(Circulation. 2000;102:438.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Myocardial Blood Flow and Myocardial Uptake of 201Tl and 99mTc-Sestamibi During Coronary Vasodilation Induced by CGS-21680, a Selective Adenosine A2A Receptor Agonist
From the Section of Cardiology, Baylor College of Medicine/Methodist Hospital, Houston, Tex. Dr He’s current address is Fu Wai Hospital, Dept of Nuclear Medicine, Beijing, China.
Correspondence to Mario S. Verani, MD, Professor of Medicine, Baylor College of Medicine, 6550 Fannin, SM 677, Houston, TX 77030. E-mail mverani{at}bcm.tmc.edu
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Abstract |
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Background—We investigated the hemodynamic and coronary vasodilatory effects of CGS-21680, a potent selective adenosine A2A agonist, as well as its potential use as a new stress modality in combination with perfusion scintigraphy.
Methods and Results—A stenosis of the left anterior descending coronary artery (LAD) was produced in dogs to reduce the reactive hyperemic response to <20%. Adenosine and CGS-21680 were then separately infused to maximize left circumflex coronary artery (LCx) flow velocity. 201Tl (0.5 mCi) and 99mTc-sestamibi (5 mCi) were injected at the maximal dose of CGS-21680. Heart rate decreased with adenosine but increased during CGS-21680 infusion (P<0.005). The decrease in systolic blood pressure was more prominent with adenosine than with CGS-21680 (P<0.005). In the control LCx zone, maximal myocardial blood flow (MBF) (measured by radioactive microspheres) increased 3.1-fold during adenosine infusion (P<0.005) and 3.8-fold during CGS-21680 infusion (P<0.005). In the stenotic LAD zone, MBF did not change significantly. During adenosine and CGS-21680 infusion, stenosis/control zone MBF ratios were comparable (0.32±0.11 versus 0.27±0.10, P=NS), and transmural 201Tl and 99mTc-sestamibi count-activity ratios (0.48±0.11 and 0.51±0.09, respectively) were also comparable (P=NS). Myocardial scintigraphy uncovered perfusion defects in all dogs.
Conclusions—CGS-21680 elicits coronary vasodilation comparable to that of adenosine and produces profound heterogeneity of MBF and of 201Tl and 99mTc-sestamibi myocardial uptake, rendering it a promising agent for pharmacological myocardial perfusion imaging.
Key Words: adenosine • receptors • CGS-21680 • radioisotopes • imaging • coronary disease
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Introduction |
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Stress radionuclide myocardial perfusion imaging is the most commonly used noninvasive technique for the detection of coronary artery disease. Pharmacological stress with a coronary vasodilator1 2 or an inotropic3 drug is often used in patients unable to undergo an exercise stress test.4 5 6 7 8
In animal models, 201Tl- as well as 99mTc-labeled agents underestimate the regional flow disparity between the stenotic and the normal perfusion beds during pharmacological stresses, although the underestimation is greater with the 99mTc-labeled agents than with 201Tl.9 10 11 12 Nevertheless, clinical studies have shown that pharmacological stress myocardial perfusion imaging with either 99mTc-labeled sestamibi13 14 or tetrofosmin15 16 has a good sensitivity for the diagnosis of coronary artery disease.
Coronary vasodilation induced by dipyridamole or adenosine is mediated by the stimulation of adenosine A2A receptors.17 The concomitant nonspecific stimulation of the adenosine A1, A2B, or A3 receptors is thought to be responsible for most side effects produced by these drugs. Thus, selective adenosine A2A receptor agonists may be better tolerated than dipyridamole or adenosine. Several highly selective adenosine A2A receptor agonists have been synthesized.18 19 20 21 22 Glover et al23 recently demonstrated in dogs the potential utility of WRC-0470, another adenosine A2A agonist, for pharmacological stress myocardial perfusion imaging.
The goals of the present study were to compare (1) the myocardial blood flow changes during maximal coronary vasodilation produced by adenosine and by 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido adenosine (CGS-21680) (the latter is a highly selective adenosine A2A receptor agonist with a 170-fold selectivity for the A2 versus the A1 receptor18 19 ) and (2) the myocardial uptake of 99mTc-sestamibi and 201Tl during maximal coronary vasodilation with CGS-21680. The hypotheses tested in this study were that (1) CGS-21680 is a coronary vasodilator at least as potent as adenosine and (2) differences in myocardial uptake of both 201Tl and 99mTc-sestamibi between the stenotic and normal perfusion beds, sufficient to allow scintigraphic detection of a coronary stenosis, can be achieved during coronary vasodilation with CGS-21680.
