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(Circulation. 1997;96:2332-2338.)
© 1997 American Heart Association, Inc.

Articles

Myocardial ^99mTc-Tetrofosmin Uptake During Adenosine-Induced Vasodilatation With Either a Critical or Mild Coronary Stenosis

Comparison With ²⁰¹Tl and Regional Myocardial Blood Flow

David K. Glover, ME; Mirta Ruiz, MD; Joo Y. Yang, MD; William H. Smith, MS; Denny D. Watson, PhD; ; George A. Beller, MD

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

Correspondence to David K. Glover, Experimental Cardiology Laboratory, Cardiovascular Division, Department of Medicine, University of Virginia, Health Sciences Center Box 158, Charlottesville, VA 22908. E-mail dglover{at}virginia.edu

	Abstract

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Background Clinical studies have shown a comparable coronary stenosis detection rate between ^99mTc-tetrofosmin and ²⁰¹Tl but with smaller defect magnitudes for ^99mTc-tetrofosmin. The goals of this study were to measure the first-pass extraction fraction (EF) of ^99mTc-tetrofosmin in canine myocardium and to compare ^99mTc-tetrofosmin with ²⁰¹Tl uptake during adenosine-induced vasodilatation in dogs with various degrees of coronary stenosis.

Methods and Results EF was calculated in 4 anesthetized, open-chest dogs after intracoronary administration of ¹²⁵I-labeled albumin and ^99mTc-tetrofosmin. In another 16 dogs with either critical (n=6) or mild (n=10) left anterior descending coronary artery (LAD) stenoses, ²⁰¹Tl and ^99mTc-tetrofosmin were administered during adenosine infusion (250 µg · kg^-1 · min^-1). Dogs were killed 5 minutes later, and tracer activities were determined by ex vivo imaging of heart slices and by well counting. Mean ^99mTc-tetrofosmin EF was 54.0±3.7%. In the 6 critical-stenosis dogs, the LAD-to-left circumflex artery (LCx) microsphere flow ratio was 0.22±0.02 with adenosine. The LAD-to-LCx activity ratios were 0.37±0.04 for ²⁰¹Tl and 0.67±0.05 for ^99mTc-tetrofosmin (P<.01). For the 10 mild-stenosis dogs, the LAD-to-LCx flow ratio was 0.44±0.05. The ²⁰¹Tl activity ratio was 0.58±0.04, compared with 0.81±0.04 for ^99mTc-tetrofosmin (P<.01). Thus, in both groups, ^99mTc-tetrofosmin uptake underestimated the flow disparity more than ²⁰¹Tl. Similarly, magnitudes of ex vivo image defects were significantly greater for ²⁰¹Tl than for ^99mTc-tetrofosmin in both groups.

Conclusions In this canine model, relative underperfusion with adenosine stress is better resolved with ²⁰¹Tl than with ^99mTc-tetrofosmin and may be explained by the lower EF for ^99mTc tetrofosmin. With clinical imaging, greater ²⁰¹Tl attenuation and redistribution may lessen this advantage.

Key Words: adenosine • technetium • thallium

	Introduction

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The compound ^99mTc-tetrofosmin is a new lipophilic cationic complex that is rapidly cleared from the blood with intravenous injection and exhibits a relatively slow myocardial clearance with no significant delayed redistribution.¹ The tracer is taken up by myocardial tissue in proportion to blood flow and myocyte viability. Sinusas et al² showed that relative ^99mTc-tetrofosmin activity underestimated flow at high flow ranges, >2.0 mL · min^-1 · g^-1. Like ^99mTc-sestamibi, ^99mTc-tetrofosmin accumulates in mitochondria, and uptake is driven by the electropotential gradient according to the Nernst equation.^{3 4} Uptake of ^99mTc-tetrofosmin is inhibited by metabolic inhibitors and excessive calcium. Several clinical studies^{5 6 7 8 9 10 11} have been reported that showed comparable diagnostic accuracy of exercise ^99mTc-tetrofosmin and exercise ²⁰¹Tl scintigraphy in the same patients, although defect contrast was superior with ²⁰¹Tl in several of these reports^{5 6 9} ; that is, defect magnitude was less with ^99mTc-tetrofosmin on stress images. One proposed explanation for this lesser defect contrast for ^99mTc-tetrofosmin is a low first-pass EF compared with ²⁰¹Tl, as assessed in the isolated Langendorff rabbit heart model.¹²

