Vol. 274, Issue 3, H923-H929, March 1998
Heterogeneous fatty acid uptake early after reperfusion in rat
hearts
Yuriko
Yamane1,
Nobumasa
Ishide1,
Yutaka
Kagaya1,
Daiya
Takeyama1,
Nobuyuki
Shiba1,
Masanobu
Chida1,
Tetsuji
Nozaki1,
Toshihiro
Takahashi2,
Tatsuo
Ido2, and
Kunio
Shirato1
1 First Department of Internal
Medicine, Tohoku University School of Medicine, Sendai; and
2 Cyclotron and Radioisotope
Center, Tohoku University, Sendai 980-8574, Japan
 |
ABSTRACT |
We determined
whether spatial distributions of substrate uptake are heterogeneous
within the area at risk during reperfusion. Quantitative
autoradiography with imaging plates and two long-lived radioisotopes
was applied to 15 open-chest, anesthetized rats subjected to 30 min of
coronary artery ligation and 30 min of reperfusion. Regions showing
increased
-methyl-[1-14C]heptadecanoic
acid ([14C]BMHDA) uptake (166 ± 17% of that in the nonischemic area) appeared at the lateral
borders and subepicardial layer within the area at risk, and
2-deoxy-D-[1-3H]glucose
([3H]DG) uptake was 103 ± 24% in these regions. Regions with decreased [14C]BMHDA uptake (28 ± 11%) occupied the midmyocardial layer except at the lateral borders
within the area at risk, and
[3H]DG uptake was 62 ± 18%
in these regions. The percentage interregional coefficientsof variation
(index of heterogeneity) in
[14C]BMHDA uptake,
[3H]DG uptake, and blood flow
were higher in the area at risk than in the nonischemic area (76 ± 23 vs. 21 ± 7%, 39 ± 10 vs. 21 ± 7%, and 49 ± 19 vs. 14 ± 4%, respectively). Heterogeneous distributions of substrate
uptake may explain the conflicting results concerning substrate
metabolism during reperfusion.
glucose metabolism; imaging plate; double-tracer autoradiography
| |
INTRODUCTION |
RESTORATION OF BLOOD FLOW in patients with evolving
myocardial infarction has become an established therapeutic
intervention (21). Techniques that distinguish necrotic tissue from
injured but viable tissue after coronary revascularization are
necessary to determine the extent of the ischemic injury and the
prognosis. Because regional ventricular function recovers slowly after
reperfusion in reversibly injured myocardium (2), metabolic activity
may be a better indicator for myocardial viability early after coronary revascularization.
Fatty acids are the major energy source for myocardium in the fasting
state (3). Glucose, on the other hand, is utilized after a
carbohydrate-rich meal and in the ischemic myocardium (3, 20). However,
substrate metabolism in the reperfused myocardium is not fully
understood, and studies concerning this issue have yielded conflicting
results. In isolated perfused rat hearts subjected to 25-60 min of
global no-flow ischemia and reperfusion, palmitate oxidation
was decreased (7), did not change (15), or was increased (22), and
glucose oxidation was increased (7) or did not change (15). In
extracorporeally perfused working swine hearts undergoing regional
low-flow ischemia (60% coronary flow reduction for 30-45
min) followed by reperfusion, palmitate uptake did not differ from
control (18), and its oxidation did not differ (18) or was increased
(14). During reperfusion after greater degrees of regional
ischemia (1-3 h of coronary occlusion) in dog hearts,
palmitate uptake was decreased (17), and its oxidation was reduced (10)
or did not change (17); however, glucose uptake was increased (17).
The pattern of substrate utilization in reperfused myocardium is likely
to be related to the degree of ischemic tissue injury. Various degrees
of ischemic tissue injury are observed in evolving myocardial
infarction (8). Therefore, the spatial distribution of substrate uptake
is assumed to be heterogeneous during reperfusion after transient
regional ischemia. Studies using regional coronary venous blood
sampling (14, 17, 18) and positron emission tomography (10) may have
failed to depict the heterogeneous distribution of substrate metabolism
during reperfusion after acute regional ischemia.