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Methods |
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Baylor College of Medicine is an American Association for Accreditation of Laboratory Animal Care–approved facility, and the research protocol was approved by our Institutional Animal Care and Use Committee in accordance with the NIH Guide for the Care and Use of Laboratory Animals.
Animal Preparation
Twelve adult mongrel dogs were anesthetized with 25 to
35 mg/kg IV sodium pentobarbital, intubated, and ventilated on a
respirator with positive end-expiratory pressure of 4
cm H2O. Additional small amounts of sodium
pentobarbital were used as needed to maintain anesthesia.
An ECG lead was continuously monitored. The right femoral vein was
cannulated for the administration of fluids, medications,
99mTc-sestamibi, and 201Tl.
Both femoral arteries were also cannulated for blood withdrawal and for
continuous monitoring of arterial blood pressure.
A thoracotomy was performed at the level of the fifth left intercostal
space, and the heart was suspended in a pericardial cradle. A
polyethylene catheter was inserted into the left atrial appendage for
continuous pressure monitoring and for the injection of radiolabeled
microspheres. The left anterior descending (LAD) and the
proximal circumflex (LCx) coronary arteries were dissected free
of the epicardium, and ultrasonic Doppler flow probes were placed
around these vessels. A screw occluder for producing a coronary
stenosis and a snare occluder for performing temporary total
occlusions were placed around the LAD just proximal to the Doppler
probe (Figure 1
).
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Study Protocol
The study protocol is shown schematically in Figure 2. After animal instrumentation and a
60-minute rest period had been completed, a first set of radioactive
microspheres (50 µCi in 1.0- to 1.5-mL total volume) was
administered into the left atrium to measure baseline coronary
blood flow. Simultaneously, a 2-minute reference blood
sample was withdrawn from the femoral artery. Microspheres
(15 µm in diameter) were labeled with either
85Sr, 95Nb,
51Cr, or 46Sc and randomly
selected to minimize bias. To measure the normal reactive
hyperemic response, the LAD was briefly occluded for 10 seconds
with the snare occluder while the Doppler flow velocity signal
showing hyperemia was recorded on a strip-chart
recorder. The peak-to-resting ratio (P/R) was calculated as the
ratio of the maximum velocity during reactive hyperemia after
the release of the snare to the resting velocity before the 10-second
occlusion. The LAD occluder was then adjusted to produce a critical
stenosis, defined as the point at which the baseline flow
velocity was unchanged or reduced by <20% and the reactive
hyperemic response to a 10-second ligation was reduced to
<20% (P/R <1.20). After that, no further adjustments in the occluder
were necessary. An intravenous infusion of
adenosine was begun at a rate of 150 µg ·
kg-1 ·
min-1 and titrated upward
(to a maximum of 1200 µg ·
kg-1 ·
min-1) to produce maximal
LCx blood flow velocity. When the maximal flow was achieved, a second
set of microspheres was injected to measure myocardial blood
flow. The intravenous infusion of adenosine was
stopped 2 minutes after the injection of microspheres, followed
by a 60-minute resting interval.
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After the LCx and LAD flows had returned to the baseline level, a third
set of radioactive microspheres was used for flow measurement.
Infusion of CGS-21680 hydrochloride (Research Biochemicals
International) (Figure 3) was begun at a
dose of 0.5 µg ·
kg-1 ·
min-1 and increased until
maximal LCx flow velocity was achieved. The maximal required dose of
CGS-21680 was 4 µg · kg-1. Once the maximal
Doppler coronary blood flow was reached, 0.5 mCi of
201Tl, 5 mCi of
99mTc-sestamibi, and a fourth set of radioactive
microspheres were injected simultaneously. Ten
minutes later, planar scintigraphy was performed. The dogs
were then euthanized, and the hearts were removed and carefully sliced
into 5 rings of approximately uniform 1-cm thickness from apex to base.
The slices were trimmed of excess fat and adventitia, placed on a thin
piece of cardboard, covered with cellophane wrap, and then imaged on
the gamma camera.
