Vol. 280, Issue 4, H1896-H1904, April 2001
Mechanism of reversible 99mTc-sestamibi
perfusion defects during pharmacologically induced
vasodilatation
Kevin
Wei,
Elizabeth
Le,
Jian-Ping
Bin,
Matthew
Coggins,
Ananda R.
Jayawera, and
Sanjiv
Kaul
Cardiac Imaging Center and Cardiovascular Division, University
of Virginia School of Medicine, Charlottesville, Virginia 22908
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ABSTRACT |
Reversible
perfusion defects on 99mTc-sestamibi imaging during
hyperemia are thought to occur due to myocardial blood flow (MBF) "mismatch" between regions with and without stenosis. We have recently shown that myocardial blood volume (MBV) distal to a stenosis
decreases during hyperemia, resulting in a reversible perfusion defect
on myocardial contrast echocardiography (MCE). In this study, we
hypothesized that a reversible perfusion defect on
99mTc-sestamibi imaging during hyperemia results from the
same mechanism. We tested our hypothesis under the following
conditions: 1) increases in MBF in the absence of changes in
MBV by using direct intracoronary infusion of adenosine (group
I, n = 10 dogs); 2) decrease in MBV despite an increase in MBF by left main infusion of adenosine proximal
to a noncritical coronary stenosis placed on either coronary artery
(group II, n = 13 dogs); and 3)
reduction in both resting MBF and MBV by placement of a severe stenosis
(group III, n = 7 dogs). In group
I dogs, no difference in MBV or 99mTc-sestamibi uptake
was found between the two coronary beds despite an up to fourfold
increase in MBF in one bed with adenosine. In group II dogs,
MBV distal to the stenosis decreased during hyperemia despite a twofold
increase in mean MBF. A good correlation was found between
99mTc-sestamibi uptake and MBV ratios from the stenosed
versus normal bed (r = 0.91, P < 0.001). In group III dogs, both MBF and MBV were decreased
in the stenosed bed at rest with a good correlation noted between
99mTc-sestamibi uptake and MBV ratios from the stenosed
versus normal bed (r = 0.92, P = 0.004). We conclude that reversible defects on
99mTc-sestamibi during vasodilator stress imaging are
related to decreases in MBV distal to a stenosis and not to "flow
mismatch" between beds. The decrease in MBV results in reduced
99mTc-sestamibi uptake during hyperemia.
myocardial blood volume; myocardial blood flow; hyperemia
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INTRODUCTION |
IN THE
ABSENCE of a prior myocardial infarction, resting myocardial
blood flow (MBF) and function are normal when a stenosis involves
85% of the coronary luminal diameter (8). To detect the
presence of such stenoses, coronary hyperemia is produced through
either an increase in myocardial oxygen demand (exercise or
catecholamine infusion) or with coronary vasodilators (which act
directly on coronary arterioles). Coronary arteries with <50% luminal
diameter stenosis can exhibit maximal hyperemia (coronary blood flow
4-5 times that at rest), whereas those with 50-85% luminal
diameter stenosis show an attenuated hyperemic response (8). This MBF "mismatch" during hyperemia, which is
not seen at rest, is thought to be the cause of a reversible perfusion defect on 99mTc-sestamibi imaging during pharmacologically
induced coronary vasodilatation.
Several studies (6, 7) have shown that, whereas
99mTc-sestamibi uptake decreases with a reduction in
resting MBF, it does not increase significantly in the normal
myocardium during pharmacologically induced hyperemia. Thus MBF
mismatch alone cannot explain the occurrence of a reversible perfusion
defect distal to a coronary stenosis or the high sensitivity and
specificity of 99mTc-sestamibi perfusion imaging for the
detection of coronary artery disease during pharmacological
vasodilatation (23, 26, 27).
We (30) and others (3, 4) have previously
shown that in the absence of a stenosis, coronary vasodilators increase MBF velocity without changing myocardial blood volume (MBV), which is
the volume of blood resident within myocardial microvessels (vessels 200 µm in diameter). We also demonstrated that,
whereas MBV distal to a noncritical stenosis remains unchanged at rest, it decreases during pharmacologically induced coronary hyperemia (13). Furthermore, the magnitude of decrease in MBV
correlates closely with the severity of stenosis and occurs to maintain
a constant capillary hydrostatic pressure (12, 13).
