(Circulation. 1999;100:1653-1659.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Myocardial Uptake of 99mTc-N-NOET and 201Tl During Dobutamine Infusion
Comparison With Adenosine Stress
From the Experimental Cardiology Laboratory, Cardiovascular Division, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville. Dr Calnon is now at MidOhio Cardiology Consultants, Columbus, Ohio.
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Abstract |
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Background—The myocardial uptake of 99mTc-sestamibi is attenuated by dobutamine stress, resulting in underestimation of ischemia. N-Ethyl-N-ethoxy-dithiocarbamato-N-99mTc (99mTc-N-NOET) is a new 99mTc-labeled perfusion agent that is highly extracted by the myocardium by a mechanism different from that defined for 99mTc-sestamibi. We therefore hypothesized that 99mTc-N-NOET uptake would not be attenuated by dobutamine and that 99mTc-N-NOET uptake would be comparable to 201Tl uptake during dobutamine stress.
Methods and Results—In 28 open-chest dogs, after placement of a stenosis in the left anterior descending coronary artery that reduced flow reserve by >50%, adenosine (300 µg · kg-1 · min-1; n=15) or dobutamine (2.5 to 30 µg · kg-1 · min-1; n=13) was infused. During adenosine stress, the stenotic-to-normal activity ratio for 99mTc-N-NOET was 0.55±0.05. The stenotic-to-normal flow ratio was 0.33±0.04 at the time of 99mTc-N-NOET injection. During dobutamine stress, the stenotic-to-normal 99mTc-N-NOET activity ratio was 0.63±0.04, comparable to the 201Tl activity ratio of 0.59±0.04. The stenotic-to-normal flow ratio was 0.47±0.04 at the time of 99mTc-N-NOET and 201Tl injection. The relationship between 99mTc-N-NOET uptake and blood flow was comparable for adenosine and dobutamine stress, with no evidence of attenuation of 99mTc-N-NOET extraction by dobutamine.
Conclusions—In the presence of coronary stenoses that reduced regional flow reserve, the myocardial uptake of 99mTc-N-NOET and 201Tl are closely proportional to blood flow during both adenosine and dobutamine stress, suggesting that the adverse effect of dobutamine on 99mTc-sestamibi uptake is a tracer-specific phenomenon rather than a generalized effect. The clinical implication of this finding is that 99mTc-N-NOET might be preferable to 99mTc-sestamibi when used with dobutamine stress for detection of coronary stenoses.
Key Words: imaging • radioisotopes • inotropic agents • adenosine
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Introduction |
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For detection of coronary artery disease, the success of pharmacological stress myocardial perfusion imaging relies on 2 fundamental principles: (1) the pharmacological stressor must produce a blood flow disparity between myocardial regions supplied by normal and stenotic arteries, and (2) the radionuclide tracer must be distributed in the myocardium in proportion to blood flow. Therefore, selection of an optimal perfusion imaging protocol requires a thorough understanding of the unique properties of the available pharmacological stressors and radionuclide tracers and their potential for interactions with one another.
Until recently, it was believed that the myocardial uptake of a perfusion tracer was determined entirely by the intrinsic properties of the tracer and the myocardial blood flow distribution present at the time of tracer injection. However, we1 and others2 have shown that the myocardial uptake of 99mTc methoxyisobutyl isonitrile (99mTc-sestamibi) is "stressor dependent," with less favorable myocardial sestamibi uptake during dobutamine stress than during adenosine stress (uptake plateaus at flows of 1.0 mL · min-1 · g-1 versus 2.0 to 2.5 mL · min-1 · g-1, respectively). This observation has fueled speculation that other tracers might be preferable to 99mTc-sestamibi for dobutamine stress myocardial perfusion imaging.
