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(Circulation. 1997;96:2353-2360.)
© 1997 American Heart Association, Inc.

Articles

Effects of Dobutamine Stress on Myocardial Blood Flow, ^99mTc Sestamibi Uptake, and Systolic Wall Thickening in the Presence of Coronary Artery Stenoses

Implications for Dobutamine Stress Testing

Dennis A. Calnon, MD; David K. Glover, ME; George A. Beller, MD; Gérald Vanzetto, MD; William H. Smith, MS; Denny D. Watson, PhD; ; Mirta Ruiz, MD

From the Experimental Cardiology Laboratory, Cardiovascular Division, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville.

	Abstract

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Background Although dobutamine stress is used with both ^99mTc sestamibi (sestamibi) myocardial perfusion imaging and echocardiography for detecting coronary artery stenoses, the impact of stenosis severity on test end points (myocardial sestamibi uptake and systolic thickening, respectively) has not been clearly defined.

Methods and Results In 15 open-chest dogs, dobutamine (2.5 to 30 µg · kg^-1 · min^-1) was infused after placement of an LAD stenosis that reduced (n=8) or abolished (n=7) flow reserve. In dogs with reduced flow reserve, the stenotic-to-normal sestamibi activity ratio (0.86±0.03) significantly underestimated the 2-to-1 dobutamine-induced flow disparity at the time of sestamibi injection (flow ratio, 0.53±0.04; P<.001). Stenotic-zone thickening increased at low but not at higher doses of dobutamine (2.9±0.4 versus 4.2±0.4 mm in normal zone at peak dobutamine; P=.055) but did not fall below baseline (2.7±0.3 mm). Similarly, in dogs with absent flow reserve, the sestamibi activity ratio (0.78±0.02) underestimated the 2.5-to-1 dobutamine-induced flow disparity (flow ratio, 0.41±0.05; P<.001), and failure to increase systolic thickening was observed in the stenotic zone (2.7±0.4 versus 4.6±0.3 mm in the normal zone at peak stress, P<.01). In both groups of dogs, myocardial sestamibi uptake and image defect magnitudes were less than expected for the dobutamine-induced hyperemia, suggesting that dobutamine adversely affects myocardial sestamibi binding. Finally, a significant reduction in stenotic-zone thickening was seen during postdobutamine recovery, consistent with myocardial stunning.

Conclusions In the presence of stenoses that reduced or abolished regional flow reserve, (1) myocardial sestamibi uptake significantly underestimated the dobutamine-induced flow heterogeneity, (2) a "failure to increase systolic thickening" rather than a reduction in thickening was observed during dobutamine stress, and (3) myocardial stunning was observed during postdobutamine recovery.

Key Words: imaging • inotropic agents • radioisotopes • stunning, myocardial

	Introduction

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For optimal detection of coronary artery disease, the success of pharmacological stress myocardial perfusion imaging relies on two fundamental principles: (1) the pharmacological stressor must be capable of producing adequate 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 over the range of flows produced by the stressor.

The uptake of ^99mTc methoxyisobutyl isonitrile (sestamibi) is proportional to myocardial blood flow at normal flow rates, but during adenosine stress, uptake plateaus as flow increases to >2 to 2.5 times normal flow, resulting in an underestimation of high coronary flow rates. In canine models of coronary stenoses that reduced but did not abolish regional flow reserve, adenosine stress increased blood flow in the stenotic zone to the range in which sestamibi uptake plateaus, resulting in relatively little contrast in sestamibi activity between the stenotic and normal zones.¹ Unlike adenosine and other vasodilator stressors, dobutamine stress tends to produce relatively modest increases in blood flow. We hypothesized that dobutamine stress, by causing myocardial flow heterogeneity over a relatively lower range in which sestamibi uptake is more directly proportional to flow, might produce greater contrast in myocardial sestamibi activity, leading to better detection of milder coronary artery stenoses. Accordingly, the primary objective of the present study was to define the relationship between regional myocardial blood flow and myocardial sestamibi activity during dobutamine stress in the presence of coronary artery stenoses. A second objective was to better define the effect of stenosis severity on regional myocardial systolic thickening during and after dobutamine stress, with implications for dobutamine stress echocardiography and gated SPECT imaging.

