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Circulation. 1995;92:994-1004

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(Circulation. 1995;92:994-1004.)
© 1995 American Heart Association, Inc.

Articles

Comparison of Thallium-201 Resting Redistribution With Technetium-99m–Sestamibi Uptake and Functional Response to Dobutamine for Assessment of Myocardial Viability

Vedat Sansoy, MD; David K. Glover, ME; Denny D. Watson, PhD; Mirta Ruiz, MD; William H. Smith, MS; Juris P. Simanis, BS; George A. Beller, MD

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


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background 201Tl scintigraphy is useful for determination of viability in patients with coronary artery disease and depressed left ventricular function. Whether 99mTc sestamibi is adequate for viability detection remains controversial. The primary goal of this study was to compare 99mTc-sestamibi uptake with 201Tl uptake in canine models of sustained low flow and regional asynergy for determination of viability. A secondary objective was to compare myocardial uptake of these tracers with the functional response to low-dose dobutamine.

Methods and Results In protocol 1, 14 open-chested, anesthetized dogs with a 50% reduction in resting left anterior descending coronary artery (LAD) flow underwent 1 hour of transient LAD occlusion followed by reperfusion through the severe stenosis. Then 1.0 mCi of 201Tl was injected, and serial imaging was performed 5 minutes and 2 hours later. After acquisition of the delayed 201Tl image, 10 mCi of 99mTc sestamibi was injected, and imaging was repeated 45 minutes later. No significant difference was seen between the 201Tl defect ratio (LAD/left circumflex coronary artery [LCx]) on redistribution images (0.62±0.02) and 99mTc-sestamibi defect ratio (0.60±0.02). Similarly, LAD/LCx activity ratios by gamma-well counting were comparable (0.62±0.02 versus 0.59±0.04) and reflected the flow decrement. Systolic thickening was -11±3% at the time of tracer injection. In protocol 2, 16 dogs underwent serial 201Tl and 99mTc-sestamibi imaging during a 50% reduction in LAD flow with no superimposed transient LAD occlusion. In this model, the 99mTc-sestamibi LAD/LCx image defect ratio (0.61±0.03) was significantly less than the 201Tl redistribution image defect ratio (0.66±0.03, P<.01). In 10 dogs, the stenosis was released, resulting in a significant increase in systolic thickening (P=.003), which increased further in response to 5 µg · kg-1 · min-1 of dobutamine (P=.02). In contrast, thickening increased only from -7±3% to 2±4% (P=.004) in response to dobutamine infusion in the remaining 6 dogs with persistent severe LAD stenoses. In protocol 3, 5 dogs received both 201Tl and 99mTc sestamibi to compare the degree of delayed redistribution between tracers at 2 hours. The LAD/LCx microsphere flow ratios when 201Tl and 99mTc sestamibi were injected were 0.44±0.06 and 0.43±0.05 (P=NS), respectively. The LAD/LCx activity ratio by gamma-well counting was greater for 201Tl (0.56±0.08) than 99mTc sestamibi (0.50±0.07) at 2 hours of redistribution (P<.05), indicating greater redistribution for 201Tl. The LAD/LCx 99mTc-sestamibi defect ratios on serial imaging improved from 0.49±0.07 to 0.52±0.07 (P=.0005), consistent with a slight amount of 99mTc-sestamibi redistribution. In protocol 4, no difference between 201Tl and 99mTc-sestamibi defect magnitudes was seen in 4 dogs undergoing 3 hours of total LAD occlusion and ligation of visible coronary collaterals. Infarct size was 68±19% of the risk area.

Conclusions Although 99mTc-sestamibi and 201Tl defect magnitudes and regional activities were comparable in dogs with sustained low coronary flows and superimposed subendocardial infarctions and in dogs with large infarctions, approximately 5% more 201Tl than 99mTc-sestamibi uptake was observed in dogs with chronic low flow and severe systolic dysfunction. Substantial 99mTc-sestamibi uptake in asynergic zones was observed in this low-flow model, with some slight resting 99mTc-sestamibi redistribution observed on serial images. Systolic thickening was negligibly enhanced during dobutamine infusion in dogs with sustained low flow, whereas 201Tl uptake was only mildly reduced.


Key Words: thallium-201 • technetium-99m sestamibi • ischemia • imaging


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
The noninvasive determination of myocardial viability is becoming increasingly important for clinical decision making. Several approaches have been described to identify viable but asynergic myocardium.1 2 3 201Tl scintigraphy is currently the most widely used noninvasive technique for the determination of viability in patients with severely depressed left ventricular (LV) function. To circumvent the radiophysical limitations of 201Tl, new myocardial perfusion agents labeled with 99mTc have been developed recently. Myocardial perfusion studies with 99mTc isonitriles, particularly 99mTc sestamibi, have some advantages over 201Tl, including on-site availability and higher-quality images.4 5 Despite good results as a flow tracer for detecting stress-induced ischemia, whether 99mTc sestamibi is adequate for detecting myocardial viability remains controversial. Although some recent experimental and clinical data indicated that 99mTc sestamibi is a valid marker of myocardial cellular viability,6 7 8 9 10 11 12 13 14 15 16 17 18 other reports suggested that 99mTc-sestamibi imaging may underestimate the extent of viable myocardium.19 20 21 22 23 24

Low-dose dobutamine echocardiography is another emerging noninvasive approach for determination of myocardial viability in both postinfarction patients and patients with chronic coronary artery disease (CAD).25 26 27 28 29 Although these reports are encouraging in terms of the accuracy of this technique for predicting improved systolic function after revascularization, other reports suggest that a significant number of asynergic regions unresponsive to dobutamine are viable by 201Tl or positron emission tomographic criteria.30 31 32