We developed quantitative double-tracer autoradiography with imaging
plates and two long-lived radioisotopes (30). The features of this
method are high spatial resolution (pixel area = 50 × 50 µm),
high sensitivity, and superior linearity over the dynamic range from
104 to
105. To clarify whether spatial
distributions of myocardial substrate uptake and blood flow are
heterogeneous during reperfusion after acute regional ischemia,
we applied this method to rat hearts subjected to 30 min of left
coronary artery ligation and 30 min of reperfusion.
| |
METHODS |
Radiopharmaceuticals.
Regional myocardial free fatty acid uptake was assessed with a
branched-chain fatty acid analog,
-methyl-[1-14C]heptadecanoic
acid ([14C]BMHDA; NEN, Boston,
MA), with a specific activity of 2.13 GBq/mmol (4, 5, 29, 30). Regional
myocardial glucose uptake was determined with
2-deoxy-D-[1-3H]glucose
([3H]DG; Amersham,
Buckinghamshire, UK), with a specific activity of 640 GBq/mmol (27, 29,
30). Regional myocardial blood flow was assessed with
4-[N-methyl-14C]iodoantipyrine
([14C]IAP; NEN), with a specific
activity of 2.2 GBq/mmol (23, 29).
Protocols.
The purpose and nature of this study were approved by the Committee of
Animal Experiments in the Cyclotron and Radioisotope Center of Tohoku
University (Sendai, Japan). Fifteen male Wistar rats, weighing 283 ± 38 g (mean ± SD), were fed normal rat chow and tap water ad
libitum until they were subjected to the surgical procedure, which was
begun at about 2:00 PM. The rats were anesthetized with an
intraperitoneal injection of pentobarbital sodium (40 mg/kg). Catheters
(PE-50) were placed in the right common carotid artery for monitoring
arterial blood pressure with an oscillograph (model MPU 0.5, Nihon
Koden, Tokyo, Japan) and arterial blood sampling and in
the right jugular vein for the administration of radiopharmaceuticals.
After a left thoracotomy was performed under artificial ventilation, a
snare (6-0 nylon) was placed around the left coronary artery. To
confirm that the snare was positioned around the left coronary artery,
we pulled both suture ends for a few seconds to determine whether
myocardial cyanosis and wall motion abnormalities appeared. Arterial
blood was sampled for the determination of plasma concentrations of
glucose (9, 25), insulin (28), and free fatty acids (24). After 1 mg/kg
lidocaine was injected to prevent ventricular arrhythmias, the left
coronary artery was ligated. Thirty minutes after the initiation of the left coronary artery ligation, the snare loop was released.
In group A
(n = 8), 5 min after reperfusion, 3.7 MBq of [3H]DG were injected
intravenously for 30 s, and 30 s later, 0.185 MBq of
[14C]BMHDA dissolved in 0.2 ml
of an aqueous solution of bovine serum albumin (11) was injected
intravenously for 30 s. Thirty minutes after the
[3H]DG was injected, the left
coronary artery was ligated again, and the rats were then injected
intravenously with 2% methylene blue solution (0.5 ml) to demarcate
the area at risk by negative staining (29, 30). Immediately afterward,
the rats were killed by administration of saturated KCl solution (0.3 ml). The hearts were removed rapidly and frozen in dry ice.
In group B
(n = 7), 5 min after the reperfusion
following 30 min of ligation of the left coronary artery, 3.7 MBq of
[3H]DG were injected
intravenously for 30 s. Thirty minutes after the
[3H]DG injection, 0.185 MBq of
[14C]IAP dissolved in 1.8 ml of
0.9% NaCl solution was injected intravenously at a constant rate for
30 s with an infusion pump (STC-521, Terumo, Tokyo, Japan). To
determine blood [14C]IAP
activities, we collected serial arterial blood samples at 0, 1, 3, 5, 8, 13, 18, 23, and 28 s after the initiation of the [14C]IAP infusion. Time-activity
curves of the blood [14C]IAP
concentrations were obtained using a liquid scintillation counter
(2050CA, Packard, Downers Grove, IL). Thirty seconds after the
initiation of the [14C]IAP
infusion, the rats were killed by cutting the ascending aorta and the
pulmonary trunk. The hearts were removed rapidly and frozen in dry ice.