We, therefore, hypothesized that reversible 99mTc-sestamibi
perfusion defects during pharmacologically induced coronary
vasodilatation occur because of a reversible decrease in MBV distal to
a stenosis. Because ~90% of the MBV is resident in capillaries
(16), the decrease in MBV would reduce the capillary
surface area available for 99mTc-sestamibi uptake during
hyperemia compared with that available at rest, resulting in a
reversible perfusion defect. We tested our hypothesis in an open-chest
canine model under the following conditions: 1) increases in
MBF in the absence of changes in MBV, 2) decrease in MBV
despite an increase in MBF, and 3) reduction in both MBF and MBV.
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METHODS |
Animal preparation.
The study protocol was approved by the Animal Research Committee at the
University of Virginia and conformed to the American Heart Association
Guidelines for Use of Animals in Research. Thirty open-chest
anesthetized dogs were used for the study. Catheters were placed in
both femoral veins for administration of fluids and microbubbles and in
both femoral arteries for duplicate reference arterial sample
withdrawal for radiolabeled microsphere analysis. A catheter was
inserted into the right atrium via the right external jugular vein for
the measurement of right atrial pressure.
Proximal portions of the left anterior descending (LAD) and left
circumflex (LCx) coronary arteries were dissected free from the
surrounding tissue. Ultrasonic time of flight flow probes (series SB,
Transonics) were placed around these arteries and connected to a
flowmeter (model T206, Transonics). Catheters were positioned in the
ascending aorta via the right carotid artery for measurement of central
aortic pressure as well as in the left atrium for pressure measurement
and for injection of radiolabeled microspheres. A 20-g Teflon catheter
was placed distal to the artery undergoing either subselective
adenosine infusion or placement of a stenosis. In the latter setting,
it was also used to measure distal coronary artery pressure. All
catheters were connected to pressure transducers, which, like the
flowmeter, were connected to a multichannel recorder (model ES 2000, Gould Electronics).
In group I (n = 10 dogs), the purpose was to
evaluate regional 99mTc-sestamibi uptake during increases
in MBF without changes in MBV. MBF in the LAD bed was increased to
different levels using various doses of adenosine administered
subselectively into the LAD in separate dogs (Fig.
1). In group II
(n = 13 dogs), regional 99mTc-sestamibi uptake was measured when MBF was increased
to different degrees in both coronary arteries from a left main
infusion of adenosine while MBV in one bed was decreased distal to a
noncritical stenosis (Fig. 2). In
group III (n = 7 dogs) regional
99mTc-sestamibi uptake was assessed when both resting MBF
and MBV were reduced with a flow-limiting stenosis. Coronary driving
pressure (CDP) was measured as the difference between mean aortic (or
distal coronary in case of stenosis) pressure and right atrial
pressure. Myocardial vascular resistance (MVR) was calculated by
dividing CDP by the mean coronary blood flow.
Ex vivo 99mTc-sestamibi imaging and measurement of
myocardial activity.
Approximately 8 mCi of 99mTc-sestamibi (DuPont
Pharmaceuticals) was injected intravenously in each dog. At the end of
the experiment, the heart slice corresponding to the MCE image (1 cm
thick) was placed on the center of the scan head of a gamma
scintillation camera (Technicare 420, Ohio Nuclear) to obtain an ex
vivo image. An all-purpose medium energy collimator with a 20% energy
window centered around the 140-keV peak of 99mTc was used.
Images were acquired in a 128 × 128 matrix with collection of
1 × 106 counts for each acquisition.
After the ex vivo imaging was completed, the heart slice was divided
into 16 segments. Each segment was further divided into epi-, mid-, and
endocardial thirds. Because there is no means of assessing changes in
absolute myocardial 99mTc-sestamibi uptake between dogs, a
piece of skeletal muscle was also taken from the hindlimb and divided
into 12 segments to serve as a control against which to compare
myocardial 99mTc-sestamibi uptake. Because adenosine was
administered directly into the coronary artery, it was assumed not to
affect skeletal muscle blood flow. Regional myocardial and skeletal
muscle 99mTc-sestamibi uptake were measured using a gamma
well counter (LKB Wallac).