Among the available agents, 201Tl would be a rational choice as a first-line tracer for dobutamine stress perfusion imaging. However, 201Tl has well-known limitations as a perfusion imaging agent, including a long physical half-life (which limits the injectable dose) and a low photon energy, which results in less optimal image quality compared with that achieved with technetium-labeled tracers. N-Ethyl-N-ethoxy-dithiocarbamato-N-99mTc (99mTc-N-NOET) is a recently developed, technetium-labeled neutral lipophilic myocardial perfusion imaging agent3 that has favorable myocardial uptake properties during dipyridamole-induced hyperemia4 and, like 201Tl, redistributes in the myocardium over time.4 5 6 7 8 9 Therefore, 99mTc-N-NOET would appear to be well suited for pharmacological stress perfusion imaging, because 99mTc-N-NOET combines the favorable myocardial kinetic properties of 201Tl with the favorable radiophysical properties of Tc-labeled tracers.
However, we hypothesized that the myocardial uptake of 201Tl and 99mTc-N-NOET might also be attenuated by dobutamine stress, reflecting a "generalized" (rather than a "tracer-specific") effect of dobutamine on tracer uptake. Therefore, the objectives of the present study were (1) to define the initial myocardial uptake of 99mTc-N-NOET and 201Tl during dobutamine stress in the presence of coronary artery stenoses and (2) by comparison to uptake during adenosine stress, to determine whether the dobutamine-induced attenuation of myocardial 99mTc-sestamibi uptake represents a tracer-specific phenomenon or a generalized effect.
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Methods |
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Surgical Preparation
Twenty-eight fasted adult mongrel dogs (mean weight, 27.4 kg) were anesthetized with sodium pentobarbital (30 mg/kg IV), tracheally intubated, and mechanically ventilated with room air (Harvard Apparatus) with a positive end-expiratory pressure of 4 cm H2O. Arterial blood gases were monitored (model 158, Ciba-Corning) and maintained in the normal physiological range. The left femoral vein was cannulated with an 8F catheter for the administration of fluids, 99mTc-N-NOET, 201Tl, and sodium pentobarbital. Both femoral arteries were cannulated with 8F catheters and used for microsphere reference blood withdrawal. An additional 7F catheter was placed in the right femoral artery for arterial pressure monitoring. A 7F Millar high-fidelity pressure catheter was inserted into the left ventricle through an 8F sheath in the left carotid artery. The left external jugular vein was cannulated with an 8F catheter for administration of adenosine or dobutamine.
A left lateral thoracotomy was performed at the level of the fifth intercostal space, and the heart was suspended in a pericardial cradle. A flare-tipped catheter was inserted into the left atrium for pressure measurement and for the injection of radiolabeled microspheres. A snare ligature was placed loosely on a proximal portion of the left anterior descending coronary artery (LAD). Ultrasonic flow probes (T201, Transonic Systems, Inc) were placed on a more distal portion of the LAD and on the left circumflex coronary artery (LCx). Throughout each protocol, the ECG, arterial and left atrial pressures, LAD and LCx flows, and left ventricular pressure and its first time derivative (dP/dt) were monitored continuously and recorded on an 8-channel strip-chart recorder (model 7458A, Hewlett-Packard).
All experiments were performed with the approval of the University of Virginia Animal Research Committee and were in compliance with the position of the American Heart Association on the use of research animals.
Experimental Protocols
Group 1: Myocardial Uptake of NOET During Adenosine Stress
In 15 dogs, after instrumentation, microspheres were
injected to determine baseline myocardial blood flow (Figure 1
). The LAD was then occluded for 10
seconds, and the peak flow that followed was recorded as the normal
reactive hyperemic response. The snare ligature was then
adjusted to create an LAD stenosis that reduced the normal
reactive hyperemic response by 
50% without reducing resting
flow. Microspheres were injected 15 minutes later to determine
myocardial flow in the presence of the stenosis.
Adenosine (300 µg · kg-1
· min-1 IV) was then infused for 
5 minutes,
with continuous monitoring of blood flow in the normal LCx to indicate
the point of maximal adenosine-induced hyperemia.
99mTc-N-NOET (8 mCi, 296 MBq) and
microspheres were injected simultaneously during
maximal adenosine-induced hyperemia, and the
adenosine infusion was terminated 1 minute later. The animals
were euthanized with an overdose of sodium pentobarbital and potassium
chloride 5 minutes after 99mTc-N-NOET injection,
and regional myocardial blood flow and
99mTc-N-NOET activity were measured by gamma-well
counting and ex vivo gamma-camera imaging.