Quantitative autoradiography.
Quantitative double-tracer autoradiography with
3H and
14C was performed as described
previously (29, 30). In brief, 20-µm-thick frozen heart sections
taken perpendicular to the long axis of the left ventricle were
prepared. The sections along with the 3H- and
14C-labeled graded standards
(Amersham) were placed in contact with 3H-sensitive imaging plates (Fuji
Photo Film, Tokyo, Japan) for 2 wk and with general use imaging plates
(Fuji Photo Film) for another 2 wk.
The autoradiograms were analyzed using a computer-assisted
imaging-processing system (BAS3000, Fuji Photo Film). The image data
were recorded as digitized values of each pixel (50 × 50 µm) in
the analyzing unit of this system. Discrimination between electrons
emitted from 3H and
14C was possible because of
their different energy distributions (30).
On the color monitor display of the image processor, circular regions
of interest (the area of each region of interest was 0.0925 mm2) were placed throughout the
left ventricular wall of one midventricular-level section in each rat.
In each image, the numbers of the regions of interest in the
nonischemic area and the area at risk were 133 ± 36 and 338 ± 80 (means ± SD, n = 8) in
group A and 134 ± 23 and 343 ± 55 (means ± SD, n = 7) in
group B, respectively. We traced the
regions of interest of the general use-imaging plate image on a
transparent film attached to the display. Using the traced film, we put
the regions of interest on the
3H-sensitive-imaging plate image
at the same site as that of the general use-imaging plate image. The
autoradiographic intensities of
[14C]BMHDA and
[14C]IAP were determined by
averaging the values of all pixels in the region of interest of the
general use-imaging plate image. The autoradiographic intensities of
[3H]DG were determined by
subtracting the value of the region of interest of the general
use-imaging plate image from that of the 3H-sensitive-imaging plate image,
which was corrected using the 14C
calibration lines (30). For further analysis, we converted the
autoradiographic intensities into tissue
3H and
14C contents using the calibration
lines obtained from the 3H- and
14C-labeled graded standards.
In group A, we determined both
regional myocardial [14C]BMHDA
uptake and [3H]DG uptake in each
region of interest on the left ventricular wall. In
group B, we determined both regional
myocardial [3H]DG uptake and
blood flow in each region of interest. Myocardial blood flow was
obtained with myocardial
[14C]IAP activities and the
time-activity curve of the blood
[14C]IAP concentrations (23). We
obtained the percentages of
[14C]BMHDA
uptake, [3H]DG
uptake, and blood flow by normalizing regional values
to the mean value of all regions of interest in the nonischemic area in
each rat. As a measure of heterogeneity, the percentage interregional coefficients of variation (%ICV), calculated as [(SD/mean) × 100] (26), in [14C]BMHDA
uptake, [3H]DG uptake, and blood
flow were determined in the nonischemic area and the area at risk in
each rat. In group A, we determined the nonischemic area and the area at risk subjected to ischemia and reperfusion by positive and negative staining with methylene blue
solution, respectively (29, 30). In group
B, the nonischemic area was determined as the area
showing homogeneous distributions of both
[3H]DG and
[14C]IAP in the interventricular
septum and the left ventricular posterior wall. We confirmed that the
ratio of the area at risk to the total area of the left ventricular
wall in group B was comparable to that
in group A (72 ± 5 vs. 71 ± 9%, means ± SD; n = 7 and 8, respectively).
Data analysis.
The data are presented as means ± SD. The statistical significance
of mean values between groups A and
B was assessed with the two-tailed
unpaired Student's t-test. The
statistical significance in mean values among regions and among the
percentages of [14C]BMHDA
uptake, [3H]DG uptake, and blood
flow was assessed with the two-tailed paired Student's
t-test. The two-factor analysis of
variance with repeated measures on one factor was applied to compare
the increase in %ICV in the area at risk relative to the nonischemic
area among [14C]BMHDA uptake,
[3H]DG uptake, and blood flow. A
value of P < 0.05 was considered significant.
| |
RESULTS |
No significant differences in the plasma concentrations of glucose
(11.4 ± 2.8 vs. 12.9 ± 2.7 mmol/l), insulin (8.0 ± 4.4 vs.
