2 yu,c of isotope was
given.
Microspheres were suspended in a solution of
20% dextran of medium molecular weight (with a
small amount of polyoxyethylene-80-sorbitan
mono-oleate [Tween 80] to prevent aggregation
[9]), placed in a small stirring chamber of about
3-ml capacity and stirred with a Teflon-covered
magnet until no clumps were seen. Then they
were flushed into the left atrium through a thin
polyvinyl catheter with about 15 to 20 ml saline in
12 to 50 sceonds.
The reference flow was collected from a
catheter tied into an artery, usually the brachial
but occasionally the femoral or internal mammary. To avoid trapping microspheres between
the arterial wall and the catheter, the ligature was
tied as close to the tip of the catheter as possible.
The reference flow was adjusted to about 20
ml/min and its actual volume obtained by
weighing a timed sample and measuring its
density. The reference flow was started a few
seconds before the injection of microspheres and
was collected for 15 to 30 seconds after finishing
the injection; it was collected in fractions for 1 to
5 minutes after the end of the injection in ten
injections in five dogs to determine the time taken
for all the microspheres to emerge.
Each dog was killed by intravenous injection of
sodium pentobarbital, the heart was excised,
cleaned of blood on its surface and the cavities
flushed with water and swabbed with gauze. The
visible epicardial fat and large vessels were
removed and counted together with the valves
and chordae tendineae. The atria were split into
the left and right atrial free walls and septum.
Both ventricular free walls were cut as close as
possible to the ventricular septum. This was
relatively easy for the right ventricle; however,
although the posterior limit of the free wall for
the left ventricle was defined by the right border
of the posterior papillary muscle, the anterior
limit had to be chosen arbitrarily. The left
ventricular free wall was divided into anterior and
carbon and 33% oxygen, but their exact composition
has not been disclosed.
Circulation Research, Vol. XXV, November
1969
TOTAL AND REGIONAL CORONARY BLOOD FLOW
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posterior papillary muscles (pooled) and four
layers across the wall, each extending from apex
to base; the inner (or subendocardial) layer made
up of the trabeculated muscle, and the outer (or
subepicardial) layer were each 1 to 2 mm thick,
and thinner than the other two layers, which
consisted of the intermediate muscle split in
halves. The right ventricular free wall was
divided into the major papillary muscles (pooled),
the inner layer of trabeculated muscle, a thin
subepicardial layer, and a thicker intermediate
layer. The septum was divided into three layers of
equal thickness—left, middle, and right layers.
The heart and blood samples were placed in
glass vials (9) and counted in a well scintillation
detector connected to a 400-channel pulse-height
analyzer.2 The total activity for each radioisotope
was obtained by modifying the method of
Rudolph and Heymann (9) for use with six
radioisotopes. Because of the overlap of spectral
energies for 40Sc and 91Nb, the former was not
often used. All blood samples were centrifuged
and the supernatant fluid was counted to
determine the amount of radioactivity not bound
to microspheres.
Right Heart By-pass.—Nine mongrel dogs
weighing 22 to 33 kg were anesthetized with
sodium pentobarbital, 35 mg/kg iv, with subsequent smaller doses as needed. The blood from
both venae cavae was drained into the reservoir of
a system previously filled with dog blood or 6%
dextran solution in saline and returned by a roller
pump into the pulmonary artery. A no. 14 Bardic
catheter with side holes was introduced into the
right ventricular cavity through the azygos vein to
drain the coronary venous return from the right
chambers of the heart into the reservoir. Both the
output of the pump and the coronary venous return were measured continuously by cannulating
electromagnetic flowmeter transducers (Statham
M-4001) to verify constancy of flow during the
studies. By changing the output of the pump,
different coronary blood flows were obtained. In
two dogs, the aorta was constricted by a clamp,
and two other dogs were made hypoxemic
(oxygen tensions of 14 and 26 mm Hg) and
hypercapnic (carbon dioxide tensions 84 and 62
mm Hg) by breathing in a closed circuit; both
maneuvers produced high coronary flows.
A catheter was tied into a brachial artery in
seven dogs, in a femoral artery in one dog, and in
both arteries in another. While the reference flow
from these arteries was being collected, the
coronary venous return was drained directly into
a graduated cylinder, then measured. In some
experiments, including those in which coronary
2
Technical Measurements Corporation, 404C Multiple Pulse Height Analyzer, North Haven, Conn.
Circulation Research, Vol. XXV,
November
1969
583
venous return was increased two- to threefold by
hypoxemia, the total coronary venous return was
counted to detect any radioisotope which might
pass through the myocardial vascular bed.
In eight of the nine dogs, between two and five
sets of microspheres, each with a different
isotope, were injected successively; the remaining
dog had two injections, each with two different
sets of microspheres mixed in the stirring
chamber. In some dogs, both large and small
microspheres were injected.
Conscious Dogs.—In seven other dogs a thin
polyvinyl catheter was implanted into the left
atrium; in two of them we placed an electromagnetic flowmeter transducer around the root of the
aorta and a Microsystems 1017 pressure gauge
through the left ventricular wall with its surface
flush with the endocardium. One to ten days after
surgery, a polyvinyl catheter was inserted under
local anesthesia into the brachial artery. In one
dog the catheter for the reference flow was placed
in the internal mammary artery at the time of
surgery. With the dogs lying quietly on their right
sides, between two and six sets of microspheres,
each labeled with a different radioisotope, were
injected into the left atrium, and the reference
flow was collected. Each experiment lasted about
1 to 2 hours and the interval between each
injection varied from 15 to 30 minutes. After
the last injection, the dogs were killed by large
intravenous doses of pentobarbital and the hearts
removed and divided.
To get more information about the distribution
of microspheres within the heart, similar studies
were made on four additional conscious dogs,
except that the reference flow was not measured.
In three of them, smaller microspheres of mean
diameter 14.1/x or 22 Afj, were alternated with the
larger microspheres.
Dogs with Nonfunctioning Left Ventricles.—
To study the regional distribution of microspheres, several different preparations were devised in which the left ventricle did not work.
In one dog, large catheters were placed in the
left atrium and ventricle to drain blood into the
reservoir, from which it could be pumped into
both femoral arteries. Prior to by-pass, two control
injections of microspheres were given; then the
pump was started, adjusted to return aortic
pressure to control levels, and one set of
microspheres was injected into the output of the
pump.