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Group 2: Myocardial Uptake of 99mTc-N-NOET and
201Tl During Dobutamine Stress
In 13 dogs, after baseline measurements were made and the LAD
stenosis was created, dobutamine was infused
intravenously in 3-minute dose increments of 2.5, 5, 10,
20, and 30 µg · kg-1 ·
min-1 (Graseby Medical infusion pump, model
3400). 99mTc-N-NOET (8 mCi, 296 MBq),
201Tl (0.75 mCi, 27.8 MBq), and
microspheres were simultaneously injected at the
peak 30-µg · kg-1 ·
min-1 dobutamine dose, and the
dobutamine infusion was terminated 2 minutes later. Animals
were euthanized 5 minutes after tracer injection (Figure 1
).
Image Acquisition and Quantification of the
Stenotic-to-Normal Count Ratio
Our ex vivo imaging protocol has been described
previously.10 The hearts were divided into 4 concentric
slices from apex to base, and these slices were placed directly on the
collimator of a standard nuclear medicine gamma camera (Technicare 420,
Ohio Nuclear). 99mTc-N-NOET images were acquired
with an all-purpose, low-to-medium-energy collimator with a 20% window
centered around the 99mTc photopeak and
recorded with a 128x128 matrix for 4 minutes. In the
dobutamine group (group 2), after at least 24 hours had
passed (to allow for 99mTc decay),
201Tl images were acquired with a 25% window
centered around the 201Tl photopeak. Image
quantification was performed on a nuclear medicine computer (Sopha
Medical Systems). No background subtraction, thresholding, or filtering
was applied to the images. A region of interest (ROI) was drawn on the
anteroseptal wall to represent the stenotic zone, and a
second ROI was drawn on the normally perfused posterolateral wall. The
stenotic-to-normal count ratio was calculated by dividing the
counts per pixel in the stenotic ROI by the counts per pixel in
the normal ROI. The stenotic-zone ROI was limited to an area of
20% of the LV in the central stenotic zone. The normal-zone
ROI was limited to 20% of the LV in the area with maximal
myocardial counts.
Determination of Regional Myocardial Blood Flow and Sestamibi
Activity
The microsphere technique used in our laboratory has
been described previously.11 To measure regional
tracer activity and microsphere-determined blood flow, each of
4 left ventricular slices was divided into 6 transmural
sections, which were then subdivided into epicardial, midwall, and
endocardial segments. The resulting 72 myocardial tissue samples were
counted in a gamma-well scintillation counter (MINAXI 5550, Packard
Instruments) with standard window settings. The tissue counts were
corrected for background, decay, and isotope spillover, and
regional myocardial blood flow was calculated with computer software
(PCGERDA, Scientific Computing Solutions, LLC). Blood flow and tracer
activities for each of the 24 transmural sections were calculated as
the weighted average of the 3 corresponding epicardial, midwall, and
endocardial segments. The 5 transmural sections with the lowest flows
at the time of tracer injection were defined as the stenotic
region, and the 5 transmural sections with the highest flows were
defined as the normal region. Stenotic-to-normal ratios for
blood flow and tracer activities were calculated by dividing the
average flow or tracer activity in the stenotic region by the
average values in the normal region.
Statistical Analysis
All statistical computations were made with SYSTAT software
(SYSTAT, Inc). The results are expressed as the mean±SEM. Differences
between means within a group were assessed by a repeated-measures ANOVA
or by a paired t test as appropriate. Comparisons between
groups were made with 1-way ANOVA and Tukey's post hoc testing.
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Results |
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Hemodynamics
As expected, mean heart rate (Table 1
) increased only modestly during
adenosine stress (121±5 to 134±5 bpm, P<0.05) but
increased markedly during dobutamine stress (127±4 to
208±7 bpm, P<0.001). Similarly, peak positive left
ventricular dP/dt (an index of global left
ventricular contractility) increased only
slightly during adenosine (1729±74 to 2140±105 mm Hg/s,
P<0.001) and increased more during dobutamine
(1950±84 to 6619±446 mm Hg/s, P<0.001).