7.8 ± 4.2 ng/ml), or free fatty acids (1.7 ± 0.8 vs. 2.1 ± 0.9 meq/l) were found between groups A
and B. No significant differences in
mean arterial pressure were found between groups
A and B during the
left coronary artery ligation (71 ± 18 vs. 79 ± 13 mmHg) or during the reperfusion (94 ± 29 vs. 100 ± 25 mmHg).
Fatty acid uptake, glucose uptake, and blood flow.
Figures 1 and
2 demonstrate representative
autoradiograms of the heart sections from rats in
groups A and
B, respectively. Mean
[14C]BMHDA uptake, mean
[3H]DG uptake, and mean blood
flow in the area at risk were lower than in the nonischemic area (0.93 ± 0.55 vs. 1.44 ± 0.36 Bq/mg, 82 ± 56 vs. 110 ± 64 Bq/mg, and 61 ± 27 vs. 91 ± 34 ml · 100 g
1 · min1,
respectively) (Fig. 3,
A, C,
and E). The %ICV in
[14C]BMHDA uptake,
[3H]DG uptake, and blood flow
were higher in the area at risk than in the nonischemic area (76 ± 23 vs. 21 ± 7%, 39 ± 10 vs. 21 ± 7%, and 49 ± 19 vs.
14 ± 4%, respectively) (Fig. 3,
B, D,
and F). The increase in %ICV in the
area at risk relative to the nonischemic area was more prominent in
[14C]BMHDA uptake than in
[3H]DG uptake
(P < 0.0005;
n = 8 and 15, respectively) and was
more prominent in blood flow than in
[3H]DG uptake
(P < 0.01;
n = 7 and 15, respectively). The
increase in %ICV in the area at risk relative to the nonischemic area
tended to be more prominent in
[14C]BMHDA uptake than in blood
flow (P = 0.07;
n = 8 and 7, respectively).
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Fig. 1.
Double-tracer autoradiograms of apical- and midventricular-level heart
sections labeled with
-methyl-[1-14C]heptadecanoic
acid ([14C]BMHDA) and
2-deoxy-D-[1-3H]glucose
([3H]DG). In each image in
rats 2 and
5, the left ventricular anterior wall
is at the top and the posterior wall
is at the bottom. Locations of
nonischemic area (Non-isch) and area at risk (Risk) of
midventricular-level heart sections are shown in Fig. 4.
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Fig. 2.
Double-tracer autoradiograms of apical- and midventricular-level heart
sections labeled with
4-[N-methyl-14C]iodoantipyrine
([14C]IAP) and
[3H]DG. In each image in
rats 9 and
11, the left ventricular anterior wall
is at the top and the posterior wall
is at the bottom. Locations of
Non-isch and Risk of midventricular-level heart sections are shown in
Fig. 6.
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Fig. 3.
[14C]BMHDA uptake
(A),
[3H]DG uptake
(C), and blood flow
(E) and their respective
%interregional coefficients of variation (%ICV)
(B,
D, and
F) in Non-isch and Risk. Values are
means ± SD; each line represents data obtained from 1 rat.
* P < 0.05 vs. Non-isch.
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In our preliminary experiments,
[3H]DG and
[14C]BMHDA were injected in
sham-operated rats (n = 2) using the
same procedure as that for rats in group
A. In other sham-operated rats
(n = 2), [3H]DG and
[14C]IAP were injected using the
same procedure as that for rats in group
B. In the left ventricular wall in sham-operated rats, %ICV values in [14C]BMHDA
uptake (19 ± 0%),
[3H]DG uptake (25 ± 10%),
and blood flow (18 ± 2%) were comparable to those in the
nonischemic area in rats of groups A
and B (Mann-Whitney U test). No significant differences in
%ICV in [14C]BMHDA uptake,
[3H]DG uptake, or blood flow
were found among the interventricular septum, anterior wall, lateral
wall, and posterior wall in sham-operated rats (Kruskal-Wallis test).