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In Vivo and Ex Vivo Myocardial Imaging
In vivo planar scintigraphy was performed using the
peak photon energy of 99mTc (140 keV) and a 20%
window in the anterior, 45° left anterior oblique, and left lateral
views. Acquisitions were for 5 minutes per view with a high-resolution,
low-energy collimator. The slices were imaged directly on the inverted
detector head with the same collimator and acquisition of 500 000
counts on the 99mTc photopeak with a 20% window.
The planar images were interpreted qualitatively by 2 expert nuclear
cardiologists (Z.X.H., M.S.V.). Only a definite reduction in
tracer uptake involving 
10% of the image perimeter was considered
abnormal.
Quantification of Myocardial Blood Flow and 201Tl and
99mTc-Sestamibi Activities
Each of the 5 myocardial slices were equally divided into 8
transmural sections, which were then further subdivided into
epicardial, midwall, and endocardial thirds (except for the apical
slice), resulting in a total of 104 samples for each dog. These samples
were then counted in a gamma-well scintillation counter within 24 hours
for 99mTc and 48 to 72 hours later for
201Tl. The samples were re-counted for
microsphere flows 3 weeks later when the
201Tl and 99mTc had already
totally decayed. The tissue radioactivity counts (cpm/g) were corrected
for background, decay, and isotope spillover. The
microsphere content in the 2-minute reference blood collection
was used to calculate absolute flow (mL ·
min-1 ·
g-1) with a dedicated
computer system.24
Transmural myocardial blood flow and 201Tl and 99mTc-sestamibi activities on each myocardial section were calculated as the weighted average of the 3 myocardial segments. The 5 transmural sections with the highest flows at the time of 201Tl and 99mTc-sestamibi injection were defined as the normal region and the 5 transmural sections with the lowest flows as the stenotic region. Stenotic-to-normal region ratios for myocardial blood flow and 201Tl and 99mTc-sestamibi activities were calculated by dividing the average flow and 201Tl or 99mTc-sestamibi activities in the stenotic region by the average values in the normal regions. Coronary flow reserve was calculated by dividing the myocardial flow during pharmacological vasodilation by the resting myocardial blood flow.10 11 12
Statistical Analysis
Data are presented as mean±SD. Changes from baseline to
adenosine or CGS-21680 infusion were tested by Wilcoxon
signed-rank test, and differences between 2 groups were compared by the
Mann-Whitney test. Comparison between categorical variables used a
2 test. Regression analysis was used
to compare the microsphere proximal flow ratio
(stenosis/normal region) to the 201Tl and
99mTc-sestamibi uptake ratios (determined by well
counting). ANOVA was used to assess differences of flow among
myocardial layers, and significant differences were further evaluated
with a Bonferroni-adjusted t test.
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Results |
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Hemodynamic Data
The hemodynamic data are summarized in Table 1
. Heart rate decreased
insignificantly during adenosine infusion; in contrast, it
increased significantly during CGS-21680 infusion. Both
systolic and diastolic arterial blood
pressure decreased significantly during adenosine and CGS-21680
infusion. However, the decrease produced by CGS-21680 was significantly
less than that caused by adenosine.
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Doppler Flow Data
During control, before coronary stenosis was
produced, Doppler flows were 16.2±5.2 and 12.6±3.7 mL/min in the
LAD and LCx, respectively. The peak/resting flow ratio after a
10-second total occlusion before stenosis was 3.32±0.76 for
the LAD and 3.87±0.71 for the LCx. After critical stenosis,
LAD flow was reduced by an average of 15% to 13.7±4.8 mL/min, and the
peak/resting flow ratio after a 10-second occlusion was reduced to
1.18±0.15. Thus, the peak hyperemic flow in the LAD with a
critical stenosis was approximately the same as the resting
flow in the LAD before stenosis (13.7 mL/minx1.18=16.2
mL/min).
The peak/resting flow ratio was 1.26±0.82 in the LAD and 2.76±0.90 in the LCx during adenosine administration and 1.21±0.53 in the LAD and 3.12±0.88 in the LCx during CGS-21680 infusion. After CGS, it took 30 minutes for the flow in the control LCx to return halfway to the predrug baseline level.
Regional Myocardial Blood Flow
Regional myocardial blood flow at baseline and during
adenosine and CGS-21680 infusion is summarized in Table 2. Baseline transmural myocardial blood
flows in the LAD and the LCx vascular territories were similar during
control before adenosine or CGS-21680 infusion
(P=NS).