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Regional Myocardial Blood Flow
Myocardial blood flow was unchanged by placement of the LAD
stenoses (Table 2). In the normal
zone, endocardial, midwall, epicardial, and transmural flow increased
significantly during adenosine and dobutamine
infusion (P<0.001). Adenosine (300 µg ·
kg-1 · min-1)
increased transmural flow in the normal zone by a factor of 4 to 5
times baseline resting flow, to a mean peak flow of 4.52±0.17 mL
· min-1 · g-1.
Dobutamine (30 µg ·
kg-1 · min-1)
increased transmural flow in the normal zone by a factor of 2.5 to 3
times resting flow, to a mean peak flow of 2.50±0.28 mL ·
min-1 · g-1. These
stressor-induced hyperemic flows were identical to those
reported previously in these canine models.1 12 By
design, flow reserve was significantly reduced in the stenotic
zone, with a mean peak transmural flow of just 1.49±0.21 mL ·
min-1 · g-1 during
adenosine stress and 1.18±0.17 mL ·
min-1 · g-1 during
dobutamine stress, similar to the stenotic-zone
flows reported previously in these models.1 12
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Stenotic-to-Normal Ratios for Myocardial Blood Flow and
99mTc-N-NOET and 201Tl Activity
Adenosine Stress
The left panel in Figure 2 depicts
the mean stenotic-to-normal ratios for transmural myocardial
flow at the time of 99mTc-N-NOET injection during
adenosine stress, with corresponding
99mTc-N-NOET activity ratios by gamma-well
counting and ex vivo imaging. A stenotic-to-normal image count
ratio <0.75 is typically associated with visually detectable
perfusion defects on clinical imaging. Although
99mTc-N-NOET count ratios by gamma-well counting
(0.55±0.05) and ex vivo imaging (0.58±0.04) underestimated the
adenosine-induced blood flow disparity at the time of NOET
injection (flow ratio=0.33±0.04; P<0.001), the NOET ratios
easily exceeded the 0.75 threshold, suggesting that perfusion defects
would be easily detectable on adenosine
99mTc-N-NOET perfusion imaging. For comparison,
the right panel in Figure 2 depicts the corresponding
201Tl ratios during adenosine stress from
previous studies in our laboratory using the same canine
model.12 Note that 99mTc-N-NOET
uptake during adenosine stress in the present study is
similar to that reported previously for
201Tl.12
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Dobutamine Stress
The left panel in Figure 3 depicts
the mean stenotic-to-normal ratios for transmural myocardial
flow at the time of tracer injections during dobutamine
stress, with corresponding 201Tl and
99mTc-N-NOET activity ratios by gamma-well
counting and ex vivo imaging. Although the 201Tl
and 99mTc-N-NOET activity ratios by gamma-well
counting (0.59±0.04 and 0.63±0.04, respectively) and ex vivo imaging
(0.60±0.05 and 0.57±0.03, respectively) underestimated the
dobutamine-induced blood flow disparity at the time of
tracer injection (flow ratio=0.47±0.04; P<0.001), the
ratios are again <0.75, implying that perfusion defects would be
detectable on dobutamine perfusion imaging. The
201Tl and 99mTc-N-NOET
activity ratios observed during dobutamine stress in the
present study are markedly different from the previously reported
stenotic-to-normal activity ratio for
99mTc-sestamibi (Figure 3, right
panel).1 Despite an identical
dobutamine-induced flow ratio of 0.47±0.03 at the time of
sestamibi injection, the 99mTc-sestamibi activity
ratios were much less favorable (0.82±0.02 and 0.81±0.03 by
gamma-well and ex vivo imaging, respectively) and did not achieve the
0.75 detection threshold.1 Thus,
99mTc-N-NOET uptake was not attenuated by
dobutamine infusion as was previously observed with
99mTc-sestamibi.
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Relationship Between Myocardial Blood Flow and 201Tl
and 99mTc-N-NOET Uptake
Figure 4 is a scatterplot of
normalized myocardial 99mTc-N-NOET activity
versus flow (normalized to 1 mL ·
min-1 · g-1) at
the time of 99mTc-N-NOET injection during
adenosine stress, plotted together with the mathematically
derived curve relating flow and 201Tl and
99mTc-sestamibi activity during adenosine
stress in the same canine models.12 The curve fits are
based on the solute transport model of Gosselin and
Stibitz.13 Note that the myocardial uptake of
99mTc-N-NOET and 201Tl is
proportional to myocardial blood flow over a wide range of
adenosine-induced hyperemic flows.