Determination of regional radiolabeled microsphere MBF.
At each stage, ~2 × 106 of 11-µm radiolabeled
microspheres (DuPont Medical Products) suspended in 4 ml of 0.9%
saline and 0.01% Tween 80 were injected into the left atrium slowly
over 10-20 s. Duplicate reference blood samples (10 ml each) were
withdrawn from the femoral arteries over 130 s with a
constant-rate withdrawal pump (model 944, Harvard Apparatus).
Myocardial microsphere counts were determined 1 wk after the experiment
to allow complete decay of 99mTc activity. MBF to each
epi-, mid-, and endocardial piece was calculated from the equation
Qm = (Cm × Qr)/Cr, where Qm is blood flow to
the myocardial piece (in ml/min), Cm is tissue counts, Qr is the rate of arterial sample withdrawal (in ml/min),
and Cr is arterial reference sample counts
(11). Transmural MBF (in
ml · min
1 · g1) to each of
the 16 wedge-shaped segments was calculated as the quotient of the
summed flows to the individual pieces within that segment and their
combined weight. To exclude the effect of collateral MBF on the lateral
borders of the perfusion bed, we calculated MBF to each bed (defined by
Monastral blue dye injection, see Experimental protocol) by
averaging the transmural MBF in the central 50-75% segments in
each bed.
Myocardial contrast echocardiography.
Myocardial contrast echocardiography (MCE) was performed using
intermittent harmonic imaging as previously described
(30). All system settings were optimized at the beginning
of each experiment and held constant throughout. A solution consisting
of 2 ml of Optison (Mallinckrodt Medical) diluted in 23 ml of normal
saline was infused into the femoral vein at a rate of 80-100 ml/h.
Imaging was initiated after a steady-state concentration of
microbubbles was achieved (~2 min after initiating infusion).
Ultrasound transmission was gated to the electrocardiogram. All pulsing
intervals (PI) greater than one cardiac cycle (ranging from 1 to 20)
were obtained using a single trigger positioned at end systole (peak of
the T wave). Dual triggers (the "imaging trigger" was placed at end systole and the "microbubble destruction" trigger was placed
200-400 ms before the imaging trigger) were used to obtain PI less
than one cardiac cycle. Up to seven end-systolic images were acquired at each PI.
Images were transferred from a videotape to an offline image analysis
system. At least five images from each PI were selected and aligned
using computer cross-correlation along with five background images
acquired before infusion of microbubbles. Regions of interest were
placed over the LAD and LCx beds in one of the aligned images, which
were defined in vivo (see Experimental protocol). These were
always drawn over the anterior half of the myocardial short axis (Fig.
3) to avoid any potential shadowing from
microbubbles in the LV cavity and also to sample the myocardium at the
same beam thickness. PI versus background-subtracted video intensity (VI) plots were generated for both regions of interest and fitted to
the following exponential function: y = A (1 
e
t), where y
is the VI at PI t, A is the plateau VI
representing MBV, and 
is the rate of rise of VI representing the
mean microbubble velocity. The product A × represents MCE-derived MBF (30). In addition, parametric
images were also obtained by fitting the exponential function described
above to the VI versus PI plot obtained for each pixel in the set of
background-subtracted and aligned images (19). These
images were used to compare the topography of reduced MBV on MCE with
that of the perfusion defect on ex vivo 99mTc-sestamibi
imaging.
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Fig. 3.
Placement of regions of interest (ROI) over the left anterior
descending (LAD) and left circumflex (LCx) coronary artery beds
(B). LAD bed was defined by a direct inctracoronary
injection of Albunex (A). See text for details. Arrows in
A, LAD perfusion bed. Colored areas in B, ROI
over the LAD and LCx bed.
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Experimental protocol.