Accordingly, the objectives of the current investigation were (1) to better define myocardial 99mTc-sestamibi uptake in canine models of low-flow ischemia with and without superimposed infarction, (2) to compare 99mTc-sestamibi uptake with 201Tl uptake for viability detection in zones of asynergy, (3) to compare the degree of uptake of 201Tl in asynergic myocardium with the functional response to low-dose dobutamine, and (4) to measure the change in 99mTc-sestamibi defect magnitudes with stenosis release and dobutamine infusion. The latter was undertaken to determine whether flow restoration and dobutamine-enhanced thickening in zones of asynergy would improve defect magnitude caused by a reversal of the partial volume effect.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Surgical Preparation
Experiments were performed in 39 fasted adult mongrel dogs anesthetized with sodium pentobarbital (30 mg/kg), intubated, and ventilated on a respirator (Harvard Apparatus) with 4 cm of positive end-expiratory pressure. Arterial blood gases were monitored with levels maintained in physiological ranges. The right femoral vein was cannulated with an 8F polyethylene catheter for administration of fluids, medications, 201Tl, and 99mTc sestamibi. Both femoral arteries were isolated and cannulated with 8F polyethylene catheters and used for collection of arterial blood samples and microsphere reference blood withdrawal. A cutdown on the left side of the neck was performed, and a Millar pressure catheter was advanced through the carotid artery to the LV cavity.

The basic open-chested canine model used in these experiments was described previously.13 Briefly, a thoracotomy was performed at the level of the fifth intercostal space, and the heart was suspended in a pericardial cradle. A flare-tipped polyethylene tube was inserted into the left atrium through the left atrial appendage for continuous pressure measurement and for the injection of radiolabeled microspheres. An approximately 1.5-cm segment of the left anterior descending coronary artery (LAD) was dissected free of the epicardium, and an ultrasonic flow probe (T201, Transonic Systems, Inc) and one or two snare ligatures, depending on the protocol, were placed around the vessel. A similar ultrasonic flow probe was placed around the left circumflex coronary artery (LCx). Sonomicrometer crystals (Crystal Biotech) were sutured to the epicardial surface of the heart in regions supplied by the LAD and LCx for continuous monitoring of systolic thickening. Throughout each protocol, lead II of the ECG, arterial and left atrial pressures, LAD and LCx flows, systolic thickening, and LV pressure and its first derivative 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
Protocol 1: Comparison of 201Tl and 99mTc-Sestamibi Uptake During Sustained Low Flow and 60 Minutes of Transient LAD Occlusion
Experiments were performed in 14 dogs. After instrumentation of the animals, steady-state hemodynamic measurements were made for 30 minutes. After this baseline period, the LAD was partially occluded to produce a 50% reduction in baseline LAD flow. After 30 minutes of sustained low flow, the LAD was totally occluded for 60 minutes with a second snare occluder, followed by reperfusion through the severe stenosis. Sixty minutes after reflow, 201Tl (1 mCi) was injected. An initial 201Tl image was acquired 5 minutes later, and a final (redistribution) 201Tl image was acquired 2 hours later. 99mTc sestamibi (10 mCi) was injected 5 minutes after 201Tl imaging was completed, and 5 and 45 minutes later, initial and final 99mTc-sestamibi images, respectively, were acquired. Regional myocardial blood flow was assessed serially with radioactive microspheres. The dogs were then killed with an overdose of potassium chloride and sodium pentobarbital.

Protocol 2: Comparison of 201Tl and 99mTc-Sestamibi Uptake During Sustained Low Flow and Effect of Dobutamine on 99mTc-Sestamibi Defect Magnitude and Systolic Thickening
After instrumentation of 16 open-chested dogs, steady-state hemodynamic measurements were made for 30 minutes. After this baseline period, the LAD was partially occluded to produce a 50% reduction in baseline coronary flow. After 30 minutes of stable low flow, 201Tl (1 mCi) was injected intravenously, and an initial 201Tl image was acquired 5 minutes later. A redistribution 201Tl image was acquired 2 hours later. 99mTc sestamibi (10 mCi) was injected 5 minutes after acquisition of the final 201Tl images, and a 99mTc-sestamibi image was acquired 5 minutes later. In 10 dogs (group A), the LAD stenosis was released, permitting restoration of normal flow. Thickening was quantified after stenosis release to assess recovery of function with flow restoration, and another 99mTc-sestamibi image was acquired. Dobutamine was then infused at 5 µg · kg-1 · min-1 with repeated measurement of hemodynamics and acquisition of a final 99mTc-sestamibi image. The infu-sion lasted for approximately 10 to 15 minutes. The 5 µg · kg-1 · min-1 dose of dobutamine was selected on the basis of dose-response data acquired in 2 dogs in which higher doses in this canine model failed to further increase thickening. Also, even this low dose resulted in a significant increase in heart rate (see Table 2Down). The dogs were then killed. Regional myocardial blood flow was assessed serially with microspheres. Also, systolic thickening in the LAD and LCx territories was measured throughout the experiment.


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  		Table 2. Hemodynamic Variables in 16 Dogs With Sustained Low Flow With (Group A) and Without (Group B) Stenosis Release (Protocol 2)

In the 6 remaining dogs (group B), the LAD stenosis was not released after acquisition of the first 99mTc-sestamibi image, and dobutamine was infused with the LAD still stenotic. The same measurements were made as described in group A dogs.