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Figure 5 is a scatterplot of normalized
myocardial 201Tl and
99mTc-N-NOET activity versus flow (normalized to
1 mL · min-1 ·
g-1) at the time of tracer injection during
dobutamine stress, plotted together with the mathematically
derived curve relating flow and 99mTc-sestamibi
activity during dobutamine stress in the same canine
models.1 The data points represent 429 individual
myocardial tissue samples from the present study. First, note that
the myocardial uptake of 201Tl and
99mTc-N-NOET during dobutamine stress
(Figure 5) is nearly identical to that during adenosine
stress (Figure 4), suggesting the absence of a
stressor-dependent effect of dobutamine on the myocardial
uptake of these tracers. In addition, note that the myocardial uptake
of 201Tl and 99mTc-N-NOET
during dobutamine stress (Figure 5) is much more
favorable than that of
99mTc-sestamibi,1 with a plateau in
201Tl and 99mTc-N-NOET
uptake only at very high flow rates (>4 mL ·
min-1 · g-1),
compared with the earlier plateau in
99mTc-sestamibi uptake at flow rates of only 1
mL · min-1 ·
g-1. During dobutamine stress, for
any given level of hyperemic flow, there is relatively greater
myocardial uptake of 201Tl and
99mTc-N-NOET than uptake of
99mTc-sestamibi.
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Discussion |
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The major finding of this study was that in these canine models of coronary stenoses, the myocardial uptake of 201Tl and 99mTc-N-NOET was favorable during both adenosine and dobutamine stress, implying the absence of a stressor-dependent effect of dobutamine on the myocardial uptake of these tracers. These findings suggest that the dobutamine-induced attenuation of myocardial 99mTc-sestamibi uptake1 is a tracer-specific phenomenon rather than a generalized effect.
Effects of Adenosine and Dobutamine Stress on
Myocardial Blood Flow
For purposes of myocardial perfusion imaging, the capacity to
increase blood flow in normally perfused myocardium is the
most important attribute of a pharmacological stressor, because flow in
the stenotic zone is determined largely by the severity of the
coronary stenosis. In the present study,
adenosine increased blood flow in normal myocardium
by a factor of 5 times baseline flow, and dobutamine
increased blood flow by a factor of 2.5 to 3 times resting flow. The
degree of hyperemia produced by both stressors is adequate for
myocardial perfusion imaging, provided that the tracer selected is
taken up by the myocardium in proportion to blood flow over
the range of flows produced by the stressor.
Myocardial Uptake of 99mTc-N-NOET and 201Tl
During Adenosine and Dobutamine Stress
The myocardial uptake of all diffusable tracers is dependent on
both myocardial blood flow and myocardial extraction of the tracer. The
myocardial uptake of 99mTc-sestamibi, a
lipophilic cationic molecule, is thought to occur through electrical
charge-driven diffusion across sarcolemmal membranes, with cellular
retention in mitochondrial membranes due to the negative transmembrane
potential.14 Dobutamine stress produces a less
favorable relationship between myocardial blood flow and sestamibi
uptake than that produced by adenosine stress in the same
canine models,1 suggesting the presence of a
stressor-specific adverse effect of dobutamine on
myocardial sestamibi uptake. This attenuation of uptake yields poor
perfusion defect contrast on dobutamine
99mTc-sestamibi images. A possible explanation
for this phenomenon is that the myocardial uptake of sestamibi is
diminished by dobutamine-induced calcium influx, with
blunting of the negative mitochondrial membrane driving potential due
to mitochondrial calcium sequestration.15 Although the
effect of dobutamine stress on the myocardial uptake of
99mTc-tetrofosmin is unknown, an attenuation of
99mTc-tetrofosmin uptake by
dobutamine would be expected on the basis of the similar
myocardial binding mechanisms of
99mTc-tetrofosmin and
99mTc-sestamibi.