The LAD or LCx perfusion bed size was first defined in vivo using 0.1 ml of Albunex diluted to 1 ml with normal saline and injected
subselectively into either artery. Figure 3A shows the method of defining the LAD bed. In group I dogs, LAD
hyperemia was induced with a subselective intracoronary infusion of
adenosine ranging in dose from 0.5 to 5.0 µg · kg1 · min1 in
different dogs (Fig. 1). The purpose was to increase coronary blood
flow to different degrees in separate dogs without causing systemic
hemodynamic effects. After coronary blood flow had stabilized at the
desired level, 99mTc-sestamibi and radiolabeled
microspheres were injected, and MCE was performed. In group II
dogs, varying degrees of noncritical stenoses were placed either
on the LAD or the LCx of different dogs, and their severity was
determined by the transstenotic pressure gradient. MCE was performed at
rest and subsequently repeated during hyperemia, at which time
99mTc-sestamibi and radiolabeled microspheres were also
injected intravenously. In group III dogs, resting MBF was
reduced in either the LAD or LCX to different degrees in each dog with
a flow-limiting stenosis. After coronary blood flow had stabilized,
99mTc-sestamibi as well as radiolabeled microspheres were
injected, and MCE was performed.
At the end of the experiment, the LAD bed was defined again by
occlusion of the LAD and injection of Monastral blue dye (Sigma) into
it. The dogs were euthanized using a mixture of pentobarbital sodium
and KCl, and the heart was removed for processing. It was cut
into five short-axis slices. The LAD bed was defined ex vivo as the
region that was stained blue, whereas the LCx bed was unstained.
Statistical methods.
Data are expressed as means ± SD. Comparisons between stages were
performed using either the paired or the unpaired Student's t-test. Correlations were performed using linear regression
analysis. For differences among groups, a P value of <0.05
(two-sided) was considered significant.
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RESULTS |
Group I dogs.
There were small changes in heart rate (109 ± 13 to 104 ± 12 beats/min, P = 0.02) and right atrial pressure
(9 ± 5 to 10 ± 5 mmHg, P = 0.04) without
any changes in aortic or left atrial pressures during the subselective
infusion of adenosine into the LAD. A wide range of flow mismatch
between the LAD and LCx beds (range 1-4) was induced in separate
dogs by using different doses of adenosine. Adenosine reduced the MVR
in the LAD bed, which was associated with an increase in the mean MBF
in the entire group of dogs by more than twofold (Table
1). MBF in the control LCx bed remained
unchanged during adenosine, although a slight decrease in CDP produced
a small but significant decrease in MVR. No change in absolute plateau
VI was noted between the hyperemic and control beds. Consequently,
increases in MBF induced by adenosine were met by a corresponding
increase in microbubble velocity ().
Figure 4A shows an example of
a MCE color-coded parametric image representing plateau VI (or MBV)
from a group I dog where the LAD MBF was increased by
approximately four times during subselective LAD infusion of adenosine,
while the LCx MBF remained unchanged. The entire myocardium shows
homogenous opacification, indicating a similar MBV in both the LAD and
LCx beds despite the disparity in regional MBF. The corresponding
99mTc-sestamibi image of the same short-axis heart slice
depicted in Fig. 4B also shows equal uptake of sestamibi in
the entire myocardium. Figure 5 shows the
relation between MBF and 99mTc-sestamibi uptake from all
group I dogs. Despite large increases in MBF to the LAD bed,
the ratio of 99mTc-sestamibi uptake between the two beds
was flat. There was no difference in the ratio of 99mTc
sestamibi uptake in the myocardium versus the skeletal muscle for the
LAD compared with the LCx bed (13 ± 3 versus 15 ± 3, P = 0.37) despite a greater than twofold increase in
MBF to the LAD bed.
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Fig. 4.
Myocardial contrast echocardiography (MCE; A) and an ex
vivo 99mTc-sestamibi image (B) from a
group I dog during adenosine infusion into the LAD.
Myocardial opacification and uptake of 99mTc-sestamibi
uptake are uniform despite a fourfold disparity in MBF between the LAD
and LCx beds. See text for details.