Protocol 3: Comparison Between 201Tl and 99mTc-Sestamibi Redistributions During Sustained Low Flow
Five additional dogs underwent partial LAD occlusion to produce a 50% reduction in flow in a manner similar to that described in protocol 2. After 30 minutes of stable flow reduction, 0.5 mCi of 201Tl was injected, and an image was acquired 5 minutes later. Immediately thereafter, 10 mCi of 99mTc sestamibi was injected, and images were acquired 5, 60, and 120 minutes later to quantify the extent of delayed 99mTc-sestamibi redistribution. Radioactive microspheres were injected serially into the left atrium.

Protocol 4: Comparison of 201Tl and 99mTc-Sestamibi Uptake During Total LAD Occlusion and Effect of Dobutamine on 99mTc-Sestamibi Defect Magnitude and Systolic Thickening
After the baseline measurements were made, the LAD and visible feeder collaterals from the LCx in 4 dogs were totally occluded for 3 hours. Initial and 2-hour 201Tl images were obtained with the occlusion still present. Then, 5 minutes after acquisition of the delayed 201Tl images, 99mTc sestamibi (10 mCi) was injected, and a 99mTc-sestamibi image was obtained with the occlusion still present. Regional flow and systolic thickening before and after dobutamine administration were assessed.

Determination of Regional Myocardial Blood Flow With Radioactive Microspheres and Quantification of Tracer Uptake
The technique used in our laboratory to quantify regional myocardial blood flow by the radioactive microsphere technique was described previously.11 13 For flow determination, paired arterial reference samples were obtained by continuous arterial withdrawal (Harvard Apparatus) over 130 seconds, beginning 10 seconds before the injection of each set of spheres. After the dogs were killed, 201Tl and 99mTc-sestamibi activities and microsphere-determined flow in the myocardial tissue samples were measured; the left ventricle and septum were separated from the remainder of the heart and trimmed of epicardial fat and vessels; and each of the four myocardial slices were divided into eight transmural sections that were further subdivided into epicardial, midwall, and endocardial segments, resulting in a total of 96 myocardial segments for each dog. The myocardial segments and arterial blood samples were counted for 201Tl and 99mTc activities in a gamma-well scintillation counter (MINAXI 5550, Packard Instruments) within 24 hours. The myocardial samples were counted for myocardial flow determination 3 weeks later, when 201Tl activity was negligible. For the myocardial counting, window settings were Sn-113, 340 to 440 keV; Ru-103, 450 to 550 keV; Nb-95, 640 to 840 keV; and Sc-46, 842 to 1300 keV. Tissue counts were corrected for background, decay, and isotope spillover, and regional myocardial blood flow was calculated with computer software developed for this purpose (PCGERDA, Packard Instruments). The transmural regional flow values for a specific sample were derived from the average of epicardial, midwall, and endocardial values for that sample. To facilitate comparisons between tracer activity and flow, the 201Tl and 99mTc-sestamibi activities and microsphere flows were normalized to the average value of 15 to 18 samples taken from the nonischemic region supplied by the LCx.

Image Acquisition and Quantification of Defect Magnitude
Images were obtained with a standard nuclear medicine gamma camera and computer (Technicare 420, Ohio Nuclear) by use of an all-purpose, low-to-medium-energy collimator with a 20% window centered around the photopeaks of 201Tl or 99mTc and recorded with a 128x128 matrix for 10 minutes. All images were acquired in the left lateral projection. A lead shield was placed over the abdomen of the dog to reduce liver and splanchnic activity. Background was subtracted from all images by use of a previously validated algorithm. To quantify images, a region of interest (ROI) was drawn on the defect area of the anteroseptal LV wall on the initial 201Tl image. A second ROI was then drawn on the same image to encompass the normally perfused posterior wall. The serial 201Tl and 99mTc-sestamibi images were aligned, and average counts were taken from precisely the same regions on each image. No thresholding or filtering was applied to the images. The image perfusion defect ratio was computed by dividing the average counts in the ischemic ROI by the average counts in the nonischemic ROI.

Postmortem Analysis
In dogs in protocols 1 and 4 in which infarctions were produced, the LAD was briefly reoccluded, and monastral blue dye was injected into the left atrial catheter to delineate the anatomic risk area as previously described. The hearts were then divided from apex to base into four slices of approximately equal thicknesses. The slices were then photographed, placed on cardboard, and covered with plastic wrap. The endocardial and epicardial borders of each slice and the risk area were then carefully traced onto acetate sheets. The slices were then bathed in PBS of triphenyltetrazolium chloride for 20 minutes to define the infarcted myocardium, rephotographed, and retraced onto acetate sheets for the infarct area. Risk and infarct areas were determined with a digital planimeter program as described previously.11

Statistical Analysis
Mean and SEM computations were performed by use of SYSTAT software (SPSS, Inc) on an IBM-compatible personal computer. Comparisons within each group were made with either a paired t test or repeated-measures ANOVA with post hoc comparisons of changes determined a priori to be of interest.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Protocol 1: Comparison of 201Tl and 99mTc-Sestamibi Uptake During Sustained Low Flow and 60 Minutes of Transient LAD Occlusion
Hemodynamics
Table 1Down summarizes the hemodynamic parameters of heart rate, systemic arterial pressure, left atrial pressure, and LAD flow measured at baseline, after the LAD stenosis, during transient LAD occlusion, and after reflow when 201Tl and 99mTc sestamibi were administered. Heart rate and arterial pressure remained stable throughout the experiment. LAD flow fell significantly after setting of the LAD stenosis. Flow fell to zero with total occlusion of the LAD. After reflow through the persistent stenosis, flow was 10±1 mL/min. Flow was unchanged (10±1 mL/min) when 99mTc sestamibi was administered. 99mTc sestamibi was injected after 2 hours of 201Tl redistribution.