In eight dogs not used in other studies, a
cannula connected to a reservoir was placed in
the root of the aorta. After a control injection of
microspheres through this aortic cannula, the
heart was stopped by inducing ventricular
fibrillation with electrical shock in two dogs;
injection into the left atrium or aorta of 30% KC1
DOMENECH, HOFFMAN, NOBLE, SAUNDERS, HENSON, SUBIJANTO
584
STROKE
VOLUME
LEFT
VENTRICULAR
PRESSURE
(mm Mg)
LEFT
VENTRICULAR
DIASTOLIC
20
PRESSURE
(mmHg)
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FIGURE 1
Left ventricular pressures and ascending aortic flow
recordings in a conscious dog immediately after six
successive injections of large microspheres into the left
atrium. The flowmeter was not calibrated. The lowest
tracing was recorded at high gain to show left ventricular diastolic pressure more clearly. The intervals
between injections varied from 3 to 5 minutes.
in two dogs; or continuous infusion of 0.1%
acetylcholine into the left atrium or aorta in four
dogs. At the same time, in five of these dogs the
descending aorta and the arteries arising from the
arch were occluded, and microspheres were
injected into the root of the aorta while the
coronary vascular bed was perfused at approximately the preexisting aortic pressure from the
reservoir; in the other three dogs, perfusion took
place with aortic pressures of 10 to 20 mm Hg. In
the two dogs injected with potassium chloride
and one with acetylcholine, the venae cavae and
azygos vein were occluded, and the right chambers of the heart drained to estimate coronary
blood flow during the injection of microspheres
into the arrested heart.
In two of these dogs, the inner and outer layers
of the left ventricular free wall were digested
with 70% nitric acid. The microspheres so
obtained were measured with a calibrated
eyepiece to study the relative distribution of
different sizes in these regions.
atrium in one conscious dog with a flowmeter
transducer around the aortic root and a
Microsystems model 1017 strain gauge in the
left ventricular wall flush with the endocardium. A similar result was obtained in another
dog. In these dogs there were no consistent
changes of pressures or flows after successive
injections of microspheres. In the remaining
conscious dogs in which only arterial pressure
and heart rate were recorded, no changes in
heart rate or arterial pressure were observed
during the injection of the microspheres. None
of the dogs showed any sign of discomfort.
After injection, no radioactivity was detected on the Teflon-coated stirring bar or in
the effluent obtained by subsequently flushing
out the stirring chamber. Furthermore, in
seven injections in five dogs, successive
separate fractions of the reference flow
revealed no significant numbers of large
microspheres circulating more than 30 seconds
beyond the end of the injection; over 99% of
the total microspheres were recovered in the
reference flow within 1 minute of the begin-
320
280
240
200
I 60
120
80
40
4-0
80
120
160
200 240
280
320
CORONARY VENOUS RETURN (ml/min)
360
FIGURE 2
Results
Figure 1 records the left ventricular
stroke volume, left ventricular pressure, and
first derivative of ventricular pressure with
respect to time (dP/dt) after each injection of
six successive sets of microspheres into the left
Linear correlation between the directly measured
coronary venous return to the right chambers of the
heart and the values for total coronary blood flow
calculated from the large microspheres in the right
heart by-pass preparations. Solid circles = brachial
artery; Open circles = femoral artery; Dashed lines
represent 95% confidence limits for points.
Circulation Research, Vol. XXV.
November
1969
585
TOTAL AND REGIONAL CORONARY BLOOD FLOW
ning of the injection. However, in three
injections of small microspheres in three dogs,
only S5% to 92% of the total amount of
microspheres collected in the reference sample
appeared within 1 minute after the beginning
of the injection; the remainder appeared
slowly over the next 4 minutes.
TOTAL FLOW
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Right Heart By-pass.—Figure 2 shows the
correlation between the directly measured
coronary venous return to the right chambers
of the heart and the values for total coronary
blood flow calculated from the large microspheres in the right heart by-pass preparation.
In 27 measurements in seven dogs, the
calculated flow was within 5% of the measured
flow in 12, within 10% in 19 and within 20% in
24 measurements. Two of the 3 with the
largest errors (24%, 20%, and 33%) were in one
dog with abnormally low coronary blood flow.
When small microspheres were used, coronary
blood flow was overestimated by 6% to 70%
(average 29%) in all studies in which the
reference flow was collected for no more than
30 seconds from the end of the injection. Too
few measurements were made with small
microspheres and longer collection of reference flow to assess their accuracy in measuring
total coronary flow.
The total number of microspheres in the
heart varied from 230 to 8,000 for large and
from 9,000 to 25,000 for small microspheres.
In the three dogs in which a total of ten
injections of large microspheres were made
and the coronary venous return was examined
to detect any microspheres going through the
coronary vascular bed, the radioactivity in the
coronary venous return (after discounting the
small amount in the supernatant fluid obtained by centrifuging the sample) was
always under 0.5%, and usually less than 0.1%
of the total radioactivity in the heart for every
radioisotope. The coronary venous return
measured in these dogs varied from 130 to 340
ml/min, the highest flow occurring in dogs
with hypoxemia. Similar results were obtained
in three dogs which had four injections of
small microspheres (the smallest, 14.1 ± 2.52/x
in diameter); the coronary venous return in
Circulation Research. Vol. XXV. November 1969
these ranged from 120 to 180 ml/min.
Conscious Dogs.—Table 1 shows the values
for total coronary blood flow in the seven
conscious dogs; coronary flow is also expressed
per kilogram total body weight as well as per
100 g wet heart weight. The arterial pressures
for these dogs varied from 160 to 180 mm Hg
systolic and 70 to 90 mm Hg diastolic. The
heart rates were 114 to 156 beats per minute;
blood oxygen tensions 88 to 99 mm Hg and
carbon dioxide tensions 22 to 35 mm Hg;
blood pH varied from 7.30 to 7.42. In any one
dog, none of these variables seemed to be
related to the amount of coronary blood flow.
The numbers of microspheres in the heart
varied from 360 to 8,800 (large) and 6,400 to
65,100 (small).
DISTRIBUTION TO LARGE REGIONS
Figure 3 shows the percent distribution of
the microspheres in the atria, right ventricular
free wall, septum, left ventricular free wall,
and septum plus left ventricular free wall in
the 11 conscious dogs. The results obtained
with small microspheres are included with
those for the large microspheres in the three
dogs in which large and small microspheres
were injected, since no differences in the
distribution of microspheres of different sizes
were noted (Table 2). The proportions of
total coronary flow going to left ventricular
free wall plus septum, the right ventricular
free wall or the atrium were almost constant,
but the relative amounts to the septum and
left ventricular free wall varied from dog to
dog.
From the values of total coronary blood
flow obtained in seven dogs and the corresponding percent distribution, the coronary
blood flow per gram of tissue for these regions
of the heart was calculated (Table 3). An
analysis of variance showed a significant
difference between left and right ventricular
free wall (P < 0.05) and between atria and
right ventricular free wall (P<0.05), except
in two dogs (P<0.10, 0.20). No significant
difference was found between left ventricular
free wall and septum except in one dog
(P<0.025); however, taking 21 pairs of
differences in the six dogs with two or more
DOMENECH, HOFFMAN, NOBLE, SAUNDERS, HENSON, SUBIJANTO
586
TABLE 1
Total Coronary Blood Flow (CBF) in Conscious Dogs
Body
No.
wt
observations
Dog
(kg)
1
2
3
4
5
6
7
27.5
23.8
1
2
4
5
20
18
20
28
4
2
4
22.7
CBF/kg body wt
(mlmin-'kg-')
Mean
Range
Total CBF
(ml-min"1)
Mean
Eange
239
177
159
136
132
234
153
8.69
7.44
7.96
7.54
6.61
8.37
6.75
175-179
137-201
123-155
99-154
220-249
144-164
7.35- 7.53
6.85-10.05
6.83- 8.61
4.95- 7.70
7.86- 8.89
6.34- 7.22
CBF/100 g heart wt
(mlmln-'lOO g"1)
Range
Mean
150
95
132
114
108
99
114
94- 96
114-167
103-131
81-126
93-106
107-122
The same number is used for the same dog in all the tables.