We previously reported that with adenosine-induced hyperemic flow in a canine stenosis model, both ²⁰¹Tl and ^99mTc-sestamibi significantly underestimated the magnitude of the flow disparity between stenotic and normal perfusion beds.¹³ The degree of underestimation was greater for ^99mTc-sestamibi. The purpose of the present study was to directly compare ^99mTc-tetrofosmin with ²⁰¹Tl uptake during adenosine-induced vasodilatation in dogs with various degrees of coronary stenosis. A secondary objective was to quantify the first-pass myocardial EF of ^99mTc-tetrofosmin in dogs. As previously shown for ^99mTc-sestamibi, we hypothesized that myocardial ^99mTc-tetrofosmin uptake would underestimate the adenosine-induced flow disparity between stenotic and normal beds. This underestimation might be greater for ^99mTc-tetrofosmin than either ²⁰¹Tl or ^99mTc-sestamibi if the first-pass EF is confirmed to be lower for ^99mTc-tetrofosmin than for the other two tracers.

	Methods

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Surgical Preparation
Twenty-three fasted adult mongrel dogs (mean weight, 23.3 kg; range, 18 to 38 kg) were anesthetized with sodium pentobarbital (30 mg/kg), intubated, and ventilated on a respirator (Harvard Apparatus) with 4 cm H₂O positive end-expiratory pressure. Arterial blood gases were monitored (model 170, CIBA-Corning), and pH, PO₂, PCO₂, and HCO₃ levels were maintained at physiological levels. ECG lead II was monitored continuously. The right femoral vein was cannulated with an 8F polyethylene catheter for the administration of fluids and medications as well as for ²⁰¹Tl and ^99mTc-sestamibi. Both femoral arteries were also isolated and cannulated with 8F polyethylene catheters to serve as sites for the collection of arterial blood samples and for microsphere reference blood withdrawal. A 7F catheter was placed in the right femoral artery for continuous monitoring of systemic arterial pressure.

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 catheter was inserted into the left atrial appendage for continuous left atrial pressure measurements and as a site for the injection of radiolabeled microspheres. The LAD was then dissected free of the epicardium, and an ultrasonic flow probe (T201, Transonic Systems) and snare ligature were placed around the vessel. A similar flow probe was placed around the LCx.

The hemodynamic parameters of heart rate, systemic arterial and left atrial pressures, and LAD and LCx flows were continuously recorded on an 8-channel strip-chart recorder (7758D, Hewlett-Packard) throughout each protocol. All experiments were performed with the approval of the University of Virginia Animal Research Committee in compliance with the position of the American Heart Association on use of research animals.

Protocol 1: Determination of First-Pass EF of ^99mTc-Tetrofosmin in Canine Myocardium in Dogs With Normal Coronary Flow
The method used for measurement of the first-pass EF has been described previously.¹⁴ For these experiments, 4 anesthetized open-chest dogs underwent LAD cannulation directly with a 22-gauge needle-tipped catheter. A second catheter was inserted into the right jugular vein and advanced until its tip rested in the coronary sinus. The catheter was connected to a withdrawal pump with a fixed withdrawal rate. An isotope mixture was prepared containing 0.185 to 0.37 MBq (5 to 10 µCi) of ¹²⁵I-labeled albumin and 0.74 to 1.11 MBq (20 to 30 µCi) of ^99mTc-tetrofosmin, which was then diluted by a factor of 20. A small aliquot of the dilute isotope mixture was injected directly into the coronary artery while venous blood was simultaneously withdrawn from the coronary sinus catheter. For repeat measurements, the injectate volume was doubled each time to overcome increasing background activity. The EF was calculated by the formula (1)

(1) EF=[1-(^99mTc-tetrofosmin_CSx¹²⁵I-albumin_inj)]/

where the subscripts inj and CS are injectate and coronary sinus, respectively.