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  		Table 1. Hemodynamic Variables in 14 Dogs With Sustained Low Flow and 1 Hour of Interspersed Transient Occlusion of the LAD (Protocol 1)

Regional Myocardial Blood Flow and 201Tl and 99mTc Activities
No difference in regional myocardial blood flow ratios (LAD/LCx) in the hypoperfused LAD region at the time of 201Tl and 99mTc-sestamibi injections were observed, indicating a constant level of regional flow reduction (0.64±0.05 versus 0.58±0.06, Fig 1Down). The final transmural 201Tl activity ratio (LAD/LCx) measured by gamma-well counting was 0.62±0.02. This ratio, determined 3 hours after 201Tl administration, was not different from the myocardial flow ratio when 201Tl was injected (0.64±0.05). Similarly, the 99mTc-sestamibi activity ratio (0.59±0.04) was not significantly different from the microsphere-determined flow ratio when 99mTc sestamibi was injected (0.58±0.06) 45 minutes earlier. Thus, in this model of sustained low flow with an interspersed 1 hour of transient LAD occlusion, no difference between final 201Tl and 99mTc-sestamibi activity ratios was observed in the LAD supply zone.



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  		Figure 1. Bar graph comparing 201Tl and 99mTc-sestamibi activities in 14 dogs with sustained low flow and interspersed 1 hour of transient LAD occlusion. Solid bars show comparable regional blood flows in the left anterior descending coronary artery (LAD) zone during 201Tl and 99mTc-sestamibi injections. Shaded bars show comparable 201Tl and 99mTc-sestamibi uptake expressed as LAD/left circumflex coronary artery (LCX) activity ratios.

Image Defect Ratios
In these dogs, the mean final 201Tl defect ratio (LAD/LCx) was not significantly different from the initial 201Tl defect ratio (0.62±0.02 versus 0.61±0.02, P=NS), indicating no resting redistribution under these experimental conditions (Fig 2Down). No significant difference was seen between the 2-hour redistribution 201Tl defect ratio and the 99mTc-sestamibi image defect ratio from 99mTc-sestamibi images obtained 45 minutes after tracer injection (0.62±0.02 versus 0.60±0.02, Fig 2Down). These results are consistent with the gamma-well counting data summarized above that show comparable final 201Tl and 99mTc-sestamibi activities when derived 3 hours after 201Tl administration.



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  		Figure 2. Bar graph showing ischemic/normal count ratios on initial and 2-hour resting 201Tl images and initial and 45-minute 99mTc-sestamibi images in 14 dogs with sustained low flow and interspersed 1 hour of total left anterior descending coronary artery (LAD) occlusion (protocol 1). Note the comparability of 2-hour 201Tl and 99mTc-sestamibi defect ratios (shaded bars) and absence of resting 201Tl redistribution (solid bars).

Wall Thickening
In 4 dogs, thickening data could not be obtained because of technical difficulties. In the remaining 10 dogs, systolic thickening in the LAD territory was 22±2% at baseline, fell to -3±3% after the LAD stenosis, and fell further to -14±4% during LAD occlusion. Thickening was -11±3% and -11±2% at the time of 201Tl and 99mTc-sestamibi administration, respectively (P=NS). Thus, the degree of LV dysfunction in the LAD perfusion zone was comparable during 201Tl and 99mTc-sestamibi injections.

Risk Area and Infarct Size
In these protocol 1 dogs undergoing 1 hour of LAD occlusion in the presence of a severe LAD stenosis, the risk area by monastral blue dye injection was 29±1% of the left ventricle. Mean infarct size was 8.4±1% of the total left ventricle and 19±3% of the LAD risk area. All dogs had a subendocardial infarction ranging from 1% to 16% of the left ventricle.

Protocol 2: Comparison of 201Tl and 99mTc-Sestamibi Uptake During Sustained Low Flow and Effect of Dobutamine on 99mTc-Sestamibi Defect Magnitude and Systolic Thickening
Hemodynamics
Table 2Up summarizes the hemodynamic data for group A and B dogs in protocol 2. Heart rate remained stable in the entire group of 16 dogs after the LAD stenosis was set and was unchanged until infusion of dobutamine. Systemic arterial pressure also remained constant during the low-flow state. There was no difference in LAD flow at the times of 201Tl and 99mTc-sestamibi injections. In the 10 group A dogs, release of the stenosis resulted in an increase in flow from 9±7 to 22±3 mL/min (P<.01) (Table 2Up). Flow increased further to 44±6 mL/min after dobutamine administration. In group B dogs with the LAD stenosis in place, dobutamine infusion caused a significant decrease in arterial pressure from 109±6 to 78±4 mm Hg (P<.05). LAD flow remained unchanged with dobutamine administration. In groups A and B, LCx flow rose to comparable values during dobutamine infusion (77±7 and 77±17, respectively).

Regional Myocardial Blood Flows
In the entire group of 16 dogs, creation of LAD stenoses resulted in a 50.5% mean flow reduction. During this low-flow state, the LAD/LCx flow ratios during 201Tl and 99mTc-sestamibi injections were not significantly different (0.56±0.04 versus 0.58±0.06). 201Tl and 99mTc-sestamibi activities could not be validly compared with initial flow values or the image defect ratios because dobutamine was infused with the LAD open in 10 of the dogs before termination of the experiment. Opening of the LAD and infusion of the inotrope may have resulted in altered 201Tl uptake or clearance kinetics. The images were obtained in all 16 dogs after 2 hours of low flow and before LAD stenosis release and dobutamine administration.

Image Defect Ratios
For the entire group of 16 dogs, initial and 2-hour-delayed 201Tl defect ratios (LAD/LCx) on serial left lateral images were 0.60±0.02 and 0.66±0.03, respectively (P<.0001), confirming resting 201Tl redistribution (Fig 3Down). The 99mTc-sestamibi image defect ratio (0.61± 0.03) was on average 5% less than the delayed 201Tl defect ratio at redistribution (0.66±0.03, P<.01).