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radioisotopes injected, the flow to the left
ventricular free wall averaged 0.15 ml/g
higher than that to the septum. The magnitude of this difference in each dog was
unrelated to the relative distribution of flow to
the septum and left ventricular free wall.
In comparing the distribution of micro-
spheres to these large regions in the conscious
dogs and those on right heart by-pass, there
were significant differences (unpaired f-test)
in the percent distribution to the right
ventricular free wall and the left ventricular
free wall plus septum. For the right ventricular free wall, the mean percent of total
&
80
1
70
§
o
60
Q: 5 0
§ 40
30
° 20
i
k 10
ATRIA
RIGHT
VENTRICULAR
LEFT
LEFT
VENTRICULAR
SEPTUM
VENTRICULAR VENTRICULAR
FREE WALL
FREE WALL
FREE WALL
+ SEPTUM
FIGURE 3
Distribution of coronary blood flow to different regions of the heart in conscious dogs. In
each group one bar represents one dog, and the sequence of bars is the same for the different
groups. Vertical lines at the tops of the bars represent the ranges of measurements in the
dogs with over two measurements. Solid circles indicate that large and small microspheres
were used.
Circulation Research. Vol. XXV, November 1969
587
TOTAL AND REGIONAL CORONARY BLOOD FLOW
TABLE 2
Percent Distribution of Large and Small Microspheres to Ventricles
:RV free wall
Type of study
Dog
Conscious dog
If
2t
3
Anesthetized,
closed chest
st
9
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Open chest
10J
Right heart by-pass
lit
12t
51-61/1*
51-61,1*
14-23,1*
14.1
19.2
1S.9
17.6
16.7
17.S
17.4
17.S
73.2
70.9
70.9
70.9
66.2
6S.9
70.6
68.9
19.5
16.6
15.7
19.6
1S.1
14.6
17.6
16.2
15.9
19.1
17.8
13.4
10.7
74.S
77.6
76.9
76.9
76.6
77.7
85.3
84.9
S3.6
76.6
77.8
71.3
73.7
75.4
78.9
83.6
84.3
S5.3
9.0
9.0
11.3
13
LV including septum
14-23,.*
9.3
10.0
0.57
0.5 > P > 0.4
t
P
1.76
0.2 > P > 0.1
RV = right ventricle; LV = left ventricle.
*Microsphere diameter.
tSimultaneous injection of small and large microspheres. In the others, small and large microspheres were injected with a short interval between them and with relatively stable heart rates
and aortic blood pressures; the order of injection varied.
tDuplicate studies in the same dog.
coronary blood flow was 13.4 ± 3.2 SD
(n = 22) in the right heart by-pass and
17.2 ±2.1 SD (n = 40) in the conscious dog
(P < 0.001). For left ventricular free wall plus
septum the mean percent was 79.4 ± 4.0 SD
(n = 21) in the right heart by-pass and
75.3±3.2 SD (n = 40) in the conscious dog
(P < 0.001). No significant difference was
found for atrial flow distribution.
In conscious dogs or anesthetized dogs
(some with right heart by-pass), the proportional distribution of microspheres to the right
ventricular free wall and the left ventricle plus
septum was independent of microsphere size
(Table 2).
DISTRIBUTION TO SMALL REGIONS
In the two dogs in which the inner and
outer layers of the left ventricle were digested
so that the microsphere diameters could be
measured, the same distribution of diameters
was found in both layers for large (mean
diameter 51/n and 55/i.) and medium-sized
(mean diameter 22AJX) microspheres.
Circulation Research, Vol. XXV,
November
1969
Table 4 shows the proportional distribution
of radioactivity to different regions of the
heart in a conscious dog after successive
injections of large microspheres labeled with
different isotopes. The proportions were similar
for the different injections in this dog as well
as in the other ten conscious dogs. In addition,
the flow per gram was calculated for each
region (Table 4), assuming that flow and
radioactivity were proportional (see below).
There was almost always a gradient in the
distribution of radioactivity across the free
walls of both ventricles, the inner layers
having the greatest amount per gram and the
outer layers the least. The only exceptions to
the gradients shown in Table 4 occurred in
three dogs in which the outer layer had a
greater amount of radioactivity per gram than
the layer next to it, but the inner layer
still had more radioactivity per gram than
the outer. In 38 measurements with large
microspheres in 11 conscious dogs, the radioactivity per gram of the inner layer divided by
DOMENECH, HOFFMAN, NOBLE, SAUNDERS, HENSON, SUBIJANTO
588
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the radioactivity per gram of the outer layer
gave mean ratios for the right ventricular free
wall of 1.8 ±0.5 SD (n = 14), and for the left
ventricular free wall 2.7 ± 0.8 SD (n = 14). A
gradient of radioactivity per gram was also
noted across the interventricular septum, with
a mean ratio (left:right) of 2.4 ± 0.7 SD
(n = 14).
When small (mean diameter 14.1/x) or
medium-sized microspheres (mean diameter
20.5/LA or 22.4/A) were injected simultaneously
with, or within a short time of, large,
microspheres (mean diameter 50.9 to 60.9^i)
there were significant differences in the ratios
of radioactivity per gram of inner to outer
ventricular layers or left- to right-sided
ventricular septal layers (Table 5). These
differences from the ratios with large microspheres were significantly larger (unpaired ttest) with the small microspheres than those
of medium size for the free wall of the left
ventricle (P<0.05) and the ventricular septum (P < 0.05) but not for the right ventricular free wall (P = 0.2).
In the right heart by-pass studies with large
microspheres, the ratio of radioactivity per
gram (inner:outer) was 2.0 ± 0.8 SD (n=16)
for the right ventricular free wall—not significantly different from that for the conscious
dogs (0.5<P<0.6). However, the ratio of
radioactivity per gram of inner to outer layers
of 1.9 ± 0.7 SD for the left ventricular free wall
was significantly less than for conscious dogs
(P < 0.01). The ratio for the left to right sides
of the septum was 1.9 ±0.6 SD (n=16) and
was not significantly lower than that in
conscious dogs (0.10 > P > 0.05).
In each nonvvorking left ventricle with
normal aortic pressures there was usually no
change in the ratio of radioactivity per gram
(inner to outer layers) of the ventricular free
walls or of the left to right sides of the
ventricular septum compared to control values
(Table 6). In three of these dogs whose hearts
were arrested and whose coronary venous
return was measured, the flows were 140,200
and 300 ml/min. In three other dogs with very
low perfusing pressures after acetylcholine
arrest, the ratios were below 1.