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Fig. 5.
Relation between myocardial blood flow (MBF) and
99mTc-sestamibi uptake ratios from the LAD and LCX beds in
all group I dogs. See text for details. SEE, standard error
of the estimate.
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Group II dogs.
Infusion of adenosine into the left main coronary artery did not result
in significant changes in heart rate or aortic and right atrial
pressures, whereas the left atrial pressure increased slightly (from
14 ± 2 to 17 ± 4 mmHg, P = 0.004). Because
the stenoses were noncritical, MBF in the stenosed bed still increased during adenosine, although it was significantly less than that in the
normal bed (Table 2). Even though MVR in
the stenosed bed decreased due to maximal arteriolar vasodilatation
during adenosine, it did not decrease to the same extent as that in the group I dogs who had no stenosis (P < 0.01 between the two groups) because of a decrease in MBV distal to the
stenosis during hyperemia.
MBF, microbubble velocity (), and MCE-derived MBF (A × ) were similar at baseline in the beds with and without
stenosis, resulting in ratios close to unity. During hyperemia,
however, despite an absolute increase in these values in both beds, the relative change in the bed with stenosis was significantly less than
that in the normal bed, resulting in lower ratios for these values in
the stenosed versus control bed (Table
3). In contradistinction to group
I dogs, where regional differences in MBF were induced in the
absence of changes in MBV (Fig. 4), plateau VI decreased in group
II dogs distal to the stenosis during hyperemia, indicating a
reduction in MBV (A). Because MBV did not change in the
normal bed during hyperemia, the MBV ratio between the stenosed and
control beds decreased.
Figure 6A shows a color-coded
parametric image of plateau VI (or MBV) from a group II dog
during hyperemia in whom MBF in the stenosed bed doubled from 1.0 to
2.0 ml · min1 · g1 with
infusion of adenosine. The corresponding 99mTc-sestamibi
image from the same dog is shown in Fig. 6B. Similar to the
parametric MCE image, a perfusion defect in the LAD bed is clearly seen
despite an increase in the absolute LAD MBF during hyperemia. The
perfusion defect corresponds in both location and spatial extent to the
region with decreased MBV on the MCE image. The ratio of
99mTc-sestamibi uptake in the myocardium versus the
skeletal muscle was less for the stenosed LAD compared with the control
LCx bed (12 ± 4 versus 18 ± 7, P = 0.02)
despite an almost twofold increase in MBF in the LAD bed.
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Fig. 6.
MCE (A) and an ex vivo 99mTc-sestamibi image
(B) from a group II dog with a moderate LAD
stenosis during hyperemia. A perfusion defect can be seen in the LAD
bed on the 99mTc-sestamibi image that corresponds closely
to the area with reduced myocardial blood volume (MBV) on MCE despite a
twofold increase in MBF to the LAD
bed.
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A good correlation was noted between 99mTc-sestamibi uptake
and plateau VI (MBV) ratios in the beds with and without stenosis in
all group II dogs (Fig.
7A). In this setting, where
MBV decreased in the bed subtended by a stenosed artery and did not
change in the bed supplied by a normal artery, a fair correlation was
also found between 99mTc-sestamibi uptake and the MBF
ratios in the two beds (Fig. 7B).
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Fig. 7.
Relation between 99mTc-sestamibi uptake and
MBV (A) as well as MBF ratios (B) from the beds
with and without stenosis during hyperemia in all group II
dogs. See text for details.
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Group III dogs.
Although the heart rate decreased slightly (from 108 ± 14 to
103 ± 13 beats/min, P = 0.04) after placement of
stenoses, no changes were noted in aortic, left, or right atrial
pressures. The stenosis resulted in a 50% reduction in the CDP
and a little <50% and resting MBF compared with baseline (Table
4). MVR showed a mild decline, as did all
the MCE parameters compared with the normal nonstenosed bed (Table
5).
Figure 8A illustrates an
example of a color-coded parametric image from one group III
dog with a flow-limiting LCx stenosis where the resting transstenotic
pressure gradient was 60 mmHg and the resting MBF was reduced to 30%
of normal. The resulting reduction in resting MBV caused a resting
perfusion defect in the lateral wall. The corresponding
99mTc-sestamibi image from the same dog in Fig.