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In the LCx zone, epicardial, midwall, and endocardial coronary
blood flow increased significantly during adenosine infusion
(P<0.005). Transmural myocardial blood flow also increased
during adenosine infusion (P<0.005). In contrast,
in the stenotic LAD zone, only epicardial myocardial blood flow
increased slightly during adenosine infusion
(P<0.05), whereas transmural flow did not increase
significantly (Table 2
). The maximal epicardial blood flow
reserve elicited by adenosine was significantly greater than
that of the endocardial flow of both the LCx and the LAD vascular
territories (Table 3).
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Likewise, in the LCx zone, epicardial, midwall, and endocardial
coronary blood flow increased significantly during CGS-21680
infusion (P<0.005). Transmural LCx artery myocardial blood
flow increased during CGS-21680 infusion (P<0.005). In the
stenotic LAD zone, only the epicardial blood flow increased
slightly during adenosine infusion (P<0.05),
whereas transmural myocardial blood flow was unchanged. The increase in
epicardial blood flow elicited by CGS-21680 was significantly greater
than that in the endocardium of both the LCx and the LAD zones (Table 3).
The epicardial blood flow reserve elicited by CGS-21680 in the LCx zone
was significantly greater than that elicited by adenosine
(P<0.05). CGS-21680 also showed a tendency to elicit a
greater transmural blood flow reserve than adenosine in the LCx
zone (Table 3). Coronary blood flow reserve elicited in
the LAD zone was similar with adenosine and CGS-21680 (Table 3).
Endocardial-to-Epicardial Myocardial Blood Flow Ratio
Both adenosine and CGS-21680 produced a fall in
endocardial-to-epicardial myocardial blood flow ratios (Table 2). There was a significant, albeit modest, difference in
endocardial-to-epicardial flow ratios between the LCx and LAD zones at
baseline; however, endocardial-to-epicardial flow ratios produced by
adenosine or CGS-21680 infusion were similar in the LCx and the
LAD zones (Table 2).
Stenotic-to-Normal Myocardial Blood Flow Ratios
The LAD/LCx myocardial blood flow ratios at baseline and during
adenosine and CGS-21680 infusion are summarized in Table 4. The stenotic-to-normal blood
flow ratios in the epicardial, midwall, and endocardial segments fell
significantly during both adenosine and CGS-21680
administration. Transmural flow ratios were 0.32±0.11 during
adenosine and 0.27±0.10 during CGS-21680 infusion. The
stenotic-to-control flow ratios across the left
ventricular wall during CGS-21680 are illustrated in Figure 4.
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Regional Myocardial 201Tl and
99mTc-Sestamibi Uptakes
The stenotic-to-normal 201Tl and
99mTc count activity ratios during CGS-21680 were
similar and are summarized in Figure 5.
Transmural stenotic/normal 201Tl and
99mTc-sestamibi ratios during CGS-21680
administration were also similar. Both 201Tl and
99mTc-sestamibi activities underestimated the
true reduction in flow ratios (Figure 6).
There was, however, a strong correlation between the
microsphere flow and the 201Tl uptake
(linear) and 99mTc-sestamibi uptake (exponential)
during CGS-21680 administration. The relationship between flow and
sestamibi uptake plateaued at high flows (Figure 7). There was also a significant
correlation between the stenosis/control microsphere
flow ratio and the stenosis/control uptake ratio (measured by
well counting) for 201Tl (r=0.81,
P=0.001) and for 99mTc-sestamibi
(r=0.74, P=0.006).
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In all 12 dogs, CGS-21680 produced myocardial perfusion defects, which
were readily detected in the in vivo and ex vivo scintigrams (Figure 8).
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Discussion |
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Our study demonstrates conclusively that (1) CGS-21680 markedly increases the blood flow by nearly 4-fold in the myocardium supplied by a normal coronary artery, but not in the regions supplied by a significantly stenotic artery; (2) CGS-21680 and adenosine produce a similar increase in transmural myocardial blood flow, but the former causes significantly less systemic hypotension than the latter; (3) the increase in myocardial blood flow elicited by both adenosine and CGS-21680 is greater in the epicardium than in the endocardium, particularly with CGS-21680, but the LAD/LCx myocardial blood flow ratios are similar in the epicardial, midwall, or endocardial segments; and (4) in the presence of a significant coronary stenosis, CGS-21680 produces heterogeneous myocardial uptake of both 201Tl and 99mTc-sestamibi, which can be imaged with standard gamma cameras.