To depict the heterogeneous distributions of
[14C]BMHDA uptake in
the area at risk, we divided the area at risk into three regions using
the mean and SD values of all regions of interest in the nonischemic
area in each rat: high-BMHDA areas have percent values of [14C]BMHDA uptake of more
than the mean + 2SD; mid-BMHDA areas have values from the mean 
2SD to the mean + 2SD; and low-BMHDA areas have values less than the
mean 2SD. The high-BMHDA area appeared at the
lateral borders and subepicardial layer within the area at risk in
seven of the eight rats (Fig. 4). The
low-BMHDA area occupied the midmyocardial layer except at the lateral
borders within the area at risk. In some rats, the subendocardial and subepicardial layers within the area at risk were also occupied by the
low-BMHDA area. The high-, mid-, and low-BMHDA areas occupied 9 ± 8, 34 ± 18, and 58 ± 24% of the area at risk
(n = 8 for each), respectively. The
existence of high-BMHDA area was statistically significant
(P < 0.005). As shown in Fig.
5, the percentage of [3H]DG uptake in the high-BMHDA
area was comparable to that in the nonischemic area. However, in the
low-BMHDA area, the percentage of
[3H]DG uptake was lower than
that in the nonischemic and high- and mid-BMHDA areas.
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Fig. 4.
Distribution images of
[14C]BMHDA uptake, reconstructed
using quantitative data of midventricular-level heart sections of all
rats in group A. High-, mid-, and
low-BMHDA: 3 regions within Risk with high, mid, and low values of
[14C]BMHDA uptake, respectively;
see text for detailed descriptions. Low-BMHDA area occupied 23, 35, 37, 55, 64, 82, 82, and 83% of Risk in rats
5, 4,
7, 2,
8, 3,
6, and
1, respectively.
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Fig. 5.
Percentages of [14C]BMHDA uptake
and [3H]DG uptake in high-,
mid-, and low-BMHDA areas. Values are means ± SD; each line
represents data obtained from 1 rat.
* P < 0.05 vs.
%[14C]BMHDA uptake;
 P < 0.005 vs. Non-isch;
 P < 0.05 vs. Non-isch
and high- and mid-BMHDA areas.
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To depict the heterogeneous distributions of myocardial blood flow in
the area at risk, we divided the area at risk into three regions using
the mean and SD values of all regions of interest in the nonischemic
area in each rat: high-blood-flow areas have percent values of blood
flow of more than the mean + 2SD; mid-blood-flow areas have values from
the mean 2SD to the mean + 2SD; and low-blood-flow areas have
values less than the mean 2SD. The low-blood-flow area occupied
the subendocardial and midmyocardial layers except at the lateral
borders within the area at risk (Fig. 6).
In some rats, the subepicardial layer within the area at risk was also occupied by the low-blood-flow area. The high-, mid-, and
low-blood-flow areas occupied 7 ± 6, 40 ± 23, and 53 ± 29%
of the area at risk (n = 7 for each),
respectively. The existence of high-blood-flow area was statistically
significant (P < 0.01). As shown in
Fig. 7, the percentage of
[3H]DG uptake in the
high-blood-flow area was comparable to that in the nonischemic area.
However, in the low-blood-flow area, the percentage of
[3H]DG uptake was lower than
that in the nonischemic and high- and mid-blood-flow areas.
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Fig. 6.
Distribution images of myocardial blood flow, reconstructed using
quantitative data of midventricular-level heart sections of all rats in
group B. High-, mid-, and low-blood
flow: 3 regions within Risk with high-, mid-, and low-blood-flow
values, respectively; see text for detailed descriptions.
Low-blood-flow area occupied 10, 33, 35, 52, 70, 80, and 90% of Risk
in rats 9,
10,
15,
11,
13,
14, and
12, respectively.
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Fig. 7.
Percentages of blood flow and
[3H]DG uptake in high-, mid-,
and low-blood-flow areas. Values are means ± SD; each line
represents data obtained from 1 rat.
* P < 0.05 vs. %blood flow;
P < 0.01 vs. Non-isch
and high- and mid-blood-flow areas.