8B shows an identical perfusion defect secondary to lower
uptake of sestamibi in the stenosed compared with normal bed. In dogs
in whom the stenosed versus control resting MBF was <1, the ratio of
99mTc-sestamibi uptake in the myocardium versus the
skeletal muscle was significantly less for the stenosed compared with
control bed (6.5 ± 3 versus 15 ± 3, P = 0.007).
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Fig. 8.
MCE (A) and an ex vivo 99mTc-sestamibi image
(B) from a group III dog during resting
hypoperfusion. Both images show a similar perfusion defect in the
lateral myocardium. The posteromedial papillary muscle was not included
in the heart slice used to generate the 99mTc-sestamibi
image.
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An excellent correlation was found between the ratios of resting
99mTc-sestamibi activity and MBV (A) in the beds
with and without stenosis (Fig.
9A). Because the decrease in
resting MBV was associated with a decrease in resting MBF, a good
correlation was also noted between the 99mTc-sestamibi
activity versus radiolabeled microsphere-derived MBF ratios from the
beds with and without stenosis (Fig. 9B).
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Fig. 9.
Relation between 99mTc-sestamibi uptake and
MBV (A) as well as MBF ratios (B) from the beds
with and without stenosis in all group III dogs. See text
for details.
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DISCUSSION |
The new finding from this study is that reversible
99mTc-sestamibi perfusion defects during coronary
vasodilatation occur due to a reversible decrease in MBV distal to a
stenosis rather than to a MBF mismatch. We also found that
99mTc-sestamibi uptake does not increase during coronary
hyperemia when MBV remains unchanged and that it decreases when MBV is
reduced irrespective of the direction of change in MBF. Taken together, these findings indicate that 99mTc-sestamibi uptake
reflects MBV and not MBF.
In this study, we used MCE to define MBV. This approach is based on the
concept that when steady state is achieved, the tissue concentration of
a pure intravascular tracer reflects the blood volume of that tissue.
We have shown that microbubbles of the type used in this study remain
entirely within the intravascular space and have an intravascular
rheology as well as a myocardial transit rate that is similar to that
of red blood cells (14, 17). We (30) have
also shown that at the concentrations used in this study, the relation
between microbubble concentration and VI is linear. Linka et al.
(20) demonstrated that the changes in total tissue blood
volume are associated with changes in microbubble transit rate. Thus
the method used appears to be accurate and provides a transmural
distribution of MBV.
Gould et al. (8) first demonstrated that hyperemic
coronary blood flow was attenuated in the presence of stenoses that exceeded 50% of the coronary luminal diameter. At about the same time,
it became clear that in the presence of >50% coronary stenosis, reversible defects could be seen on exercise myocardial perfusion imaging with the use of radioisotopes (1, 29). Thus it was believed that reversible perfusion defects during hyperemia were secondary to MBF mismatch that developed between the beds with and
without stenosis. This belief has persisted despite repeated demonstration of a relatively flat relation between MBF and isotope uptake at levels of hyperemic flow, particularly with
99mTc-labeled tracers (Fig.
10) (6, 7).
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Fig. 10.
Data points denote relation between MBF and
99mTc-sestamibi activity during intracoronary infusion of
adenosine in group I ( ) and group
III dogs ( ). Line A shows the same
relation during intravenous adenosine administration (7).
Line B illustrates the relation between MBF and
201Tl activity during exogenously induced hyperemia
(7). Line C depicts the same relation during
exercise (19). See text for details.
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Capillaries do not have vascular smooth muscle. As a consequence, it
has always been assumed that capillary dimensions (and thus resistance)
do not change with changes in coronary blood flow. When a coronary
vasodilator is administered into the normal coronary circulation, MBV
(volume of blood within the myocardial microvasculature, 90% of which
is in capillaries; see Ref. 16) does not change despite an
increase in MBF (3, 4, 30). The latter occurs solely due
to an increase in MBF velocity caused by a decrease in arteriolar and,
to a smaller extent, venular resistance. Thus, in the normal coronary
circulation, capillary dimensions do not change during exogenously
mediated hyperemia, whereas the arteriolar and venular dimensions
increase (9, 15).