Circulation Research. Vol. XXV. November
1969
589
TOTAL AND REGIONAL CORONARY BLOOD FLOW
TABLE 4
Percent of Total Cardiac Radioactivity and Blood Flow per Gram in Different Regions (Large Microspheres)
Percent of total
cardiac radioactivity
wt
Region
Flow per gram
(K)
mi
i«Ce
»Sr
'•Nb
mi
•'"Ce
»Sr
"Nb
6.05
2.53
6.39
1.4
0.7
2.7
2.5
0.9
3.9
2.4
0.7
5.0
1.9
0.7
4.0
0.4
0.3
0.7
0.6
0.6
1.0
0.6
0.4
1.2
0.5
0.4
0.9
Right ventricle
Papillary muscle
Subendocardial layer
Middle layer
Subepicardial layer
0.S2
5.74
17.57
4.29
0.3
5.S
8.2
3.4
1.2
6.1
8.3
2.3
0.8
5.2
8.5
3.3
0.5
3.7
7.5
3.4
0.6
1.7
O.S
1.3
2.3
1.7
0.7
O.S
1.4
1.3
0.7
1.1
0.9
0.9
0.6
1.1
Ventricular septum
Right side
Middle
Left side
5.55
23.86
4.24
5.2
4.S
2.S
17.5
16.3
15.4
9.5
S.I
8.3
3.1
1S.4
S.2
1.5
1.2
3.7
1.4
1.1
3.0
0.7
1.0
2.9
O.S
1.1
2.S
Left ventricle
Papillary muscle
Subendocardial layer
Inner middle layer
Outer middle layer
Subepicardial layer
3.22
4.95
16.88
15.39
6.S7
6.2
9.0
7.0
S.2
6.2
S.9
16.2
17.8
18.5
5.4
9.6
19.7
9.2
3.6
S.4
3.6
9.2
3.9
9.5
3.6
3.2
3.0
1.6
1.0
0.9
3.4
2.6
1.7
0.9
0.8
2.S
2.7
1.6
0.9
0.8
2.4
2.8
1.7
0.9
0.8
Fat, valves, large vessels
10.19
1.0
0.7
1.0
0.8
0.2
0.1
0.1
0.1
Atrium
Right
Septum
Left
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Conscious dog (no. 7) with successive injections of large microspheres. Calculated total coronary
blood flow in ml/min was, respectively, 164, 157, 148 and 144.
Discussion
This technique permits complete injection
of microspheres and their collection in the
reference sample without causing any discomfort to the dog or detectable changes in
cardiac function. Furthermore, after successive injections of microspheres there were no
large or consistent changes of aortic pressure
or coronary blood flow; therefore, in the
numbers given, the microspheres did not alter
coronary vascular resistance. However, to
measure coronary blood flow by this technique no significant numbers of microspheres
can pass through the myocardial vascular bed,
and they must be well mixed at the root of the
aorta.
The microspheres used in these experiments
ranged in mean diameter from 14.1/x to 60.9/z
and are far larger than the diameter of the
capillaries of the dog heart (3/x to 8/LI) (11).
Therefore, only those going through large
Circulation Research, Vol. XXV, November
1969
arteriovenous and arterioluminal shunts could
pass through the coronary circulation. After
discounting the amount of free radioactivity in
the solution for each set of microspheres, less
than 0.5% (usually under 0.1%) of the total
radioactivity in the heart was found in the
coronary venous blood, even during marked
coronary vasodilation from hypoxemia and
with the smallest microspheres. Since the
microsphere diameters have a gaussian distribution, at least 2% of those with a mean
diameter of 14.Lu were below 9/i. in diameter;
therefore there were clearly no significant
arterioluminal and arteriovenous shunts above
this diameter into the right chambers of the
dog heart.
Prinzmetal et al. (12), who injected glass
spheres into the coronary arteries of the
postmortem human heart, described shunts of
about 70^. to 220/i, in diameter between the
coronary arteries and both ventricular cavities
DOMENECH, HOFFMAN, NOBLE, SAUNDERS, HENSON, SUBIJANTO
590
TABLE S
Ratios of Radioactivity per Gram of Inner lo Outer Layers of Ventricular Free Walk and Left to Right
Side of Ventricular Septum
Inner : outer layer
LV free wall
Left:right side
ventricular septum
RV free wall
Large
Medium
Large
Medium
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Dog
Large
Medium
1*
2
3
8*
9
10
11
12
13*
2.54
1.32
1.98
3.13
3.85
2.00
1.36
2.26
1.82
1.94
1.19
1.34
2.91
1.69
1.30
0.27
2.26
1.27
2.60
1.20
1.49
2.39
2.75
1.51
1.37
3.08
2.08
2.32
1.03
1.14
1.73
1.54
0.86
0.90
1.87
1.42
2.57
2.32
1.97
1.79
2.27
2.34
1.59
1.63
1.92
1.68
2.03
1.62
1.97
1.62
1.44
0.81
1.27
1.16
2.25
0.82
1.43
0.91
2.05
0.69
1.42
0.49
2.04
0.35
1.51
0.39
Large
Small
Large
Small
Large
Small
2.59
4.18
1.78
3.06
0.96
1.75
1.02
1.41
1.72
2.39
1.32
3.19
1.00
1.07
0.76
2.05
3.43
2.26
2.22
2.50
1.19
1.35
1.41
1.37
2.90
1.00
1.28
0.37
2.15
0.82
1.22
0.57
2.60
0.57
1.33
0.10
MEAN
SD
<0.02
P
2
8*
10
12
M HAN
SO
P
< 0.005
<0.02
< 0.02
<0.01
< 0.05
Large = microspheres ol-61/i in diameter; Medium = microspheres 20.5 or 22.4/x diameter;
Small = microspheres 14.1M diameter. Dogs 1-3 were conscious; dogs 8-13 were anesthetized;
dogs 8 and 9 had closed chests, dog 10 had an open chest, and dogs 11-13 had the right heart
by-passed. LV and RV as in Table 2.
*Simultaneous injection of large and smaller microspheres.
and also arteriovenous shunts into the coronary sinus of 70/JL to 170/J. in diameter.
However, even though the difference in
species and experimental conditions makes
comparison of their experiments with ours
difficult, there is in fact no conflict. They
injected 5 to 12 million spheres into the
coronary arteries. If arterioluminal or arteriovenous shunts into the right chambers of the
heart carry less than 0.1% of the coronary
blood flow (the usual upper limit from our
data), then this would have permitted 5,000 to
12,000 of their glass spheres to pass the
capillary bed. These would easily have been
detected, although they did not mention the
total number of spheres recovered from the
cardiac chambers.
MacLean et al. (13), who injected radioactive glass microspheres 20/JL in diameter into
the root of the aorta in the beating but
nonworking dog heart, found no radioactivity
in the left chambers of the heart; 4% of the
radioactivity entering the coronary arteries
drained into the right chambers of the heart.
It is possible that the difference between their
results and ours are due to their use of a
nonworking heart. Recently, Fortuin et al.