Three to four repeat measurements of EF were made in each of the 4 dogs. To validate our technique, EF measurements were also made in 3 additional dogs with ^99mTc-sestamibi, and the mean EF data obtained (68.3±4.7%) were similar to those previously reported by an independent laboratory.¹⁵

Protocol 2: Comparison of Myocardial Uptake of ^99mTc-Tetrofosmin With That of ²⁰¹Tl During Adenosine-Induced Vasodilatation in Dogs With Critical and Mild Coronary Stenoses
The experimental protocol is depicted in Fig 1. During the baseline period, before the mild or severe coronary stenoses were created, radioactive microspheres were administered to measure baseline flow as previously described. The reactive hyperemic response of the LAD was determined by snaring of the occluder for 10 seconds and then release of the snare to inscribe a reactive hyperemic response on the recorder. For dogs with a critical stenosis, the snare was adjusted to abolish the reactive hyperemic response to this transient LAD occlusion without reducing resting baseline flow. For dogs with a mild stenosis, a 50% reduction in the reactive hyperemic response was the end point. After the stenoses were set, a second injection of microspheres was administered. Then, an intravenous infusion of adenosine was begun at a rate of 250 µg · kg^-1 · min^-1. When LCx flow was maximal, 18.5 MBq (0.5 mCi) of ²⁰¹Tl and 296 MBq (8 mCi) of ^99mTc-tetrofosmin and microspheres were injected simultaneously. Five minutes later, before ²⁰¹Tl redistribution occurred, the dogs were killed. The hearts were then removed and sliced into four 1-cm rings from apex to base. The heart slices were imaged directly on the collimator of a gamma camera (model 420, TM Analytic) for maximal count time (0.75x10⁶ to 1.0x10⁶ counts) with ^99mTc window settings. The heart slices were left undisturbed on the collimator until the following day and then reimaged with ²⁰¹Tl window settings for a similar count density. The heart slice images were then quantified by regions of interest drawn on the LAD defect area of the anteroseptal wall and on the normal LCx-perfused posterior wall of the two midsection slices. The basal and apical slices were not used for image quantification because the basal slice is located above the coronary stenosis and rarely has a defect, whereas the apical slice has a negligible normal area. Defect magnitude was expressed as the ratio of the average counts in the LAD region divided by the average counts in the LCx region.

View larger version (12K): [in this window] [in a new window]   Figure 1. Experimental protocol. Tetro indicates 99mTc-tetrofosmin; mic, microsphere injection.

After imaging of the slices, each slice was divided into six segments, which were further subdivided into endocardial, midwall, and epicardial samples, resulting in a total of 72 myocardial samples for each dog. Gamma-well counting was performed on these samples to determine ²⁰¹Tl and ^99mTc-tetrofosmin activities and microsphere flows. The instrumentation and techniques used were comparable to those reported previously.¹³ The tissue counts were corrected for background, decay, and isotope spillover, and regional myocardial blood flow was calculated with specialized computer software (PCGERDA, Packard Instruments). Transmural activity and flow values were calculated as the average of the corresponding epicardial, midwall, and endocardial samples.

Data Analysis and Statistics
For each of the 16 individual dogs, raw data plots of ²⁰¹Tl and ^99mTc-tetrofosmin activities versus microsphere flow at the time of injection during adenosine stress were created with all 72 tissue segments from each dog. A plot of data pooled from all 6 critical-stenosis dogs (Fig 4) was created by normalizing the activity data from each individual dog to the activity of a segment in the same dog with a normal flow of 1.0 mL · min^-1 · g^-1.

View larger version (21K): [in this window] [in a new window]   Figure 4. Normalized 201Tl and 99mTc-tetrofosmin activities plotted as a function of microsphere flow from endocardial, midwall, and epicardial samples of critically stenotic group of dogs. Heavy solid and dashed lines are mathematically modeled curve fits with 95% CIs (see text).

Representative tissue segments from the LAD and LCx regions were then selected by definition of the LAD (stenotic) region as the 10% of transmural segments (3 transmural segments=9 tissue segments) with the lowest flow at the time of adenosine stress, whereas the LCx (normal) region was defined as the 10% of segments (an additional 9 tissue segments) with the highest adenosine flows.