With the use of MCE, we have recently shown that, even though
arterioles are the site of greatest resistance at rest, capillaries offer the greatest resistance during hyperemia (13). Thus
increases in hyperemic MBF in the normal coronary circulation are
limited primarily by capillary resistance. Even in the presence of a
stenosis, it is capillary resistance (and not stenosis resistance) that mostly limits increases in peak hyperemic MBF (13).
Although MBV remains constant in the absence of a stenosis during
hyperemia, it decreases in the presence of a stenosis, and this
decrease in MBV is proportional to the severity of the stenosis
(13).
The results of our present study demonstrate that when regional MBV
remains constant, 99mTc-sestamibi uptake does not change
despite an increase of several degrees in regional MBF. Thus a
disparity in isotope uptake during hyperemia cannot be explained on the
basis of differences in MBF alone. Our results also show that tracer
uptake decreases in proportion to the decrease in MBV independent of
the change in absolute MBF (an increase as in group II dogs
or a decrease as in group III dogs). Furthermore,
group I dogs demonstrated less reduction in 99mTc-sestamibi uptake for any given reduction in MBF (Fig.
6B) and a closer correlation was noted between
99mTc-sestamibi uptake and MBV. Thus reversible perfusion
defects on 99mTc-sestamibi imaging are caused by changes in
MBV and not MBF.
Because it is not possible to determine absolute MBF with the use of
99mTc-sestamibi, we could only express
99mTc-sestamibi uptake in relative terms. To show that
99mTc-sestamibi uptake had not increased in the hyperemic
LAD in the group I dogs and had actually decreased in the
stenosed bed during hyperemia in the group II dogs and at
rest in the group III dogs, we measured
99mTc-sestamibi uptake in the skeletal muscle as well. We
assumed that changes in MBF did not affect skeletal muscle flow. With the use of the skeletal muscle as a "reference organ," we showed that the 99mTc-sestamibi uptake in the LAD bed did not
increase during adenosine infusion in the group I dogs. We
also demonstrated reduced 99mTc-sestamibi uptake in the
stenosed bed in the group II and III dogs.
Although these measurements still reflect only relative uptake, we
would not expect skeletal muscle uptake of 99mTc-sestamibi
not be affected by change in MBF when systemic hemodynamics remained
stable between stages.
The data points in Fig. 10 shows the relation between MBF and
99mTc-sestamibi uptake ratios between the stenosed and
normal beds during hyperemia from the group I and
III dogs from our study. The results are very similar to
those of Glover et al. (7) (line A in Fig. 10)
with a linear relation noted between 99mTc-sestamibi uptake
and MBF only when resting MBF was reduced. The slightly positive
correlation between hyperemic MBF and 99mTc-sestamibi
uptake from their results compared with the virtually flat relation
from ours could be related to the use of intravenous rather than
intracoronary administration of adenosine in the former. Hypotension in
anesthetized dogs as well as a direct effect on adenosine
A1 receptors causes tachycardia, which increases myocardial O2 consumption and which in turn increases MBV
(18) via capillary recruitment required for adequate
myocyte oxygen delivery (5, 10). The increase in MBV could
in turn allow an increase in 99mTc-sestamibi uptake.
That capillary blood volume modulates tracer uptake should not be
surprising. The extraction fraction of a tracer is proportional to the
permeability-surface area product (2). The second
component of this product represents the surface area available for
nutrient exchange between capillaries and myocytes, which is directly
related to capillary blood volume. Thus when permeability-related
factors are constant, the main determinant of extraction fraction
becomes the capillary blood volume. Consequently, a decrease in
capillary blood volume should result in a proportionate decrease in
tracer uptake. Other factors that can effect the permeability-surface area product, such as the magnitude of MBF, are constant for
99mTc-sestamibi (21). In the model of
noncritical coronary stenosis used in our study, the myocyte membrane
properties that affect lipophilicity (27), the
mitochondrial negative potential that determines
99mTc-sestamibi myocyte retention (24, 25),
and the physical attributes of the tracer itself should not be
different in various myocardial regions. Taken together, these findings
imply that differences in regional 99mTc-sestamibi uptake
during coronary vasodilatation are related mainly to regional
differences in capillary blood volume.