(14) found no significant passage of microspheres 15/tt in diameter and labeled with
40
Sc into the coronary sinus.
There is less information about arterioluminal shunts into the left atrium and ventricle,
and only MacLean et al. (13) studied this
directly with microspheres. However, the
direct coronary venous drainage into the left
chambers of the dog heart is less than 5% of
the total coronary flow in the isolated heart
(15) and less than 2% in more physiological
Circulation Research, Vol. XXV, November 1969
591
TOTAL AND REGIONAL CORONARY BLOOD FLOW
TABLE 6
Ratios of Radioactivity per Gram of Inner lo Outer Layers
of Left Ventricular Free Wall in Working and Nonworkr
ing Ventricles
Method
Working
heart
Left heart by-pass
1.74, 2.61
Ventricular fibrillation
4.62
Ventricular fibrillation
2.65
Potassium chloride arrest
1.35
Potassium chloride arrest
2.57
1.20
Acetylcholine arrest
Acetyleholine arrestf
2.55
Acetylcholine arrestf
1.59
Acetylcholine arrestf
2.S9
Non-working
heart
1.92
3.28
2.74
1.26
2.59
2.17, 2.27*
0.36, 0.33*
0.91, 0.89*
1.05
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*Both sets of isotopes injected simultaneously.
fAortic pressure not maintained during arrest.
preparations (16). From all these studies it
seems that no significant numbers of microspheres escape through the coronary vascular
bed. The same studies permit us to state that
the coronary venous drainage measured in the
right heart by-pass experiments represented
over 95% of the total coronary venous drainage. Therefore the high correlation between
calculated and measured coronary flow (Fig.
2) can be interpreted as a proof of adequate
mixing of the large microspheres at the root of
the aorta and their subsequent distribution to
the heart and reference sample in proportion
to their flows after left atrial injections.
There are two possible explanations for the
overestimate of coronary blood flow in our
earlier studies with small microspheres; namely, disproportionately few microspheres in the
reference sample or disproportionately too
many in the heart. Our results show that
collecting the reference flow for 1 minute did
not allow for the long transit time of small
microspheres, so that they were underrepresented in the reference sample. We do not
know the reason for this difference in transit
time, but it may be due to a more peripheral
position of small microspheres in the arterial
lumen so that some travel in slower streams
(17). It is probably not due to recirculation of
small microspheres, since these on their
second and subsequent circulations should be
Circulation Research, Vol. XXV, November 1969
distributed in proportion to flow, thus retaining the proportionality of radioactivity to flow
in the heart and reference blood.
A disproportionately high distribution of
microspheres to the heart could occur only if
at the root of the aorta there were more small
microspheres in the periphery than near the
axis of the stream and the coronary flow came
mainly from this region. Segre and Silberberg
(17) have shown that with a steady flow in a
tube, particles are evenly distributed across
the radius of the inlet; in this respect the
aortic root resembles their model. Furthermore, Bellhouse et al. (18) have shown in
models that vortices produced in the aortic
root could provide a homogeneous distribution of particles. Both of these studies suggest
that the heart should not receive a disproportionately high number of microspheres.
Flow to Large Regions.—The flow per 100
g total heart weight was less than that per 100
g left ventricular free wall plus septum in the
TABLE 7
Coronary Blood Flow (ml • min~l) per 100 Grams of Left
Ventricle by Different Authors
No.
Ref.
measurements
Method
Mean
Range
SD
79-220
111-169
35
24
Conscious Dogs
19
*
*
20
21
22
23
24
1
25
7
27
22
N2O
microspheres
133
135
Anesthetized Dogs (Closed Chest)
138-226
microspheres 173
3
101
N,0
8
81
9
N2O
104
10
N,0
100-220
147
12
N2O
121
10
N2O
71
17
N2O
14
21
133
86
Xe
Rb
89
112
44
33
14
24
39
23
11
29
Since most dogs in these studies had several estimations of coronary blood flow, standard deviation (SD)
is not based on independent observations. However,
analysis of variance showed no significant differences
between the means for each of our dogs, so that the observations have been regarded as independent for comparison with those of other workers.
•Combined left ventricular free wall and septum,
present study.
592
DOMENECH, HOFFMAN, NOBLE, SAUNDERS, HENSON, SUBIJANTO
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seven conscious dogs; (ratio 77% to 90%, mean
83%). This follows from the lower flows
observed per 100 g of atrial or right
ventricular muscle and must be kept in mind
when interpreting coronary blood flows derived by methods which relate flow to the
mass of left ventricular muscle.
When we compared our values with those
reported for coronary blood flow per 100 g left
ventricular muscle (Table 7) with studies on
conscious and anesthetized dogs by different
methods (1, 7, 19-25), the agreement was
reasonably good; the values during anesthesia
were generally lower than in the conscious
state. The fact that our method and the
nitrous oxide method agree well is in keeping with observations that coronary sinus
blood probably represents most of the venous
drainage from the left ventricle (2).
We have not validated regional flow to the
atria, ventricular free walls, and septum but
believe that these regional flow measurements
may be correct. (1) The method can measure
small flows like those going to right or left
ventricles, as shown by the right heart bypass studies with low total coronary blood
flows (Fig. 2). (2) The regional distribution
of blood flow and its variation in different
physiological states was consistent with determinants of coronary flow. In general, coronary blood flow varies with metabolic needs
(24, 26-28) but may also depend on vascular
impedance within the myocardium for regulation of local flow (29). Thus, the greater
proportion of flow going to the left ventricle
(including septum) is expected because of
its greater muscle mass and expenditure
of energy; the latter would also explain the
greater flow per gram of left ventricular
muscle. Furthermore, the fact that in the right
heart by-pass studies the distribution of flow
to the nonworking right ventricular free wall
was less than in the conscious dog is also
consistent with the importance of metabolic
factors in regulating coronary blood flow. On
the other hand, in one experiment there was
no change in relative flows to right and left
ventricles after left heart by-pass was started,
perhaps because of proportional lowering of
the effects of left ventricular metabolism
and impedance. (3) Our results for flow per
100 g of left ventricle in conscious dogs agree
with those obtained by others using the
nitrous oxide method. (4) The percent
distribution to large regions of the heart is
similar with large and small microspheres and
with a diffusible indicator (7).
In the conscious dogs, the ratio of flow per
gram of left ventricular free wall plus septum
to right ventricular free wall varied from 1.24
to 1.59 (mean 1.43). These results differ from
those of MacLean et al. (13), who found a
greater flow per gram of tissue in the right
ventricular free wall than in the left. Nevertheless, although they used a technique similar
to ours, their experiments were done in a
nonworking heart and are not comparable. On
the other hand, our results agree with those of
Love and Burch (30) and Levy and deOliveira (31), who measured distribution of
coronary blood flow with the 8<iRb clearance
technique in the anesthetized dog with an
intact circulation; their ratios of flow per gram
of left ventricular wall plus septum to right
ventricular free wall averaged 1.48 and 1.49
respectively.