The robustness of our microsphere data was confirmed by similar directional changes in coronary blood flow assessed by the Doppler flow probe. Both techniques showed a very substantial increase in coronary flow in the control artery, with little increase in the stenotic artery during coronary vasodilation. The increase in flow was more prominent in the epicardium than in the endocardium with both adenosine and CGS-21680, although only the latter achieved statistical significance. This preferential epicardial vasodilation has been previously documented with "maximal" adenosine doses (up to 1000 µg · kg-1 · min-1), similar to the dosages used in our experiments.25 The greater increase in the epicardial layer flow with CGS-21680 than with adenosine is probably a reflection of the slightly greater potency of the former compound in the doses used in our experiments. Alternatively, this might be attributed to the smaller reduction in blood pressure with CGS-21680, leading to higher coronary perfusion pressures.
Adenosine Receptors
The coronary vasodilatory effects of
dipyridamole and adenosine are mediated by
stimulation of the A2A receptors,17
whereas their side effects are secondary to the undesirable stimulation
of adenosine A1,
A2B, and A3 receptors.
Recent studies have demonstrated that in rats, CGS-21680 is a selective coronary vasodilator.26 27 28 29 30 Makujina et al,31 in ex vivo experiments, found the coronary arteries to be more responsive than the internal mammary artery or the saphenous vein, both of which displayed only marginal relaxation with CGS-21680. The clinical significance of the latter observation is uncertain, because no studies have been performed in vivo. CGS-21680 also has significant effects on heart rate,19 30 probably as a result of reflex activation of the sympathetic nervous system rather than of any direct effect on the sinus node.19 28 During adenosine administration at maximal doses, the expected reflex tachycardia is blunted because of the direct inhibitory effect of the A1 receptors on sinus node automaticity.
Clinical Implications
Side effects occur in 
50% of patients receiving
dipyridamole32 33 34 35 and in 70% to 80%
of patients receiving adenosine.36 37 38 There are
several contraindications to the use of dipyridamole or
adenosine, including bronchospasm, hypotension, acute
myocardial infarction within the first 24 hours, and second-degree or
higher atrioventricular block. Although both
dipyridamole and adenosine have a good safety
record, there have been instances of death and other serious side
effects with these agents.33 34 35 36 37 38
Glover et al23 recently demonstrated that WRC-0470, another selective adenosine A2A agonist, increased myocardial blood flow without lowering mean arterial blood pressure. Together, their and our results demonstrate that selective stimulation of adenosine A2A receptors is a potentially effective means to perform pharmacological stress myocardial perfusion imaging.
Study Limitations
There are several limitations in our study. First,
anesthesia may have influenced the
hemodynamic and coronary vasodilatory effects
of adenosine and CGS-21680. Second, because of the shorter
half-life of adenosine, we deliberately always infused
adenosine before CGS-21680. Randomizing the order of drug
administration would have been preferable but would have extended and
possibly compromised the protocol. Third, in vivo and ex vivo images
were not quantified, and therefore, the principal findings of this
study are derived from tissue counting. Finally, the distribution and
richness of adenosine receptors in dogs differ from those in
other species, including mammalian species. Whether CGS-21680 had
significant effects on other adenosine receptors in the doses
we used cannot be inferred from the present study. This was not,
however, the purpose of this study.
In conclusion, in the presence of a significant coronary artery stenosis, CGS-21680 produces consistent myocardial blood flow heterogeneity and heterogeneous myocardial uptake of 201Tl and 99mTc-sestamibi, which can be imaged with standard gamma cameras. The present results lend support to a trial of this agent in human beings after appropriate toxicity studies are done.
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Acknowledgments |
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The authors wish to thank Peggy Jackson, Senior Research Assistant, for her skillful technical assistance and oversight in these experiments and Jo Ann Rabb for expert secretarial assistance.
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Footnotes |
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Guest Editor for this article was George A. Beller, MD, University of Virginia Health Science Center, Charlottesville.
Received September 7, 1999; revision received February 7, 2000; accepted February 29, 2000.
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