	Methods

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Surgical Preparation
Fifteen fasted adult mongrel dogs (mean weight, 22.3 kg) were anesthetized with sodium pentobarbital (30 mg · kg^-1 IV), tracheally intubated, and mechanically ventilated with room air (Harvard Apparatus) with a positive end-expiratory pressure of 4 cm water. 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, sestamibi, 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 LV through an 8F sheath in the left carotid artery. The left external jugular vein was cannulated with an 8F catheter for administration of 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 loosely placed on a proximal portion of the LAD. Ultrasonic flow probes (T201, Transonic Systems, Inc) were placed on a more distal portion of the LAD and on the LCx. Sonomicrometer crystals (Crystal Biotech) were sutured to the epicardium in regions supplied by the LAD and LCx for measurement of regional systolic thickening. Throughout each protocol, the ECG, arterial and left atrial pressures, LAD and LCx flows, myocardial thickening, and LV pressure and its first time derivative (dP/dt) were monitored continuously and recorded on an eight-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: Dobutamine Stress in the Presence of a Stenosis That Reduced Regional Flow Reserve
After instrumentation, microspheres were injected to determine baseline myocardial blood flow (Fig 1). The LAD was occluded for 10 seconds, and the peak flow that followed was recorded as the normal reactive hyperemic response. In 8 dogs, the snare ligature was then adjusted to create an LAD stenosis that reduced the normal reactive hyperemic response by 50% without reducing resting flow.¹ Microspheres were injected 15 minutes later to determine myocardial flow in the presence of the stenosis. Dobutamine was then infused in 5-minute dose increments of 2.5, 5, 10, 20, and 30 µg · kg^-1 · min^-1 IV (Graseby Medical infusion pump, model 3400). Microspheres were injected at the 10-µg · kg^-1 · min^-1 dose and were simultaneously injected with sestamibi (8 mCi, 296 MBq) at the peak dose of 30 µg · kg^-1 · min^-1. In vivo gamma camera images were acquired 5 and 45 minutes after sestamibi injection, and the dogs were killed with an overdose of sodium pentobarbital and potassium chloride.

View larger version (16K): [in this window] [in a new window]   Figure 1. Experimental protocols. µSphere indicates microspheres.

Group 2: Dobutamine Stress in the Presence of a Stenosis That Abolished Regional Flow Reserve
In 7 dogs, dobutamine was infused after placement of an LAD stenosis that abolished the reactive hyperemic response without reducing resting flow.¹ With the exception of stenosis severity, the protocol for group 2 was identical to that of group 1 (Fig 1).

Determination of Regional Myocardial Systolic Thickening
Regional systolic thickening was measured by the epicardial crystal pulsed-Doppler technique.^{2 3} This technique is atraumatic, has been previously validated in the canine model, and has been used extensively by our group. The depth of the endocardial–LV cavity interface during maximal diastolic thinning was determined by oscilloscopic display of the Doppler signal, and the pulsed-Doppler sample volume was placed at this depth. This depth represents an in vivo measure of diastolic wall thickness. The diastolic wall thickness was reassessed during each stage of the protocol, and the sample volume depth was adjusted accordingly. Myocardial systolic thickening was measured as the net increase in wall thickness from the onset to the end of systole, as defined by the initial upward and peak negative deflections of the LV dP/dt tracings, respectively. Absolute systolic thickening represents the systolic displacement of the sample volume, or end-systolic thickness minus end-diastolic thickness. Relative systolic thickening (thickening fraction) is calculated as follows: [(end-systolic thickness minus end-diastolic thickness) divided by end-diastolic thickness] times 100%. Because diastolic wall thickness tends to increase progressively during dobutamine infusion in normally perfused myocardium, mean absolute systolic thickening increases more reliably than mean relative systolic thickening (thickening fraction) during dobutamine stress in normal volunteers.⁴ Measurements of thickening were made over at least one respiratory cycle during the last minute of each stage of the protocol, and the highest measured values were reported (excluding beats that followed ventricular ectopy).