Radioactivity
of Small Region.?.—To inter-
pret the ratio of radioactivity per gram of
tissue in the inner to outer ventricular layers
(or the two sides of the septum) as a ratio of
flows, we must first know that the amount of
radioactivity in a layer is proportional to the
numbers of microspheres in it. This cannot be
assumed, because the microspheres vary in
volume. For example, microspheres with mean
diameter 50/u. ± 5fi (standard deviation)
have upper and lower 95% confidence limits
for diameter of about 60/u, and 40/u. Microspheres with these diameters have volume
ratios of 27:8 (3.4:1) and if the radioisotope is
evenly mixed with the material composing the
microsphere, then the average radioactivity of
these larger microspheres in a batch will be
3.4 times that of the smaller microspheres.
With microspheres 20/u, in diameter the
volume ratios of the larger to the smaller
microspheres in a batch is about 4.6:1.
Because of the variability of microsphere
Circulation Research, Vol. XXV, November
1969
TOTAL AND REGIONAL CORONARY BLOOD FLOW
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volume in a batch, there might be a tendency
for larger microspheres to be separated from
the smaller microspheres by variations in
arterial size, branching or position of differentsized microspheres in the stream. If this
occurred, then the radioactivity in a region
might not be proportional to number of
microspheres or to flow.
Our studies of the distribution of the
diameters of large and medium-sized microspheres in inner and outer ventricular layers
showed no significant differences, so this
source of error was not present. However,
when small or medium-sized microspheres
were used, the ratios of radioactivity per gram
in the inner to outer ventricular layers differed
from those obtained with the large microspheres and from each other (Table 5). These
differences can be explained by the known
distribution of particles in flowing streams.
Large microspheres similar to those used here
have been shown to be concentrated near the
axis of the stream (32) and so might be
underrepresented in the proximal intramural
coronary arteries which, if they resemble other
vascular beds, are supplied by microspheres
from the peripheral part of the stream.
Smaller particles take longer to reach a similar
distribution (17), so the smaller microspheres
are probably more evenly dispersed across
the lumen of the larger coronary arteries and
thus more evenly distributed to subepicardial
and subendocardial arteries. Even these small
microspheres, however, are likely to show
some tendency to axial concentration once
they are beyond the orifices of the main
coronary arteries and are thus likely to be
slightly underrepresented in subepicardial
vessels. (The equal distribution of microsphere diameters in inner and outer layers
with any one batch of microspheres injected
was probably due to the relatively narrow
range of variations of diameters found within
each batch. Thus the larger and smaller
microspheres in a batch with a mean diameter
of 50/u, had volume ratios of 3.4:1, but
microspheres of 50fi and 20/u, in diameter have
volume ratios of 15.6:1).
After they have reached the terminal
Circulation Research, Vol. XXV,
November 196i>
593
vessels, movement of microspheres is unlikely
because of the similarity of distribution before
and after cardiac arrest. Furthermore, the
similarity of distribution in the working and
nonworking left ventricle favors an anatomically determined distribution of large microspheres more than a real variation in flow
because of metabolic needs. It is possible,
however, that the arrested or fibrillating left
ventricle has a much lower than normal
impedance to flow in the inner layers because
of decrease of intramyocardial tension, rather
like a prolonged diastole, so that even when
the heart is not working, the flow in the inner
layer of the ventricle would be greater than
that in the outer layer. The only condition
which permitted lower radioactivity per gram
with the large microspheres in the inner as
compared to the outer layers were very low
aortic pressure and, probably, a very low
coronary blood flow, as in three of the four
studies with cardiac arrest after acetylcholine.
Possibly preferential streaming of microspheres to the inner layer because of their
momentum and inability to make sharp turns
was abolished at low flows.
Another possibility is that all the ratios are
correct but that microspheres of different sizes
measured different flows. Estes et al. (33)
reported that in the postmortem human heart
there was a subendocardial plexus of vessels
which formed large looping arcades. If the
flow in these vessels passes from deep to
superficial layers and if the diameter of
arteries in the deep layer is smaller than that
of the large microspheres used here, then the
large microspheres might measure total flow
going as far as the inner layer, while the small
microspheres would measure the actual or
effective flow to each layer. However, the
number, size, direction of flow in, and
function of, these arteries is not known, nor
have they been described in the dog.
Numerous studies with diffusible indicators
give a ratio of flow per gram in inner to outer
layers of the left ventricle close to 1 (4, 3438). Even though the interpretation of results
of methods using diffusible indicators has
been criticized (3, 5), it is difficult to accept
594
DOMENECH, HOFFMAN, NOBLE, SAUNDERS, HENSON, SUBIJANTO
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the ratio of 2.3 to 2.7:1 obtained with large, or
1.4 with medium-sized, microspheres as being
correct. The ratio of 1.3:1 obtained with the
smallest microspheres (Table 5) is closer to
that found with diffusible indicators, but the
weight of evidence is against microspheres of
any size measuring flow to different layers of
the ventricular wall.
Critique of the Method.— This method has
many advantages. The microspheres used for
each injection cost only 7 to 30 cents. It is
relatively easy to apply to the conscious dog,
does not disturb the dog and apparently does
not alter cardiac function or coronary circulation. It permits measurement of total coronary
blood flow and its distribution to large regions
of the heart. No theoretical assumptions have
to be made about any blood-tissue interchange, for none occurs. It is not necessary to
take heart samples immediately after the
injection to avoid diffusion of the isotope from
the tissue into the blood. With the microspheres available in our laboratory, five
measurements of total coronary blood flow
and its distribution can be made in each
animal; other radioactive nuclide-labeled microspheres are available. Finally, a steady state
is needed only for a relatively short time
(about 1 minute with the large microspheres).
There are, however, some disadvantages to
the method. Counting the tissues involves
much technical effort and the use of expensive
equipment. The method measures mean and
not phasic flow and requires a relatively
steady state; if small microspheres are used
this must last for about 5 minutes. The
microspheres must not be clumped and have
to be injected into the left side of the
circulation, probably the left atrium, so that a
catheter must be placed in the left atrium by
prior operation, or by transseptal or retrograde left atrial catheterization. If the reference sample technique is used, a catheter must
be tied into a peripheral artery. On the other
hand, if the method of measuring cardiac
output and determining the fraction of it
going to the heart is used, then radioactivity
must be measured on the whole animal after it
is killed or special techniques used to count
the total amount of radioactivity injected.
There is a limit to the number of measurements that can be made, because of the
demands on the instruments which separate
the spectral energies of the different isotopes
or because of the cumulative effect of the
numbers of microspheres on the physiology of
the animal. Finally, the animal has to be killed
to make the counts.
Acknowledgments
We wish to thank Dr. Abraham M. Rudolph for use
of counting equipment and advice; Drs. John M.
Neutze and Felix Wyler, who first demonstrated the
feasibility of the reference sample technique; Dr.
Frederick Firestone for assistance with the right heart
by-pass preparations; and Mr. Lesley Williams for
technical assistance.
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Circulation Research, Vol. XXV, November 1969
595
TOTAL AND REGIONAL CORONARY BLOOD FLOW
10.