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  		Figure 3. Bar graph showing 201Tl (left bars) and 99mTc-sestamibi (right bar) image defect ratios (ischemic/normal) in 16 dogs with sustained low flow. The final 201Tl defect magnitude at 2 hours of redistribution (shaded bar) was slightly but significantly less than the 99mTc-sestamibi defect magnitude.

In the 10 group A dogs, the 99mTc-sestamibi image defect ratio improved slightly but significantly after stenosis release and restored flow (0.62±0.04 to 0.64±0.03, P<.05). With dobutamine infusion, the defect ratio improved further to 0.69±0.03 (P<.01 versus initial 99mTc-sestamibi defect ratio). In contrast, no significant change in defect magnitude after dobutamine infusion was observed in group B dogs with sustained LAD stenoses (0.59±0.05 versus 0.61±0.05). Fig 4Down shows 201Tl and 99mTc-sestamibi images from a representative dog in this group. Note that the LAD/LCx 201Tl image defect ratio improved from 0.53 to 0.60 over 2 hours of redistribution. The 99mTc-sestamibi defect ratio was 0.53, which was similar to the initial 201Tl ratio. The 99mTc-sestamibi defect ratio improved when a repeated image was acquired after release of the stenosis.



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  		Figure 4. Photomicrographs showing initial and 2-hour resting 201Tl images (top), the initial 99mTc-sestamibi image (bottom left) and the 99mTc-sestamibi image acquired after stenosis release (bottom right) in a representative dog in group A in protocol 2. After background subtraction, the ischemic/normal (left anterior descending coronary artery [LAD]/left circumflex) count ratio for 99mTc sestamibi was less (0.53) than the ratio on the 2-hour-delayed 201Tl image (0.60). Nevertheless, substantial 99mTc-sestamibi uptake can be observed. After opening of the LAD, 99mTc-sestamibi defect magnitude improved to 0.60 without additional tracer administration.

Wall Thickening
In the 10 group A dogs that had LAD stenoses removed during the experiment, systolic thickening in the LAD territory was 26±2% at baseline, 0±4% during 201Tl administration with the stenosis in place, and 1±4% during 99mTc-sestamibi administration with the stenosis in place (Fig 5Down). After release of the stenosis, thickening in the LAD territory increased to 15±3% (P<.01), indicative of significant immediate improvement in regional function attributed to flow restoration. After dobutamine infusion, thickening increased further to 19±3% (P=.02). LCx zone wall thickening increased slightly but not significantly after the LAD stenosis was established and remained constant thereafter. In the group B dogs with persistent LAD stenoses, a similar decrease in systolic thickening in the LAD zone was observed after the stenoses were created (Fig 6Down). No difference in systolic thickening was seen during 201Tl and 99mTc-sestamibi injections. Systolic thickening increased from -7±3% to 2±4% (P=.004) with intravenous dobutamine in these dogs with sustained LAD stenoses. Fig 7Down simultaneously depicts the early and delayed resting 201Tl defect magnitudes and corresponding values for systolic thickening in these group B dogs that received dobutamine with an approximate 50% sustained flow diminution in the supply zone of the LAD. Substantial 201Tl uptake (65% of nonischemic) was observed despite minimal improvement of systolic thickening in response to dobutamine infusion.



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  		Figure 5. Line graph showing serial changes in systolic thickening in 10 group A dogs at baseline, during 201Tl and 99mTc-sestamibi injections with the stenosis in place, and after the left anterior descending coronary artery (LAD) was opened by release of the stenosis. Note that percent thickening in the LAD zone significantly increased after stenosis release. Further improvement in systolic thickening is observed during dobutamine infusion. LCX indicates left circumflex coronary artery.



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  		Figure 6. Line graph showing serial changes in systolic thickening in 6 group B dogs with a persistent left anterior descending coronary artery (LAD) stenosis. Note that thickening is not greatly enhanced with dobutamine infusion. LCX indicates left circumflex coronary artery.



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  		Figure 7. Bar graphs showing early and delayed 201Tl ischemic/normal defect magnitudes (top) versus mean systolic thickening (bottom) from the 6 dogs with a sustained reduction in left anterior descending coronary artery (LAD) flow and whose thickening data are shown in Fig 6Up. Note that there was substantial final 201Tl uptake on 2-hour redistribution images, despite the persistence of severe asynergy in response to dobutamine.

Protocol 3: Comparison Between 201Tl and 99mTc-Sestamibi Redistributions During Sustained Low Flow
Hemodynamics
Although heart rate fell slightly over the experimental time period from 115±9 to 103±11 (P<.05), arterial pressure remained stable. Mean LAD flow fell from 17±2 to 7±1 mL/min after establishment of LAD stenoses and remained stable thereafter. No difference in LAD flow was observed during 201Tl and 99mTc-sestamibi injections. LAD flow was 7±1 mL/min 2 hours after 99mTc-sestamibi injection.

Regional Myocardial Blood Flows and 201Tl and 99mTc-Sestamibi Activities
Fig 8Down shows that the LAD/LCx microsphere-determined flow ratios were comparable during 201Tl and 99mTc-sestamibi injections (0.44±0.06 versus 0.43±0.05, respectively), whereas the final 201Tl activity ratio at redistribution (0.56±0.08) was on average 6% higher than the 99mTc-sestamibi activity ratio (0.50±0.07) after 2 hours of redistribution (P<.05), indicating a greater extent of redistribution for 201Tl.