Image Acquisition and Quantification of the Stenotic-to-Normal Count Ratio
Left lateral planar images were obtained 5 and 45 minutes after sestamibi injection with a standard nuclear medicine gamma camera and computer (Technicare 420, Ohio Nuclear) 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. A lead shield was placed over the abdomen to reduce liver and splanchnic activity. Image quantification and background subtraction were performed on a nuclear medicine computer (Sopha Medical Systems). No thresholding or filtering was applied to the images. An ROI was drawn on the anteroapical wall to represent the stenotic zone, and a second ROI was drawn on the normal posterior 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 reported count ratio represents the average of three computed count ratios. The stenotic-zone ROI was drawn to include the sestamibi perfusion defect (if visible) and 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 previously described.⁵ To measure regional sestamibi activity and microsphere-determined blood flow, each of four LV 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.¹ The tissue counts were corrected for background, decay, and isotope spillover, and regional myocardial blood flow was calculated with computer software (PCGERDA, Packard Instruments). Flow and sestamibi activity 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 sestamibi 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 flow and sestamibi activity were calculated by dividing the average flow or sestamibi 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 one-way ANOVA and Tukey's post hoc testing. Values of P<.05 were considered significant

	Results

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Hemodynamics
The peak dose of dobutamine was achieved in all dogs, and there were no sustained ventricular or supraventricular arrhythmias during infusion. No hemodynamic parameters were affected by placement of the LAD stenoses (Table 1). Mean heart rate and peak positive LV dP/dt increased during dobutamine infusion in both groups (P<.001). The increase in dP/dt was relatively blunted in the group with no flow reserve, however, with a plateau seen at peak dobutamine suggesting impaired contractility. Peak positive dP/dt was mildly but significantly depressed during recovery in both groups (P<.05). Mean ultrasonic flow in the normal LCx artery increased significantly during dobutamine infusion in both groups (P=.001). In the stenotic LAD, flow reserve was reduced in group 1 and was absent in group 2. During postdobutamine recovery, ultrasonic flow was similar to baseline in both the normal LCx and stenotic LAD arteries (P=NS).

View this table: [in this window] [in a new window]   Table 1. Hemodynamic Parameters

Regional Myocardial Systolic Thickening
Regional myocardial systolic thickening was unchanged by placement of the LAD stenoses. In the normal zone, both absolute and relative systolic thickening increased significantly during dobutamine infusion, and diastolic wall thickness tended to increase progressively as well (Table 2).

View this table: [in this window] [in a new window]   Table 2. Systolic Wall Thickening

In the group with reduced regional flow reserve (Fig 2, left), a biphasic response to dobutamine was observed in the stenotic zone, with increased thickening at low doses but a failure to maintain increased thickening at the peak dose of dobutamine. This biphasic response was observed in 6 of the 8 dogs in this group. Importantly, stenotic-zone thickening was not reduced relative to baseline thickening at any stage of the dobutamine infusion. In contrast, stenotic-zone thickening was significantly reduced during recovery (45 minutes after the infusion) both compared with predobutamine thickening and compared with simultaneously measured thickening in the normal zone (P<.05). This persistent postdobutamine regional systolic dysfunction was observed in 6 of the 8 dogs with reduced flow reserve.

View larger version (27K): [in this window] [in a new window]   Figure 2. Regional systolic thickening during dobutamine stress in dogs with stenoses that reduced (left) or abolished (right) myocardial flow reserve. Thickening in normal zone (dashed lines) increased significantly during dobutamine stress in both groups. In stenotic zone (solid lines), a biphasic (left) or flat (right) response to dobutamine was seen when flow reserve was reduced or absent, respectively. Stenotic-zone thickening was significantly reduced during recovery (End) in both groups, indicative of myocardial stunning. Base indicates baseline; sten, stenosis.

In the group with no flow reserve (Fig 2, right), a flat response to dobutamine infusion was seen in the stenotic zone, with a failure to increase systolic thickening at any dose of dobutamine. At the peak dose of 30 µg · kg^-1 · min^-1 dobutamine, although there was significantly greater thickening in the normal zone than in the stenotic zone, this resulted from a "failure to increase thickening" in the stenotic zone rather than from a significant reduction in stenotic-zone thickening relative to baseline. In contrast, stenotic-zone thickening was significantly reduced during recovery 45 minutes later both compared with baseline thickening and compared with simultaneously measured thickening in the normal zone (P<.05). This persistent postdobutamine regional systolic dysfunction was observed in all 7 dogs with no flow reserve.