Use of radioactive microspheres to assess
distribution of cardiac output in rabbits. Am. J.
Physiol. 215: 486, 1968.
11.
from rate of myocardial nitrous oxide desaturation. Circulation Res. 1: 502, 1953.
NEUTZE, J. M., WYLJER, F., AND RUDOLPH, A. M.:
24. FOLTZ, E. L., PACE, R. G., SHELDON, W. F.,
WONG, S. K., TUDDENNAM, W. J., AND WEISS,
A. J.: Factors in variation and regulation of
coronary blood flow in intact anesthetized
dogs. Am. J. Physiol. 162: 521, 1950.
REYNOLDS, S. R. M., KIBSCH, M., AND BING, R.
J.: Functional capillary beds in the beating,
KCl-arrested and KCl-arrested-perfused myocardium of the dog. Circulation Res. 6: 600,
1958.
25. O'ROURKE, R. A., FISCHER, D. P., ESCOBAR, E.
E., BISHOP, V. S., AND RAPAPORT, E.: Effect of
acute pericardial tamponade on coronary blood
flow. Am. J. Physiol. 212: 549, 1967.
12. PRINZMETAL, N., SIMKIN, B., BERGMAN, H. C ,
AND KRUGER, H. E.: Studies on the coronary
circulation: II. Collateral circulation of the
normal human heart by coronary perfusion
with radioactive erythrocytes and glass spheres.
Am. Heart J. 33: 420, 1947.
26. KATZ, L. N., AND FEINBERG, H.: Relation of
cardiac effort to myocardial oxygen consumption and coronary flow. Circulation Res. 6:
656, 1958.
Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017
13. MACLEAN, L. D., HEDENSTROM, P. H., AND KIM,
27. BERGLUND, E., BORST, H. G., DUFF, F., AND
S. Y.: Distribution of blood flow to the canine
heart. Proc. Soc. Exptl. Biol. Med. 107: 786,
1961.
SCHREINER, G. L.: Effect of heart rate on
cardiac work, myocardial oxygen consumption
and coronary blood flow in the dog. Acta
Physiol. Scand. 42: 185, 1958.
14. FORTUIN, N. J., PITT, B., AND KAIHARA, S.:
Distribution of regional myocardial blood flow
in the dog (abstr.). Circulation 38: 77,
1968.
28. BRAUNWALD, E., SARNOFF, S. J., CASE, R. B.,
STAINSBY, W. N., AND WELCH, G. H., JR.:
Hemodynamic determinants of coronary flow:
Effect of changes in aortic pressure and cardiac
output on the relationship between myocardial
oxygen consumption and coronary flow. Am. J.
Physiol. 192: 157, 1958.
15. HAMMOND, G. L., AND AUSTEN, W. G.: Drainage
patterns of coronary arterial flow as determined
from the isolated heart. Am. J. Physiol. 212:
1435, 1967.
16. Morn, T. W., DRISCOL, T. E., AND ECKSTEIN, R.
29. KATZ, L. N., JOCHTM, K., AND BOHRNING, A.:
W.: Thebesian drainage in the left heart of the
dog. Circulation Res. 14: 245, 1964.
Effect of the extravascular support of the
ventricles on the flow in the coronary vessels.
Am. J. Physiol. 122: 236, 1938.
17. SEGRE, C , AND SILBERBERG, A.: Radial particle
displacements in poiseuille flow of suspensions.
Nature 189: 209, 1961.
30. LOVE, W. D., AND BURCH, G. E.: Differences in
the rate of Rb 86 uptake by several regions of
the myocardium of control dogs and dogs
receiving Z-norepinephrine or pitressin. J. Clin.
Invest. 38: 479, 1957.
18. BELLHOUSE, B. J., BELLHOUSE, F. H., AND REID,
K. A.: Fluid mechanics of the aortic root with
application to coronary flow. Nature 219:
1059, 1968.
19. SPENCER, F. C , MERRILL, D. L., POWERS, S. R.,
AND BING, R. J.: Coronary blood flow and
cardiac oxygen consumption in unanesthetized
dogs. Am. J. Physiol. 160: 149, 1950.
20.
MAXWELL, G. M., CASTILLO, C. A., CRUMPTON,
C. W., AND ROWE, G. G.: Hyperthermia: Sys-
temic and coronary circulatory changes in the
intact dog. Am. Heart J. 58: 854, 1959.
21.
22.
MAXWELL, G. M., CASTILLO, C. A., WHITE, D.
H., JR., CRUMPTON, C. W., AND ROWE, G. G.:
31.
LEVY, M. N., AND DEOLIVEIRA, J. M.: Regional
distribution of myocardial blood flow in the
dog as determined by Rb 80 . Circulation Res.
9: 96, 1961.
32. PHIBBS, R. H., WYLER, F., AND NEUTZE, J.:
Rheology of microspheres injected into circulation of rabbits. Nature 216: 1339, 1967.
33. ESTES, E. H., ENTMAN, M. L., DIXON, H. B., AND
HACKEL, D. B.: Vascular supply to the left
ventricular wall. Am. Heart J. 71: 58, 1966.
34. MOIR, T. W., AND DEBRA, D. W.: Effect of left
Induced tachycardia: Its effect upon the
coronary hemodynamics, myocardial metabolism, and cardiac efficiency of the intact dog. J.
Clin. Invest. 37: 1413, 1958.
ventricular hypertension, ischemia and vasoactive drugs on the myocardial distribution of
coronary flow. Circulation Res. 21: 65,
1967.
ROWE, G. G., CASTILLO, C. A., MAXWELL, G. M.,
WHITE, D. H., JR., FREEMAN, D. J., AND
35. CUTARELLI, R., AND LEVY, M. N.: Intraventricu-
CRUMPTON, C. W.: Effect of mecamylamine on
coronary flow, cardiac work, and cardiac
efficiency in normotensive dogs. J. Lab. Clin.
Med. 52: 883, 1958.
23. GOODALE, W. T., AND HACKEL, D. B.: Measure-
ment of coronary blood flow in dogs and man
Circulation Research, Vol. XXV, November 1969
lar pressure and the distribution of coronary
blood flow. Circulation Res. 12: 322, 1963.
36. PALMER, W. H., FAM, W. M., AND MCGREGOR,
M.: Effect of coronary vasodilation (dipyridamole-induced) on the myocardial distribution
of tritiated water. Can. J. Physiol. Pharm. 44:
777, 1966.
595
TOTAL AND REGIONAL CORONARY BLOOD FLOW
from rate of myocardial nitrous oxide desaturation. Circulation Res. 1: 502, 1953.
10. NEUTZE, J. M., WYLER, F., AND RUDOLPH, A. M.:
Use of radioactive inicrospheres to assess
distribution of cardiac output in rabbits. Am. J.
Physiol. 215: 486, 1968.
11.
24. FOLTZ, E. L., PAGE, R. G., SHELDON, W. F.,
WONG, S. K., TUDDENNAM, W. J., AND WEISS,
A. J.: Factors in variation and regulation of
coronary blood flow in intact anesthetized
dogs. Am. J. Physiol. 162: 521, 1950.