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  		Figure 8. Bar graph comparing 201Tl redistribution and 99mTc-sestamibi redistribution reflected by final left anterior descending coronary artery/left circumflex coronary artery (LAD/LCX) activity ratios in the five protocol 3 dogs with sustained low flow. Note that both tracers demonstrated rest redistribution over 2 hours, but there was greater 201Tl redistribution.

Image Defect Ratios
As Fig 9Down shows, the LAD/LCx 99m Tc-sestamibi defect ratio was 0.49±0.07 initially, 0.50±0.07 at 1 hour, and 0.52±0.07 at 2 hours (P=.0005). This is consistent with the gamma-well counting data that showed slight 99mTc-sestamibi redistribution. The initial 201Tl LAD/LCx defect ratio acquired just before 99mTc-sestamibi injection was 0.50±0.08, which is not different from the initial 99mTc-sestamibi LAD/LCx defect ratio. Delayed 201Tl imaging could not be performed because of an inability to correct images for spilldown of 99mTc activity into the 201Tl window.



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  		Figure 9. Bar graph of 99mTc-sestamibi ischemic/normal count ratios on 5-minute, 1-hour, and 2-hour serial images showing slight but significant delayed 99mTc-sestamibi redistribution. LAD indicates left anterior descending coronary artery; LCX, left circumflex coronary artery.

Protocol 4: Comparison of 201Tl and 99mTc-Sestamibi Uptake During Total LAD Occlusion and Effect of Dobutamine on 99mTc-Sestamibi Defect Magnitude and Systolic Thickening
Hemodynamics
As Table 3Down shows, mean heart rate at the time of 99mTc-sestamibi administration during total LAD occlusion was slightly less than that during 201Tl administration. Arterial and left atrial pressures remained constant throughout the experiments. No difference in mean LAD flow during 201Tl and 99mTc-sestamibi injections was noted.


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  		Table 3. Hemodynamic Variables in 4 Dogs With Total Sustained Occlusion of the LAD (Protocol 3)

Regional Myocardial Blood Flows and 201Tl and 99mTc-Sestamibi Activities
In the 4 dogs included in this protocol, myocardial LAD/LCx flow ratios during 201Tl and 99mTc-sestamibi injections were not significantly different (0.22±0.03 versus 0.24±0.05, Fig 10Down). This flow reduction was significantly more severe than the reduction seen in animals included in protocols 1 through 3. Fig 10Down shows no difference between the final 201Tl and the final 99mTc-sestamibi LAD/LCx activity ratios (0.25±0.04 versus 0.25±0.05).



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  		Figure 10. Bar graph comparing 201Tl and 99mTc-sestamibi activities in 4 protocol 4 dogs with a sustained 3-hour occlusion of the left anterior descending coronary artery (LAD) and ligation of left circumflex coronary artery (LCX) collateral branches. The right bars show comparable reductions in 201Tl and 99mTc-sestamibi uptake in this model; left, severe reductions in regional blood flows during 201Tl and 99mTc-sestamibi injections.

Image Defect Ratios
No significant difference between initial and final 201Tl defect ratios was seen in this group of dogs with total sustained LAD occlusions (0.50±0.02 versus 0.48± 0.03). The 99mTc-sestamibi image defect ratio (0.53± 0.04) was not significantly different from the delayed 201Tl defect ratio and did not change after dobutamine administration (0.51±0.05).

Wall Thickening
Systolic thickening was 24±3% at baseline and fell to -6±1% and -5±1% during 201Tl and 99mTc-sestamibi administrations, respectively. Thickening increased to only -1±2% after dobutamine administration. At the time of tracer injections and dobutamine infusion, the LAD remained totally occluded.

Risk Area and Infarct Size
In the 4 dogs in this protocol, mean infarct size was 22±6% of the left ventricle, which represented 68±19% of the LAD risk area. The infarct size in these dogs with sustained LAD occlusions was significantly greater than the infarct size in the dogs with only 1 hour of LAD occlusion followed by reperfusion in protocol 1.


*    Discussion
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*Discussion
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The major findings of this study were that (1) resting myocardial uptake of 99mTc sestamibi was comparable to resting 201Tl uptake at redistribution in a canine model of sustained low flow, with a superimposed 1 hour of LAD occlusion and reflow causing subendocardial infarction; (2) resting uptake of 201Tl after 2 hours of redistribution was greater than 99mTc-sestamibi uptake in dogs with sustained reductions in coronary flow and severe systolic dysfunction; (3) 99mTc-sestamibi redistribution occurs but was less than the amount of 201Tl resting redistribution in the same animals; (4) 201Tl and 99mTc-sestamibi uptake defect magnitudes were comparable in dogs with large anterior wall infarctions making up almost 70% of the LAD risk area; (5) intravenous dobutamine infusion only slightly enhanced systolic thickening in asynergic regions in dogs with severe LAD stenoses despite substantial preservation of 201Tl uptake; and (6) in dogs with the LAD stenosis removed, intravenous low-dose dobutamine infusion resulted in enhanced systolic thickening and improvement in 99mTc-sestamibi defect magnitude.