All statistical computations were made with SYSTAT software. The results were expressed as mean±SEM. Differences between means within a group were assessed with repeated-measures ANOVA (hemodynamics) or a paired t test (²⁰¹Tl versus ^99mTc-tetrofosmin image count ratios), with values of P<.05 considered significant. Comparisons between the two groups were made with one-way ANOVA.

	Results

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Protocol 1: First-Pass EF of Tetrofosmin
The mean myocardial first-pass EF was 54.0±3.7% for ^99mTc-tetrofosmin. The 4 dogs that composed this group remained hemodynamically stable over the time course during which the EF measurements were made. The mean coefficient of variation for the multiple ^99mTc-tetrofosmin EF measurements made in each dog was 0.037±0.007.

Protocol 2: Comparison of the Myocardial Uptake of ^99mTc-Tetrofosmin and ²⁰¹Tl During Adenosine-Induced Vasodilatation
Hemodynamics
The mean hemodynamic parameters of heart rate, arterial pressure, and left atrial pressure are summarized in Table 1. Note that although there was a significant decrease in mean arterial pressure with adenosine in both groups of dogs (critical, 116±4 to 93±5; mild, 122±5 to 103±5; P<.01 for both), as was found in our previous studies¹³ using the 250 µg · kg^-1 · min^-1 adenosine dose rate, arterial pressure remained >90 mm Hg at the peak adenosine response at the time when the tracers were administered. There were no significant changes in heart rate or left atrial pressure over the experimental time course.

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

Figs 2 (critical-stenosis dogs) and 3 (mild-stenosis dogs) depict the ultrasonically measured flow in the LAD and LCx, respectively. In both figures, the solid bar represents mean baseline flow, the hatched bar represents mean flow after the LAD stenosis was set, and the open bar represents mean flow at the peak adenosine response when ²⁰¹Tl and ^99mTc-tetrofosmin were injected. As can be seen, in both groups of dogs, no change in resting flow was seen after the LAD stenosis was set. In the critical-stenosis group (Fig 2), adenosine infusion resulted in no increase in LAD flow but in a greater than threefold increase in LCx flow. In the mild-stenosis group (Fig 3), there was a significant (P<.01) increase in both LAD and LCx flows, but the magnitude of the LCx flow increase was significantly greater than that of the LAD.

View larger version (19K): [in this window] [in a new window]   Figure 2. Ultrasonically measured flow in LAD and LCx at baseline (Base), after coronary stenosis was set (Sten), and at peak adenosine (Aden) effect at time when 201Tl and 99mTc-tetrofosmin were injected into dogs with critical LAD stenoses. LAD flow remained constant during adenosine, but there was a fourfold increase in LCx flow.

View larger version (18K): [in this window] [in a new window]   Figure 3. Ultrasonically measured LAD and LCx flow in dogs with mild LAD stenoses. In these dogs, both LAD and LCx flow increased significantly during adenosine infusion; however, flow increase was greater in normal LCx. Abbreviations as in Fig 2.

Regional ^99mTc-Tetrofosmin and ²⁰¹Tl Activities Versus Microsphere Flow
The graph shown in Fig 4 from the group of dogs with a critical stenosis plots the normalized ²⁰¹Tl and ^99mTc-tetrofosmin activity values from the endocardial, midwall, and epicardial myocardial segments versus microsphere flow at the time when the tracers were injected during adenosine vasodilatation. The curves passing through each set of data points result from mathematical modeling of the experimental data according to the kinetic transport model of Gosselin and Stibitz.¹⁶ As shown, the myocardial uptake of both ²⁰¹Tl and ^99mTc-tetrofosmin reached a plateau as coronary flow increased. However, the more rapid and lower plateau for ^99mTc-tetrofosmin indicates a greater diffusion limitation at high flow rates for this tracer.