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DISCUSSION |
In this study, we clearly demonstrated the heterogeneous distributions
of myocardial fatty acid uptake, glucose uptake, and blood flow within
the area at risk during reperfusion. Regions showing increased fatty
acid uptake (166% of that in the nonischemic area) appeared at the
lateral borders and subepicardial layer within the area at risk, and
glucose uptake was 103% in these regions. These regions occupied 9%
of the area at risk. Regions with decreased fatty acid uptake (28% of
that in the nonischemic area) occupied the midmyocardial layer except
at the lateral borders within the area at risk, and glucose uptake was
62% in these regions. Regions showing decreased blood flow (44%)
appeared at the subendocardial and midmyocardial layers except at the
lateral borders within the area at risk. The increase in heterogeneity
in the area at risk relative to the nonischemic area was more prominent
in fatty acid uptake and in blood flow than in glucose uptake.
Hale et al. (8) showed that, in rat hearts subjected to 20-60 min
of coronary artery occlusion followed by 24 h of reperfusion, myocardial necrosis delineated by tetrazolium staining appeared first
in the midmyocardium and developed toward the subepicardium, subendocardium, and the lateral borders within the area at risk as the
duration of coronary artery occlusion increased. In rats with 30 min of
coronary artery occlusion and 24 h of reperfusion, the area of necrosis
as a percentage of the area at risk was 36% (8). We did not assess the
infarct zone by using tetrazolium staining or perform histological
studies in the present study, because 30 min of coronary artery
ligation and 30 min of reperfusion may not be sufficient for accurate
detection of necrosis. However, viable myocardium with various degrees
of injury and necrotic tissue is assumed to have existed in the area at
risk in this study. Heterogeneous myocardial injury may have lead to
heterogeneous blood flow and substrate metabolism.
Miller et al. (16) measured the myocardial accumulation of another
branched-chain fatty acid analog,
125I-labeled
15-(p-iodophenyl)--methylpentadecanoic
acid ([125I]BMIPP), in a canine
model subjected to 15-60 min of coronary artery occlusion and 3 h
of reperfusion. They showed that
[125I]BMIPP uptake did not
differ from control myocardium (108% of control) in segments within
the area at risk that were stained with tetrazolium. In segments within
the area at risk that were not stained with tetrazolium,
[125I]BMIPP uptake was decreased
to 79% of that in control segments. The present study demonstrated
that regions showing high (166% of that in the nonischemic area),
moderate (92%), and low (28%) levels of
[14C]BMHDA uptake existed within
the area at risk. Possibly because the spatial resolution in the
present study (the area of each region of interest was 0.0925 mm2) is higher than that in the
report by Miller et al. (16) (1 g for each myocardial segment), we
could distinguish between regions with increased and decreased fatty
acid uptake.
Saddik et al. (22) reported that fatty acid oxidation was increased in
isolated rat hearts subjected to 30 min of global ischemia and
reperfusion. They also showed (22) that triglyceride synthesis was
significantly increased and that its lipolysis did not differ compared
with control hearts, suggesting that triglyceride pools in myocardial
cells are expanded during reperfusion. In isolated rat hearts subjected
to 60 min of global ischemia and reperfusion, Görge et
al. (7) showed that fatty acid oxidation was decreased. Fatty acid
metabolism during reperfusion may depend on the degree of myocardial
injury. Fatty acid oxidation and/or its incorporation into
lipid pools may have been increased in high-BMHDA areas during
reperfusion in the present study. However, in low-BMHDA areas, fatty
acid oxidation and/or its incorporation into lipid pools may
have been decreased during reperfusion.
In this study, the area of low BMHDA, expressed as a percentage of the
area at risk, varied from 23 to 83% (Fig. 4), probably because of
individual differences in tolerance to myocardial ischemia. In
rats with smaller low-BMHDA areas, low BMHDA was localized in the
midmyocardial layer except at the lateral borders within the area at
risk. In rats with larger low-BMHDA areas, low BMHDA occupied not only
the midmyocardial layer but also the subendocardial layer,
subepicardial layer, and lateral borders within the area at risk. It is
assumed that a low-BMHDA area appears first in the midmyocardial layer
and then expands toward the subendocardial layer, subepicardial layer,
and lateral borders within the risk area as the duration of coronary
artery occlusion increases. This is consistent with the process by
which myocardial necrosis expands, as reported by Hale et al. (8).