Regional Myocardial Blood Flow
Myocardial blood flow was unchanged by placement of the LAD stenoses (Table 3). In the normal zone, dobutamine increased endocardial, midwall, and epicardial flow in both groups. Dobutamine (at 30 µg · kg^-1 · min^-1) increased transmural flow in the normal zone by a factor of 2.5 to 3 times resting flow. In group 1, flow reserve was reduced in the stenotic zone, with a mean peak transmural flow of just 1.40±0.08 mL · min^-1 · g^-1. In group 2, there was an absence of transmural flow reserve in the stenotic zone.

View this table: [in this window] [in a new window]   Table 3. Regional Myocardial Blood Flow

Stenotic-to-Normal Ratios for Myocardial Blood Flow and Sestamibi Activity
Fig 3 compares the mean stenotic-to-normal ratios for myocardial flow at the time of sestamibi injection, sestamibi activity on initial (5 minutes) and delayed (45 minutes) imaging, and sestamibi activity on gamma-well counting. The lower the ratio, the greater the heterogeneity in flow or sestamibi activity between the stenotic and normal zones. A stenotic-to-normal image count ratio threshold of 0.75 is used on quantitative perfusion imaging to distinguish abnormal stress-induced perfusion defects from the regional heterogeneity of tracer activity in normal subjects. In both groups of dogs, the sestamibi activity ratios significantly underestimated the flow disparity at the time of sestamibi injection (P<.001). Despite a mean flow ratio of 0.53±0.04 in the group with reduced flow reserve (Fig 3, left), implying a roughly 2-to-1 dobutamine-induced flow disparity between the normal and stenotic zones, the initial and delayed image count ratios and gamma-well sestamibi activity ratios were 0.88±0.03, 0.87±0.03, and 0.86±0.03, respectively. Similarly, despite a mean flow ratio of 0.41±0.05 in the group with no flow reserve (Fig 3, right), implying a roughly 2.5-to-1 dobutamine-induced flow disparity, the mean sestamibi ratios were 0.74±0.02, 0.75±0.03, and 0.78±0.02, respectively. Perfusion defects were visually apparent in the anteroapical region in only 1 of 8 dogs with reduced flow reserve and in 3 of 6 dogs with no flow reserve (images were not available for 1 dog in this group).

View larger version (40K): [in this window] [in a new window]   Figure 3. Mean stenotic-to-normal ratios for myocardial flow (solid bars) and for sestamibi activity by initial (5 minutes) and delayed (45 minutes) in vivo imaging (hatched and open bars, respectively) and gamma-well counting (crosshatched bars). In both groups (reduced flow reserve and no flow reserve), sestamibi activity ratios significantly underestimated dobutamine-induced flow disparity at time of sestamibi injection. *P<.001 vs flow ratio.

Relationship Between Myocardial Blood Flow and Sestamibi Uptake
The relatively poor sestamibi perfusion defect resolution observed in the present study is explained by the observation that dobutamine infusion appeared to interfere with sestamibi binding in myocardial tissue, resulting in a fundamental change in the relationship between myocardial blood flow and sestamibi uptake. Fig 4 is a scatterplot of normalized myocardial sestamibi activity versus flow (normalized to 1 mL · min^-1 · g^-1) at the time of sestamibi injection during dobutamine stress, plotted together with the curve relating flow and sestamibi activity during adenosine stress in the same canine models.¹ The points represent each of the 72 myocardial tissue samples taken from 5 representative dogs undergoing dobutamine stress in the present study, and the curve fits are based on the solute transport model of Gosselin and Stibitz.⁶ From a direct comparison of the adenosine and dobutamine curves, it is evident that the myocardial uptake of sestamibi is not only flow dependent but also "stressor dependent." During dobutamine stress, myocardial sestamibi uptake begins to plateau as flow increases to just 1 to 1.5 times normal flow (versus 2 to 2.5 times normal flow during adenosine stress), and for any given level of hyperemia, there is less myocardial sestamibi uptake during dobutamine stress than during adenosine stress.