In addition to providing mechanistic insights into the role of
capillaries in coronary blood flow regulation, our results also raise
important questions regarding measurement of MBF with tracers.
Radiolabeled microspheres are considered to be the best because they
are completely entrapped in the coronary microcirculation (99%
extraction fraction) (11, 28). Thus even if capillary blood volume changes, tracer uptake will remain proportional to MBF.
MBF would not, however, be reflected accurately by tracers whose uptake
depends on diffusion across the capillary bed, for reasons discussed
above, and would instead reflect MBV.
A case in point is 201Tl, whose uptake versus MBF relation
during hyperemia is shown as line B in Fig. 10
(7). The uptake (U) of a tracer depends on the rate of
supply [the product of arterial concentration (C) and flow (F)] as
well as the rate of diffusion across the capillaries [determined by
the permeability-surface area product (PS)] given by the
following formula: U = C × F[1 e(PS/F)]. At low flows, if there
is no decrease in MBV, then because PS >> F, the above
formula reduces to U = C × F and, therefore, U is
proportional to flow. At high flows, PS << F, and the
above formula reduces to U = C × PS and,
therefore, U is proportional to PS and is independent of
flow. Because the PS is greater for the more diffusible
tracer 201Tl than 99mTc-sestamibi, the relation
between MBF and tracer uptake is more linear for 201Tl
(line B in Fig. 10). However, the uptake of even a highly
diffusible tracer like 201Tl will plateau at higher flows
during hyperemia (line B in Fig. 10) because, as shown in
this and previous studies, the capillary blood volume does not increase
appreciably during exogenously induced hyperemia.
Unlike exogenously induced hyperemia, where myocardial O2
consumption does not change significantly, hyperemia induced by exercise is associated with increased myocardial O2 demand,
which in turn results in capillary recruitment and increased MBV
(18). In this setting, PS increases with an
increase in MBF, resulting in greater tracer uptake even at a higher
MBF (line C in Fig. 10). Thus capillary recruitment could
explain the apparent disparity between the results of Neilson et al.
(22) (depicted as line C in Fig. 10), who
measured 201Tl uptake in exercising dogs, and those of
others (7, 18), who measured it during exogenously induced
coronary hyperemia. Therefore, unlike tracers that are trapped in the
microcirculation, the uptake of diffusible tracers is determined by the
status of myocardial capillaries. It is likely, therefore, that the
uptake of 99mTc-sestamibi also increases during exercise in
the normal myocardium where capillaries can be recruited, although
because of its poor diffusion the increase will be significantly less
than that of 201Tl.
| |
ACKNOWLEDGEMENTS |
This study was supported in part by National Heart, Lung, and Blood
Institute Grant R01-HL-48890, Mid-Atlantic American Heart Association
Affiliate Grant B-98458-V, the Fourjay Foundation (Williamsport, PA),
and DuPont Pharmaceuticals (North Billerica, MA). Agilent Technologies
provided an equipment grant. K. Wei was the recipient of Mentored
Clinical Scientist Development Award K08- HL-03909, and E. Le was the
recipient of National Heart, Lung, and Blood Institute Postdoctoral
Training Grant T32-HL-07355. M. Coggins was the recipient of a medical
student research grant from the American Diabetes Association
(Washington, DC).
| |
FOOTNOTES |
This paper was presented in part at the Young Investigator Award
Competition of the American Society of Echocardiography, June 2000.
Address for reprint requests and other correspondence: S. Kaul,
Box 158, Cardiovascular Div., Univ. of Virginia Health Sciences Center,
Charlottesville, VA 22908 (E-mail: sk{at}virginia.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 August 2000; accepted in final form 30 November 2000.
| |
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ABSTRACT
INTRODUCTION