Mean absolute transmural flow in the LAD and LCx zones and the transmural LAD-to-LCx flow ratios from both groups of dogs are shown in Table 2. The transmural values were calculated as the weighted average of the endocardial, midwall, and epicardial segments from each region. Although there was a trend toward higher mean LCx transmural flow with adenosine in the mild- versus critical-stenosis groups of dogs, this difference did not reach statistical significance. Fig 5 compares the transmural LAD-to-LCx activity ratios for ²⁰¹Tl and ^99mTc-tetrofosmin with the microsphere flow ratio at the time when the tracers were administered during adenosine vasodilatation. The bars on the left are from the critical-stenosis group of dogs, whereas those on the right are from the mild-stenosis group. The LAD-to-LCx flow ratio fell from 0.96 with the stenosis in place to 0.22 during adenosine infusion (P<.001) in the critical-stenosis group. Similarly, the LAD-to-LCx flow ratio fell from 0.92 with the stenosis alone to 0.44 during adenosine infusion in the mild-stenosis group. Note that in both groups of dogs, both ²⁰¹Tl (critical, 0.37±0.04; mild, 0.58±0.04) and ^99mTc-tetrofosmin (critical, 0.67±0.05; mild, 0.81±0.04) significantly underestimated the degree of flow disparity (critical, 0.22±0.02; mild, 0.44±0.05; P<.01 versus ²⁰¹Tl and ^99mTc-tetrofosmin); however, the magnitude of underestimation was greater for ^99mTc-tetrofosmin (P<.01).

View this table: [in this window] [in a new window]   Table 2. Absolute Transmural Myocardial Blood Flow

View larger version (25K): [in this window] [in a new window]   Figure 5. Mean microsphere flow and 201Tl and 99mTc-tetrofosmin activities expressed as LAD-to-LCx ratio for both critical- and mild-stenosis groups. In both groups, 201Tl and 99mTc-tetrofosmin significantly underestimated flow, but degree of underestimation was greater for 99mTc-tetrofosmin.

Ex Vivo Imaging
Representative ²⁰¹Tl and ^99mTc-tetrofosmin images from dogs with either critical or mild LAD stenoses are shown in Fig 6. Qualitatively, defects on images were more pronounced with ²⁰¹Tl than with ^99mTc-tetrofosmin in all 16 dogs. The quantitative imaging results showing mean image LAD-to-LCx count ratios for ²⁰¹Tl and ^99mTc-tetrofosmin are summarized in Fig 7. In both groups of dogs, the magnitude of the image defects (lower count ratios) was significantly greater for ²⁰¹Tl (critical, 0.61±0.01; mild, 0.74±0.03) than for ^99mTc-tetrofosmin (critical, 0.69±0.02; mild, 0.83±0.02) (P<.05; P<.01).

View larger version (66K): [in this window] [in a new window]   Figure 6. Ex vivo images from representative dogs in critical- stenosis (top) and mild-stenosis (bottom) groups of dogs. Left images are 201Tl, and right images are 99mTc-tetrofosmin. Arrowheads denote locations of corresponding image defects. Numbers in parentheses below each image are results of image quantification.

View larger version (31K): [in this window] [in a new window]   Figure 7. Mean 201Tl and 99mTc-tetrofosmin (Tetro) activities determined by ex vivo imaging of heart slices in critical- and mild-stenosis groups of dogs. Activities were expressed as LAD-to-LCx count ratios from regions of interest drawn on images. In both groups of dogs, magnitude of 201Tl defect was significantly greater (ie, lower count ratio) than for 99mTc-tetrofosmin.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The results of this study show that (1) the first-pass myocardial EF for ^99mTc-tetrofosmin (54%) is significantly lower than the previously published EF values^{14 17 18} for ²⁰¹Tl (82% to 88%) and is slightly lower than the EF for ^99mTc-sestamibi (68%); (2) both ²⁰¹Tl and ^99mTc-tetrofosmin uptake reached a plateau with the adenosine-induced flow increase, but the ^99mTc-tetrofosmin plateau was lower than the ²⁰¹Tl plateau (Fig 4); and (3) in dogs with either critical or mild LAD stenoses, ²⁰¹Tl and ^99mTc-tetrofosmin uptake underestimated the magnitude of the flow disparity. The degree of underestimation was greater for ^99mTc-tetrofosmin. The observation that the flow heterogeneity between stenotic and normal myocardial beds produced by adenosine stress in the presence of mild or severe stenoses is better resolved with ²⁰¹Tl than with ^99mTc-tetrofosmin is most likely explained by the lower first-pass myocardial extraction for ^99mTc-tetrofosmin. The findings with ^99mTc-tetrofosmin in this study are similar to those reported previously for ^99mTc-sestamibi in the same canine model, in which the magnitude of adenosine-induced flow heterogeneity was underestimated by both ^99mTc-sestamibi and ²⁰¹Tl, but more so by ^99mTc-sestamibi.¹³