Decreased [14C]BMHDA uptake may
reflect the severity of myocardial injury during reperfusion after
transient regional ischemia.
Recently, another branched-chain fatty acid analog,
123I-labeled BMIPP, was introduced
to assess myocardial fatty acid metabolism by single-photon emission
computed tomography (12, 13). Franken et al. (6) performed
scintigraphy with [123I]BMIPP
and echocardiographic studies in 18 patients 4-10 days after
myocardial infarction. Fourteen of the eighteen patients received
thrombolytic therapy and/or coronary angioplasty within 6 h
after the onset of chest pain. Functional recovery assessed by
echocardiography 6 mo after infarction was found in 75, 74, and 27% of
the segments with [123I]BMIPP
uptake of 50-65%, 35-50%, and <35% of the maximal
activity, respectively. These data also suggest that myocardial uptake
of a branched-chain fatty acid analog is useful to estimate
myocardial viability during reperfusion after acute myocardial
infarction.
Although we did not perform double labeling with a fatty acid tracer
and a blood flow tracer in this study, high-, mid-, and low-BMHDA areas
might overlap high-, mid-, and low-blood-flow areas, respectively. The
reasons are as follows. First, the areas of high, mid, and low BMHDA
expressed as percentages of the area at risk were comparable to those
of high, mid, and low blood flow (9 ± 8 vs. 7 ± 6%, 34 ± 18 vs. 40 ± 23%, and 58 ± 24 vs. 53 ± 29%, respectively).
Second, the percentages of
[3H]DG uptake in high-, mid-,
and low-BMHDA areas were comparable to those in high-, mid-, and
low-blood-flow areas (103 ± 24 vs. 98 ± 24%, 87 ± 8 vs. 92 ± 14%, and 62 ± 18 vs. 63 ± 17%, respectively). Further
studies are needed to clarify the relationship between fatty acid
uptake and myocardial blood flow during reperfusion.
Possible limitations.
BMHDA is a branched-chain fatty acid analog that is transported into
myocardial cells by the same long-chain fatty acid carrier protein
mechanism that transports natural fatty acids, but it cannot be
-oxidized (4, 5). BMHDA is stored in lipid pools mainly
as triglycerides, or it is cleared slowly as a result of limited 
-
and 
-oxidation and back diffusion of nonmetabolized BMHDA (1, 5).
Abendschein et al. (1) obtained myocardial washout curves of
-methyl-[1-11C]- heptadecanoic
acid ([11C]BMHDA) in dogs
subjected to 50 min of left circumflex coronary artery ligation. They
reported that the half-time value of the [11C]BMHDA washout curve was
prolonged in the ischemic myocardium compared with that in the control
myocardium (78 vs. 41 min). Nishimura et al. (19) reported that, in
dogs undergoing 3 h of left anterior coronary artery ligation followed
by 1 h of reperfusion, another branched-chain fatty acid analog,
[123I]BMIPP, was cleared more
slowly in the reperfused myocardium than in the control myocardium. In
the present study, the relative [14C]BMHDA uptake in the area at
risk compared with that in the nonischemic area might be overestimated,
because clearance of [14C]BMHDA
activity might be prolonged in the area at risk compared with that in
the nonischemic area.
The present study showed that spatial distributions of fatty acid
uptake, glucose uptake, and myocardial blood flow are heterogeneous early after reperfusion following 30 min of left coronary artery ligation in rat hearts. The heterogeneous distributions of substrate uptake during reperfusion after regional ischemia may explain the controversial results of the previous studies using coronary venous
blood sampling (14, 17, 18) and positron emission tomography (10).
| |
FOOTNOTES |
Address for reprint requests: K. Shirato, First Dept. of Internal
Medicine, Tohoku Univ. School of Medicine, 1-1 Seiryo-machi,
Aoba-ku, Sendai 980-8574 Japan.
Received 10 September 1996; accepted in final form 25 November
1997.
| |
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