201Tl Uptake and Viability
The finding of substantial resting 201Tl uptake in asynergic myocardium produced by sustained low coronary flow is not surprising.1 13 33 34 35 36 37 38 39 40 Previous reports from our laboratory showed unaltered myocardial 201Tl uptake and clearance kinetics in canine models of myocardial stunning produced by brief periods of coronary occlusion and reflow13 36 or with a chronic reduction in resting flow.13

99mTc-Sestamibi Uptake and Viability
Experimental studies showed that 99mTc sestamibi may also be a suitable viability agent.6 7 8 9 10 11 12 13 17 40 41 42 Piwnica-Worms et al7 reported that myocardial cellular sequestration of 99mTc sestamibi predominantly involves passive distribution across sarcolemmal and mitochondrial membranes, and at equilibrium it resides largely in mitochondria. When sarcolemmal or mitochondrial membrane potentials are depolarized, as with severe ischemic injury, uptake is inhibited and 99mTc sestamibi is not retained. Metabolic alterations consequent to ischemia or hypoxia can result in impaired 99mTc-sestamibi uptake independent of flow.7 12 Studies in intact animals demonstrated that the myocardial distribution of 99mTc sestamibi is proportional to regional flow and viability similar to what has been described for 201Tl.10 11 Tracer uptake is preserved after experimental stunning as was shown for 201Tl.13 99mTc sestamibi cannot be retained in myocardial regions that have been irreversibly injured by prolonged coronary occlusion followed by reperfusion.14 99mTc-sestamibi defect size correlates well with histological infarct size.10 11 In the present study, flow was severely reduced, producing marked regional LV dysfunction. Despite this low-flow state, substantial early uptake of 99mTc sestamibi was observed (protocol 2). Mean 99mTc-sestamibi defect magnitude was on average only 5% lower than the 2-hour-delayed 201Tl defect magnitude (61% versus 66% of nonischemic posterior wall uptake). However, 201Tl and 99mTc-sestamibi activities were comparable in 14 dogs with severe LAD stenoses that underwent 1 hour of transient LAD occlusion before tracer injections. Substantial uptake of both tracers at 3 hours after 201Tl administration and 45 minutes after 99mTc-sestamibi administration was demonstrated despite dyskinesis and a mean infarct size that represented 17% of the risk area.

201Tl Versus 99mTc-Sestamibi Redistribution
Because delayed 99mTc-sestamibi redistribution has been observed under certain experimental conditions9 40 43 44 and in certain clinical situations,19 45 we conducted additional experiments in which serial imaging was performed 5 minutes and 2 hours after 99mTc-sestamibi administration in dogs with chronic reductions in LAD flow. 201Tl was also injected, and myocardial uptake of the two tracers after 2 hours of low flow was determined by gamma-well counting. A small but statistically significant amount of 99mTc-sestamibi redistribution in the LAD zone was detected by in vivo quantitative planar imaging. Defect magnitude decreased from 49% to 52% of nonischemic values. More 201Tl than 99mTc-sestamibi redistribution was evident by gamma-well counting at 2 hours after tracer injections in this model of sustained low flow. However, the mean difference in uptake was only 6%.

This finding of greater 201Tl than 99mTc-sestamibi redistribution is consistent with those reported previously. Sinusas et al40 found more 201Tl than 99mTc-sestamibi uptake relative to microsphere flow by gamma-well counting of postmortem myocardial samples in dogs with sustained reductions in LAD flow. Serial in vivo 99mTc-sestamibi imaging was not carried out in those experiments. Glover and Okada44 could not detect 99mTc-sestamibi redistribution on serial myocardial images in an occlusion-reperfusion canine model but found evidence for delayed redistribution by gamma-well counting after the animals were killed. Li et al9 injected 201Tl and 99mTc sestamibi after 1 minute of coronary occlusion in anesthetized dogs, which was followed by reflow 6 minutes later. Serial tomographic imaging in these animals showed a perfusion defect with some slight redistribution after 2 hours. The degree of redistribution was significantly less than that observed with 201Tl. Okada et al41 failed to demonstrate a difference in the myocardial ischemic-to-normal ratio of 99mTc-sestamibi uptake 4 hours after injection in dogs with sustained low flow relative to the microsphere flow at the time of injection. There also was no significant redistribution on serial gamma camera imaging. Thus, these prior data, together with the results of the present study, indicate that with either transient ischemia or chronic low-flow experimental canine models, the degree of 99mTc-sestamibi redistribution is minimal and difficult to detect by in vivo imaging. Furthermore, 201Tl redistributes to a greater extent than 99mTc sestamibi.

Dilsizian et al19 detected some 99mTc-sestamibi redistribution in 22% of patients who underwent initial and 4-hour resting single-photon emission computerized tomographic (SPECT) redistribution imaging. Mean initial and delayed quantitative defect ratios for the entire group were not reported. In contrast, Villanueva-Meyer et al46 performed SPECT imaging 1 and 4 hours after 99mTc sestamibi was injected during peak exercise or dipyridamole stress and found no change in defect size, consistent with no significant redistribution.

201Tl and 99mTc-Sestamibi Uptake With Myocardial Infarction
201Tl and 99mTc-sestamibi activities and image defect ratios were comparable in dogs with totally occluded LADs for 3 hours at the time of administration of the two tracers. In these experiments, flow was reduced severely by ligation of visible collateral vessels originating from the LCx system. Infarct size in these dogs averaged 68% of the LAD risk area. The finding of comparable defect sizes for 99mTc sestamibi and 201Tl in this model is consistent with previous reports in the literature that the "risk area" distal to an occluded coronary artery is accurately reflected by both 201Tl and 99mTc-sestamibi defect size.10 11 14 15

Lack of 201Tl Redistribution in the Setting of Sustained Low Flow and Acute Subendocardial Infarction
The canine model of sustained low flow with a superimposed 1-hour total LAD occlusion with reflow through a critical stenosis (protocol 1) gives a pattern of defects in which myocardial 99mTc-sestamibi uptake was comparable to the delayed 201Tl uptake. This is in contrast to the experimental conditions in protocol 2 in which dogs merely had sustained LAD stenoses with no interspersed transient occlusion to produce subendocardial infarctions and severe asynergy. The lack of 201Tl redistribution over 3 hours as assessed by gamma-well counting could be caused by either a reduction of 201Tl extraction during its capillary transit or a reduction in the retention by myocardial cells after extraction. Either would result in a subnormal equilibrium concentration and persistence of reduced 201Tl accumulation in viable myocardium. Severe ischemia may impair the function of the Na+-K+ pump.47 48