Previous Experimental Studies
The findings of the present study are also consistent with previously published reports of decreased myocardial uptake of cationic radiolabeled perfusion agents with increased coronary flow consequent to infusion of dipyridamole or adenosine.^{19 20 21 22} Sinusas et al² administered ^99mTc-tetrofosmin and radiolabeled microspheres during intravenous adenosine infusion to 6 dogs with complete occlusion of the LAD. ^99mTc-tetrofosmin reached a plateau at flows >2.0 mL · min^-1 · g^-1. Myocardial ^99mTc-tetrofosmin activity correlated linearly with microsphere flow at the time of injection up to 2.0 mL · min^-1 · g^-1. In the present study, ^99mTc-tetrofosmin was administered intravenously during vasodilator stress in the setting of critical or mild LAD stenoses and compared with uptake of ²⁰¹Tl, a monovalent cation with a high first-pass EF. As shown in Fig 4, myocardial ^99mTc-tetrofosmin uptake is almost flat at 1.5 times normal flow, whereas uptake of ²⁰¹Tl continues to show an increase relative to hyperemic flows over the entire range, although flows are also underestimated in the range shown up to 5 times normal flow. Furthermore, the in vitro well-counting data and the ex vivo imaging data from this study suggest that reduced defect contrast with ^99mTc-tetrofosmin should be observed with clinical imaging in patients, particularly in the setting of mild coronary stenoses, in which it is often necessary to resolve the difference between two hyperemic flow rates (eg, 2.0 times normal versus 4.0 times normal flow). Severe stenoses, however, should be well resolved with ^99mTc-tetrofosmin because, in this situation, tracer uptake in zones of hyperemia are being compared with uptake in the stenotic myocardial bed, in which flow does not increase or may actually decrease in the endocardial layers consequent to vasodilator-induced coronary steal.

Transport Kinetics of ^99mTc-Tetrofosmin
The findings of the present study are consistent with mathematical models of transport kinetics of any diffusible indicator. The curves shown in Fig 4 are characteristic of an extractable tracer in that the amount of tracer taken up is proportional to flow only at low flow rates and changes to a plateau at high flow rates when the extraction becomes limited by membrane transport. At high flows, less tracer is directly extracted during the capillary transit, and the tracer that diffuses back into the capillary channel is less likely to be reabsorbed before it reaches the venous bed. The lower the first-pass EF of a tracer, the less the tracer is extracted at these hyperemic flows, and vasodilator-induced flow increases will be underestimated.

The heavy solid and dashed lines, with 95% CIs, passing through the ²⁰¹Tl and ^99mTc-tetrofosmin values in Fig 4 are based on the solute transport model of Gosselin and Stibitz.¹⁶ In this model, the rate of tracer transport from blood to the extravascular space as the tracer passes through the capillary bed is given by Equation 2: (2) (dm/dt)=(nb/)(1-e^-ps/b)(C_a-m)

where m is tissue tracer concentration, n is number of open capillaries per unit volume, is intracellular/extracellular partition coefficient, b is blood flow per unit volume, ps is permeabilityxsurface area product, and C_a is arterial tracer concentration.

To apply this model to the measurements of ²⁰¹Tl or ^99mTc-tetrofosmin extraction, the meaning of the term "extraction" must be carefully considered. When an extractable tracer is delivered to a capillary bed, the amount extracted changes continuously with time. The capillary membrane is exposed to a variable concentration of tracer from the arterial input. As the tracer passes through the capillary bed, some is extracted, and some of the tracer that has been extracted is released back into the vascular compartment (ie, back-diffusion). The amount of tracer extracted depends on the net balance between cellular extraction and release and is never constant. An estimate of early extraction that fairly describes what is being measured can be determined. If an impulse arterial input function in Equation 2 is considered, then the amount of tracer extracted from the impulsive input is proportional to the factor (3) b(1-e^-ps/b)