View larger version (24K): [in this window] [in a new window]   Figure 4. Normalized myocardial sestamibi activity versus flow at time of sestamibi injection, plotted together with flow vs sestamibi uptake curve produced by adenosine stress in same canine models.1 Sestamibi uptake plateaus earlier during dobutamine stress (at flows of just 1 to 1.5 mL · min-1 · g-1), and relationship between flow and sestamibi uptake is less favorable for perfusion imaging during dobutamine stress than during adenosine stress.

	Discussion

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The major finding of this study was that, in these canine models of coronary stenoses, sestamibi myocardial perfusion imaging significantly underestimated the dobutamine-induced flow heterogeneity and therefore underestimated the physiological severity of the coronary stenoses. Importantly, myocardial sestamibi uptake underestimated the dobutamine-induced hyperemia to a greater extent than had been previously observed with adenosine stress,¹ suggesting that dobutamine stress adversely affects myocardial sestamibi binding.

We observed a sustained increase in systolic thickening during dobutamine stress in myocardium with normal flow reserve, a characteristic biphasic response to dobutamine in myocardium with reduced flow reserve, and a flat response to dobutamine in myocardium with no flow reserve. Systolic thickening failed to increase during dobutamine infusion when flow reserve was absent and failed to maintain increased thickening at high doses of dobutamine when flow reserve was reduced, but notably, an absolute reduction in systolic thickening was not observed at any stage of dobutamine infusion in this study. In contrast, a significant reduction in stenotic-zone thickening was observed during recovery, consistent with dobutamine-induced myocardial stunning.

Effects of Dobutamine Stress on Myocardial Blood Flow
The capacity to increase blood flow in normal myocardium is the most important attribute of a pharmacological stressor for myocardial perfusion imaging, because flow in the stenotic zone is determined largely by the severity of the coronary stenosis. In our study, dobutamine increased blood flow in normal myocardium by a factor of 2.5 to 3 times baseline flow, from a mean flow of 0.9 mL · min^-1 · g^-1 at baseline to 2.6 mL · min^-1 · g^-1 at peak dobutamine. Although this increase in blood flow is smaller than the fourfold increase seen with vasodilator stress agents,^{1 7 8} both the relative increase from baseline and the peak flow achieved were comparable to those reported previously with dobutamine stress.^{8 9 10 11 12 13} For example, in patients with coronary artery disease^{9 10} and in healthy volunteers,¹¹ myocardial flow in normally perfused regions increased from 0.77 to 0.99 mL · min^-1 · g^-1 at rest to 2.11 to 2.25 mL · min^-1 · g^-1 at peak dobutamine (40 µg · kg^-1 · min^-1). Similar results have been observed in swine¹² and in canine models.^{8 13} Thus, dobutamine stress produces modest though adequate flow disparity between myocardial regions supplied by normal and stenotic arteries (2 to 2.5 to 1 in the present study), which should be adequate for perfusion imaging in combination with a radionuclide tracer, which is distributed in the myocardium in proportion to flow over this range.

Myocardial Uptake of Sestamibi During Dobutamine Stress
The myocardial uptake of sestamibi, like all diffusible tracers, is dependent on both myocardial blood flow and myocardial extraction of the tracer. The myocardial uptake of 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

In the present study, dobutamine stress produced 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 observation is in agreement with the preliminary report of Yun et al.¹⁵ One possible explanation 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.¹⁶ Alternatively, the effective capillary surface area available for tracer diffusion may be relatively smaller during dobutamine stress than during adenosine stress, in which case the uptake of all diffusible tracers would be relatively impaired. Although myocardial ischemia is known to reduce sestamibi uptake in cell culture,¹⁷ the stressor-specific effect of dobutamine in this study cannot be explained by dobutamine-induced myocardial ischemia, because a selective effect on the stenotic (ischemic) zone would have been expected to enhance rather than to diminish perfusion defect magnitude. Furthermore, our results cannot be explained by redistribution of sestamibi during the 45 minutes after injection, because the count ratios on initial images were nearly identical to those on delayed images.

Comparison of Dobutamine and Adenosine Stress in the Same Canine Models
Glover et al¹ studied the uptake of sestamibi during adenosine stress in the same canine models as used in the present study (Fig 4). Sestamibi activity ratios by gamma-well counting were more favorable for adenosine stress (0.79±0.03 and 0.53±0.06 in the groups with reduced and absent flow reserve, respectively) than for dobutamine stress in the present study (0.8±0.03 and 0.78±0.02, respectively). On the basis of these studies, adenosine stress appears to produce greater contrast in myocardial sestamibi activity than dobutamine stress in the presence of coronary stenoses and should therefore be superior to dobutamine stress for sestamibi myocardial perfusion imaging.