The observations of comparable 201Tl and 99mTc sestamibi in a canine model of low flow and superimposed subendocardial infarction are consistent with some clinical studies in patients with severe coronary stenoses, prior infarctions, and LV dysfunction in which resting myocardial 201Tl and 99mTc-sestamibi uptake patterns were comparable.18 49 Further experimental studies are required to determine the precise mechanism of the lack of 201Tl redistribution in the particular combination of severe reduction in resting flow and superimposed transient total LAD occlusion and reflow that produces subendocardial necrosis and myocardial stunning.

Dobutamine Infusion and Systolic Thickening in the Presence of a Severe Coronary Stenosis
In the present study, low-dose intravenous dobutamine infusion resulted in enhanced systolic thickening in those dogs that had severe LAD stenoses removed before drug administration. Little enhancement of thickening was observed in dogs that received the drug with the stenoses in place, and resting LAD flow reduced by 50%. Despite anterior wall thickening after dobutamine infusion to only 2% of normal in this latter group, substantial 201Tl uptake was seen in the LAD zone on serial resting images (see Fig 7Up). The failure to observe a greater amount of thickening in viable but chronically hypoperfused myocardium in this canine model in response to dobutamine infusion may have been due to persistence or worsening of ischemia in response to inotropic stimulation. The severe stenosis may have prevented an increase in coronary blood flow in response to inotropic stimulation and increased myocardial oxygen demand. Some increase in flow may be required to enhance thickening, even with low-dose dobutamine. Otherwise, more ischemia will develop in response to increased oxygen demand. Our findings are consistent with those of McGillem et al,50 who reported that dopamine or dobutamine failed to increase systolic thickening in dogs with severe coronary stenoses where reactive hyperemia was reduced to <20% of baseline.

Interestingly, 99mTc-sestamibi defect magnitude became slightly but significantly smaller when repeated images were acquired after release of the LAD stenosis, even though no additional dose of the radionuclide was administered. Further reduction in defect magnitude occurred when images were again acquired during dobutamine infusion after stenosis release. In dogs that did not have the stenoses removed before dobutamine infusion, 99mTc-sestamibi defect magnitude remained unaltered. The improvement in defect magnitude after inotropic stimulation is presumably due to a reversal of the partial volume effect. These findings are consistent with those of Sinusas et al,51 who found a reduction in 99mTc-sestamibi defect size with resolution of ischemic dysfunction and dobutamine-induced augmentation of regional wall motion.

Clinical Implications
Many patients with CAD have resting asynergy in the absence of significant myocardial necrosis or scar.1 2 Identifying preserved myocardial viability in the presence of profound LV dysfunction is becoming increasingly more important for clinical decision making to better select those patients with ischemic cardiomyopathy who will benefit most from revascularization.3 There has been a greater appreciation among clinicians recently for recognizing "stunned" or "hibernating" myocardium. Both states are associated with severe regional ventricular dyssynergy in the absence of necrosis. Therefore, assessment of regional systolic function alone by such techniques as contrast ventriculography, radionuclide angiography, or echocardiography is insufficient for differentiating viable from irreversibly injured myocardium.

Prior clinical studies suggested that myocardial perfusion imaging with either 201Tl or 99mTc sestamibi can provide clinically important information pertaining to the status of myocardial viability when systolic dysfunction exists in the setting of severe coronary artery disease or after an acute myocardial infarction.1 2 14 15 52 53 54 55 56 57 58 59 60 61 The experimental data from the present study indicate that substantial 201Tl and 99mTc-sestamibi uptake occurs in zones of low flow and severe regional myocardial dysfunction, although 5% to 6% more 201Tl than 99mTc-sestamibi uptake was observed. Uptake of these tracers was comparable in dogs with a subendocardial infarction and persistent low flow and in dogs with extensive infarction secondary to 3 hours of total coronary occlusion. Finally, uptake of both 201Tl and 99mTc sestamibi was a better indicator of viability than the myocardial thickening response to intravenous dobutamine in the situation of severe chronic underperfusion. Taken together, the experimental data reported in this study provide further evidence of the validity of using 201Tl and 99mTc sestamibi to assess myocardial viability in patients with CAD and reversible ischemic LV dysfunction. The 5% greater 201Tl than 99mTc-sestamibi uptake observed in dogs with a severe chronic reduction in coronary flow but without infarction in these open-chested animal experiments might not be as evident with in vivo clinical imaging in CAD patients with LV dysfunction because of greater attenuation with 201Tl.18 62 Further clinical trials comparing the two radionuclides are warranted in this regard.


*    Acknowledgments
 
This work was supported in part by grant RO1 HL-26205-11 from the NHLBI, NIH, Bethesda, Md; by American Heart Association, Virginia Affiliate Grant-in-Aid VA-94-G-20; and by a research grant from E.I. du Pont de Nemours and Co, North Billerica, Mass. Dr Sansoy was a research fellow funded by the University of Istanbul (Turkey), Institute of Cardiology. We are appreciative of the superb editorial assistance provided by Jerry Curtis in preparing this manuscript.


*    Footnotes
 
Reprint requests and correspondence to George A. Beller, MD, Cardiovascular Division, Department of Medicine, Box 158, University of Virginia Health Sciences Center, Charlottesville, VA 22908.

Received January 10, 1995; revision received February 9, 1995; accepted February 10, 1995.


*    References
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*References
 

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