REYNOLDS, S. R. M., KIRSCH, M., ANTS BING, R.
J.: Functional capillary beds in the beating,
KCl-arrested and KCl-arrested-perfused myocardium of the dog. Circulation Res. 6: 600,
1958.
25. O'ROURKE, R. A., FISCHER, D. P., ESCOBAR, E.
E., BISHOP, V. S., AND RAPAPORT, E.: Effect of
acute pericardial tamponade on coronary blood
flow. Am. J. Physiol. 212: 549, 1967.
12. PRINZMETAL, N., SIMKIN, B., BERGMAN, H. C ,
AND KRUGER, H. E.: Studies on the coronary
circulation: II. Collateral circulation of the
normal human heart by coronary perfusion
with radioactive erythrocytes and glass spheres.
Am. Heart J. 33: 420, 1947.
13. MACLEAN, L. D., HEDENSTROM, P. H., AM) KIM,
26. KATZ, L. N., AND FEINBERG, H.: Relation of
cardiac effort to myocardial oxygen consumption and coronary flow. Circulation Res. 6:
656, 1958.
27.
Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017
S. Y.: Distribution of blood flow to the canine
heart. Proc. Soc. Exptl. Biol. Med. 107: 786,
1961.
SCHREINER, G. L.: Effect of heart rate on
cardiac work, myocardial oxygen consumption
and coronary blood flow in the dog. Acta
Physiol. Scand. 42: 185, 1958.
14. FORTUIN, N. J., PITT, B., AND KALHARA, S.:
Distribution of regional myocardial blood flow
in the dog (abstr.). Circulation 38: 77,
1968.
28. BRAUNWALD, E., SARNOFF, S. J., CASE, R. B.,
STAINSBY, W. N., AND WELCH, G. H., JR.:
Hemodynamic determinants of coronary flow:
Effect of changes in aortic pressure and cardiac
output on the relationship between myocardial
oxygen consumption and coronary flow. Am. J.
Physiol. 192: 157, 1958.
15. HAMMOND, G. L., AND AUSTEN, W. G.: Drainage
patterns of coronary arterial flow as determined
from the isolated heart. Am. J. Physiol. 212:
1435, 1967.
16. MOIR, T. W., DRISCOL, T. E., AND ECKSTEIN, R.
29. KATZ, L. N., JOCHIM, K., AND BOHRNINC, A.:
W.: Thebesian drainage in the left heart of the
dog. Circulation Res. 14: 245, 1964.
Effect of the extravascular support of the
ventricles on the flow in the coronary vessels.
Am. J. Physiol. 122: 236, 1938.
17. SEGRE, G., AND SILBERBERG, A.: Radial particle
displacements in poiseuille flow of suspensions.
Nature 189: 209, 1961.
30. LOVE, W. D., AND BUBCH, G. E.: Differences in
the rate of Rb 86 uptake by several regions of
the myocardium of control dogs and dogs
receiving Z-norepinephrine or pitressin. J. Clin.
Invest. 38: 479, 1957.
18. BELLHOUSE, B. J., BELLHOUSE, F. H., AND REID,
K. A.: Fluid mechanics of the aortic root with
application to coronary flow. Nature 219:
1059, 1968.
19. SPENCER, F. C , MERRILL, D. L., POWERS, S. R.,
AND BING, R. J.: Coronary blood flow and
cardiac oxygen consumption in unanesthetized
dogs. Am. J. Physiol. 160: 149, 1950.
20.
MAXWELL, G. M., CASTILLO, C. A., CRUMPTON,
C. W., AND ROWE, G. C.: Hyperthermia: Sys-
temic and coronary circulatory changes in the
intact dog. Am. Heart J. 58: 854, 1959.
21.
22.
MAXWELL, C. M., CASTILLO, C. A., WHITE, D.
H., JR., CRUMPTON, C. W., AND ROWE, G. G.:
BERGLUND, E., BORST, H. G., DUFF, F., AND
31.
LEVY, M. N., AND DEOLIVEIRA, J. M.: Regional
distribution of myocardial blood flow in the
dog as determined by Rbsfl. Circulation Res.
9: 96, 1961.
32. PHIBBS, R. H., WYLER, F., AND NEUTZE, J.:
Rheology of microspheres injected into circulation of rabbits. Nature 216: 1339, 1967.
33. ESTES, E. H., ENTMAN, M. L., DIXON, H. B., AND
HACKEL, D. B.: Vascular supply to the left
ventricular wall. Am. Heart J. 71: 58, 1966.
34. MOIR, T. W., AND DEBRA, D. W.: Effect of left
Induced tachycardia: Its effect upon the
coronary hemodynamics, myocardial metabolism, and cardiac efficiency of the intact dog. J.
Clin. Invest. 37: 1413, 1958.
ventricular hypertension, ischemia and vasoactive drugs on the myocardial distribution of
coronary flow. Circulation Res. 21: 65,
1967.
ROWE, G. G., CASTILLO, C. A., MAXWELL, G. M.,
WHITE, D. H., JR., FREEMAN, D. J., AXD
35. CUTARELLI, R., AND LEVY, M. N.: Intraventricu-
CRUMPTON, C. W.: Effect of mecamylamine on
coronary flow, cardiac work, and cardiac
efficiency in normotensive dogs. J. Lab. Clin.
Med. 52: 883, 1958.
23. COODALE, W. T., AND HACKEL, D. B.: Measure-
ment of coronary blood flow in dogs and man
Circulation Reiearcb, Vol. XXV, November 1969
lar pressure and the distribution of coronary
blood flow. Circulation Res. 12: 322, 1963.
36. PALMER, W. H., FAM, W. M., AND MCGREGOR,
M.: Effect of coronary vasodilation (dipyridamole-induced) on the myocardial distribution
of tritiated water. Can. J. Physiol. Pharm. 44:
777, 1966.
596
37.
DOMENECH, HOFFMAN, NOBLE, SAUNDERS, HENSON, SUBIJANTO
GHIGCS, D. M., JR., AND NAKAMUBA, Y.: Effect of
coronary constriction on myocardial distribution of iodoantipyrine-I131. Am. J. Physiol.
215: 1082, 1968.
38.
BRANDI, C ,
FAM, VV. M., AND MCGREGOR, M.:
Measurement of coronary flow in local areas of
myocardium using xenon133. J. Appl. Physiol.
24: 446, 1968.
Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017
Circulation Research, Vol. XXV, November 1969
Total and Regional Coronary Blood Flow Measured by Radioactive Microspheres in
Conscious and Anesthetized Dogs
RAUL J. DOMENECH, JULIEN I. HOFFMAN, MARK I. NOBLE, KENNETH B. SAUNDERS,
JAMES R. HENSON and SUJANTO SUBIJANTO
Downloaded from http://circres.ahajournals.org/ by guest on April 29, 2017
Circ Res. 1969;25:581-596
doi: 10.1161/01.RES.25.5.581
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1969 American Heart Association, Inc. All rights reserved.
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