Comparison With Clinical Studies of Dobutamine Stress Sestamibi Perfusion Imaging
Eleven published clinical studies of dobutamine stress SPECT sestamibi imaging have reported sensitivities of 72% to 94% for the detection of coronary artery disease.^{18 19 20 21 22 23 24 25 26 27 28} However, there are several important differences between the present study and these clinical studies. In our canine model, we measured quantitative sestamibi perfusion defects produced by dobutamine stress in the setting of physiologically defined, single-vessel coronary artery stenoses in the absence of prior myocardial infarction. In contrast, none of the clinical studies used quantitative criteria for the interpretation of images. More importantly, the sensitivity of myocardial perfusion imaging is affected by the prevalence of coronary disease in the study population, prior myocardial infarction, resting wall motion abnormalities, multivessel coronary artery disease, and the angiographic severity of coronary artery stenoses. The prevalence of coronary disease in these selected populations was high (57% to 100%). Clinical evidence of prior myocardial infarction was present in up to 56% of patients, and resting wall motion abnormalities were present in up to 30% of patients without clinical evidence of infarction, implying either occult infarction or resting ischemia. Multivessel coronary artery disease was present in 47% to 75% of patients, and only a small minority of patients (4% to 11%) had angiographically mild to moderate stenoses (50% to 69% reduction in luminal diameter). Furthermore, the sestamibi defects in these clinical studies might have been enhanced by postdobutamine myocardial stunning at the time of poststress image acquisition via the partial-volume effect,²⁹ which predicts a direct relationship between average regional wall thickness and myocardial counts on summed images.

Effects of Dobutamine on Systolic Wall Thickening
In the present study, we observed a sustained increase in systolic thickening during dobutamine infusion in myocardium with normal flow reserve, a biphasic response to dobutamine in myocardium with reduced flow reserve, and a flat response to dobutamine in myocardium with no flow reserve.

We did not observe a significant reduction in stenotic-zone thickening during dobutamine infusion in this study. The manifestations of dobutamine-induced myocardial ischemia were limited to a failure to increase thickening (when flow reserve was absent) or a failure to maintain increased thickening at high doses of dobutamine (when flow reserve was reduced). Therefore, our study supports the classification of these responses as abnormal responses to dobutamine stress. Although this classification scheme would optimize the detection of single-vessel stenoses in the absence of prior myocardial infarction (the clinical setting simulated in our study), it would probably reduce the specificity of dobutamine stress echocardiography, because a failure to increase thickening has also been observed in normal subjects during dobutamine stress.³⁰

For example, Carstensen et al⁴ reported a biphasic response to dobutamine stress in normal subjects. The differences between absolute and relative measures of systolic thickening were evident in this study, in which a biphasic response to dobutamine stress was observed when a relative measure of systolic thickening (thickening fraction) was used, whereas mean absolute systolic thickening increased progressively during dobutamine infusion. The discrepancy between absolute and relative measures of systolic thickening was explained by a proportionally larger increase in diastolic wall thickness than in absolute systolic thickening during dobutamine stress, which resulted in an attenuation of the increase in computed thickening fraction. In our present study, we also observed a small but progressive increase in the diastolic thickness of normally perfused myocardium during dobutamine stress, and for this reason, we suggest using absolute rather than relative measures of systolic thickening to describe changes in regional systolic function during dobutamine stress.

Dobutamine-Induced Myocardial Stunning
A striking finding in this study was a significant reduction in stenotic-zone systolic thickening after cessation of dobutamine infusion, consistent with dobutamine-induced myocardial stunning. The observation of postdobutamine myocardial stunning is important for three reasons. First, it provides supportive evidence that myocardial stunning can occur after demand myocardial ischemia,³¹ without a preceding reduction in blood flow. Second, the consistent observation of regional myocardial stunning in our study suggests that routine acquisition of echocardiographic images during postdobutamine recovery may enhance the detection of coronary stenoses, because it was only in the recovery period that a significant reduction in systolic thickening was observed. Third, the persistence of dobutamine-induced regional systolic dysfunction during poststress perfusion image acquisition might enhance perfusion defect severity via partial-volume effects and might influence the assessment of resting LV systolic function on poststress gated SPECT imaging.