In contrast, 99mTc-N-NOET uptake during dobutamine stress in the present study yielded perfusion defects that more closely reflected the myocardial blood flow at the time of 99mTc-N-NOET injection. This lack of attenuation of 99mTc-N-NOET uptake with dobutamine stress is explained by a different mechanism of myocardial extraction of this neutral, lipophilic compound.16 Although the mechanism of myocardial uptake of 99mTc-N-NOET remains incompletely defined, studies to date have suggested that 99mTc-N-NOET binds to the hydrophilic cardiomyocyte cell membrane, with no significant accumulation in the cytosolic or mitochondrial components.16 The cellular binding of 99mTc-N-NOET appears to be linked to the L-type calcium channel, and it is independent of cellular ATP content.17 After initial myocardial uptake, 99mTc-N-NOET redistribution occurs via bidirectional exchange between red blood cells and the myocardium.5 6 7 8 9 Early clinical data suggest that exercise stress 99mTc-N-NOET single photon emission CT perfusion imaging provides diagnostic information comparable to that by 201Tl, with evidence of myocardial redistribution evident on delayed 99mTc-N-NOET images.5 To date, there are no clinical studies addressing the detection of coronary stenoses with dobutamine 99mTc-N-NOET imaging.
The biokinetics of 201Tl in humans has been defined,18 and the clinical accuracy of dobutamine stress 201Tl perfusion imaging has been well established.19 20 21 The reported sensitivity for detection of CAD has ranged from 86% to 97%. The results of the present study suggest that 201Tl might be superior to 99mTc-sestamibi for the detection of coronary stenoses during dobutamine stress, although the more favorable myocardial uptake properties of 201Tl must be weighed against the relatively unfavorable radiophysical imaging properties of 201Tl compared with 99mTc-labeled agents.
Clinical Implications
The experimental data provided in the present study suggest
that 99mTc-N-NOET should be as accurate as
201Tl and superior to
99mTc-sestamibi for the detection of
coronary artery disease with dobutamine stress
perfusion imaging. A clinical comparison is warranted.
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Acknowledgments |
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This study was supported by a grant from the American Heart Association, Virginia Affiliate, Inc, and by a research grant from CIS Bio International, Gif sur Yvette, France.
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Footnotes |
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Reprint requests to David K. Glover, ME, Cardiovascular Division, Department of Medicine, Box 158, University of Virginia Health Sciences Center, Charlottesville, VA 22908.
Received April 9, 1999; revision received June 7, 1999; accepted June 14, 1999.
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  L. M. Riou, S. Unger, M.-C. Toufektsian, M. Ruiz, D. D. Watson, G. A. Beller, and D. K. Glover Effects of Increased Lipid Concentration and Hyperemic Blood Flow on the Intrinsic Myocardial Washout Kinetics of 99mTcN-NOET J. Nucl. Med., July 1, 2003; 44(7): 1092 - 1098. [Abstract] [Full Text] [PDF]
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L. M. Riou, C. Ghezzi, G. Vanzetto, A. Broisat, J.-P. Mathieu, R. Bontron, R. Pasqualini, and D. Fagret Verapamil Does Not Inhibit 99mTcN-NOET Uptake In Situ in Normal or Ischemic Canine Myocardium J. Nucl. Med., June 1, 2003; 44(6): 981 - 987. [Abstract] [Full Text] [PDF]
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K. Takehana, G. A. Beller, M. Ruiz, F. D. Petruzella, D. D. Watson, and D. K. Glover Assessment of Residual Coronary Stenoses Using 99mTc-N-NOET Vasodilator Stress Imaging to Evaluate Coronary Flow Reserve Early After Coronary Reperfusion in a Canine Model of Subendocardial Infarction J. Nucl. Med., September 1, 2001; 42(9): 1388 - 1394. [Abstract] [Full Text] [PDF]
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D. Fagret, C. Ghezzi, and G. Vanzetto 99mTc-N-NOET Imaging for Myocardial Perfusion: Can It Offer More Than We Already Have? J. Nucl. Med., September 1, 2001; 42(9): 1395 - 1396. [Full Text] [PDF]
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