The mechanism for myocardial stunning in this model is unclear, although dobutamine-induced production of nitric oxide in myocardium perfused by the stenotic LAD is one potential mechanism. Further research is warranted to identify the cellular mechanism for dobutamine-induced myocardial stunning.

Limitations of the Present Study
Although it is possible that the effects of dobutamine stress were influenced by the use of a pentobarbital-anesthetized canine model, the myocardial blood flow response to dobutamine was comparable to the response reported in conscious humans.^{9 10 11} Second, the myocardial blood flow response to dobutamine can be influenced by instability of the coronary stenoses during the protocol or by the presence of the well-developed coronary collateral circulation of the canine species. However, because we confirmed reduced or absent flow reserve in the stenotic zone by microsphere-derived tissue blood flow measurements, it is unlikely that stenosis instability or collateral blood flow significantly influenced our results. Third, the flow heterogeneity produced by dobutamine stress might have been greater if we had advanced the infusion to 40 µg · kg^-1 · min^-1. However, the increase in normal-zone myocardial blood flow in our study was comparable to that reported in other studies^{8 9 10 11 12 13} using peak dobutamine doses of 40 µg · kg^-1 · min^-1, perhaps because we used 5-minute rather than 3-minute dose increments. Finally, it is possible that the responses to dobutamine stress in patients with chronic coronary artery disease may differ from the responses observed in this canine model of experimentally created coronary artery stenoses.

Clinical Implications
There is potential for failure of dobutamine stress sestamibi myocardial perfusion imaging to detect the presence of coronary artery stenoses, particularly those stenoses that reduce but do not abolish flow reserve. The quantitative sestamibi perfusion defects produced by dobutamine stress in this study were relatively mild in severity and would have been difficult to distinguish from the regional heterogeneity in tracer activity observed in normal subjects.

If the myocardial uptake of ²⁰¹Tl is closely proportional to flow during dobutamine stress, then ²⁰¹Tl might be preferable to sestamibi for dobutamine stress myocardial perfusion imaging, despite the less favorable imaging properties of ²⁰¹Tl (increased tissue scatter and attenuation, limited injectable dose due to longer half-life).

To optimize the detection of single-vessel coronary stenoses by dobutamine stress echocardiography, our data support the classification of a failure to increase systolic thickening as an abnormal response to dobutamine stress, because this response (rather than a significant reduction in systolic thickening) was observed in myocardium with both reduced and absent flow reserve during dobutamine infusion. In addition, because a consistent reduction in systolic thickening was observed during postdobutamine recovery, our study suggests that the sensitivity of dobutamine stress echocardiography might be further enhanced by routine acquisition of recovery images. However, it is not known how the changes in systolic thickening recorded by epicardial sonomicrometer crystals in this study would have been interpreted on two-dimensional echocardiographic imaging.

	Selected Abbreviations and Acronyms

 

LAD = left anterior descending coronary artery LCx = left circumflex coronary artery LV = left ventricular, left ventricle ROI = region of interest SPECT = single-photon emission computed tomography

	Acknowledgments

 
This study was supported by a grant from the American Heart Association, Virginia Affiliate, Inc, and by a research grant from DuPont Pharma, Radiopharmaceuticals.

	Footnotes

 
Reprint requests to David K. Glover, ME, Cardiovascular Division, Department of Medicine, Box 158, University of Virginia Health Sciences Center, Charlottesville, VA, 22908.

Presented in part at the 43rd Annual Meeting of the Society of Nuclear Medicine, Denver, Colo, June 3, 1996; the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 12, 1996, and the 46th Annual Scientific Session of the American College of Cardiology, Anaheim, Calif, March 19, 1997, and published in abstract form (J Nucl Med. 1996;37:3P-4P; Circulation. 1996;94[suppl I]:I-301; and J Am Coll Cardiol. 1997;29:383A).

Received January 28, 1997; revision received May 20, 1997; accepted May 28, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 

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