For a more realistic estimate, an exponential arterial input function with a time constant that is short in comparison to the intrinsic intracellular clearance rate may be considered. In this case, the solution to Equation 2 becomes a multiple exponential with a rapid upslope to a peak level followed by a washout phase. The amplitude of the uptake/washout curve is still proportional to the same factor (Equation 3). If a measurement of myocardial activity is undertaken after the injected bolus has mostly cleared from the arterial blood but before there has been a substantial loss of initially extracted tracer from the myocardium, the amount of net extracted tracer can be expected to follow approximately the relationship predicted above.

Clinical Studies
Clinically, ^99mTc-tetrofosmin imaging with exercise stress has yielded good sensitivity and specificity for detection of coronary artery disease, and segmental perfusion abnormalities have shown good concordance with defects on ²⁰¹Tl imaging performed in the same patients.^{5 6 7 8 9 10 11} When images were compared, image quality was better for ^99mTc-tetrofosmin than for ²⁰¹Tl.^{6 10 11 23} However, some published studies^{10 11} had a substantial number of patients with previous infarction, which enhances sensitivity of noninvasive imaging for detection of coronary artery disease. Also, because many patients presenting with angina have at least one high-grade coronary stenosis that may be comparable physiologically to the "critical" stenoses experimentally produced in the groups of dogs in the present study, it is not surprising that ^99mTc-tetrofosmin imaging with exercise stress yields a high rate of detection of patients with coronary artery disease. Furthermore, with clinical imaging, greater redistribution and scatter with ²⁰¹Tl compared with ^99mTc-tetrofosmin would tend to lessen somewhat the advantage of ²⁰¹Tl over ^99mTc-tetrofosmin seen in our experimental canine model, in which defect contrast for ²⁰¹Tl on images of myocardial slices postmortem was superior to that of ^99mTc-tetrofosmin.

Conversely, the lower EF and the greater plateau in myocardial uptake with increases in flow for ^99mTc-tetrofosmin versus ²⁰¹Tl may, indeed, affect defect magnitude or size, as well as the detection rate of reversible ischemia. In a study by Matsunari et al,⁹ defect size on exercise ^99mTc-tetrofosmin images was smaller than the ²⁰¹Tl defect size as assessed by quantitative SPECT imaging in 20 patients with coronary artery disease. In these patients, 58 segments with initial ²⁰¹Tl defects had corresponding normal ^99mTc-tetrofosmin uptake. Tamaki et al⁶ reported better ²⁰¹Tl than ^99mTc-tetrofosmin defect magnitude, particularly in regions corresponding to exercise-induced ischemic ²⁰¹Tl defects. Nevertheless, both the ^99mTc-tetrofosmin and ²⁰¹Tl studies were highly sensitive for detecting coronary artery disease (100% and 94%, respectively).

Other clinical studies have reported a higher detection rate for reversible ischemia on exercise scintigraphy for ²⁰¹Tl versus ^99mTc-tetrofosmin. Nakajima et al⁵ reported a 60% detection rate of 75% stenoses for ^99mTc-tetrofosmin versus 72% for ²⁰¹Tl, with comparable specificities of 84%. In the phase III multicenter ^99mTc-tetrofosmin trial, there was a 13% greater detection of ischemia or ischemia with scar with ²⁰¹Tl than with ^99mTc-tetrofosmin.¹⁰ In another study by Matsunari et al,²⁴ it was reported that 40% of scan segments were discordant between ²⁰¹Tl and ^99mTc-tetrofosmin perfusion images when exercise-rest ^99mTc-tetrofosmin images were compared with exercise-redistribution-reinjection ²⁰¹Tl images. Of the 115 segments with reversible defects identified by ²⁰¹Tl imaging, 73 (63%) were identified as nonreversible on ^99mTc-tetrofosmin images. In contrast, of the 94 segments with nonreversible defects identified by ²⁰¹Tl imaging, only 11 (12%) were documented as reversible by ^99mTc-tetrofosmin. In addition, in that study, exercise defect severity was also less with ^99mTc-tetrofosmin.

All of the clinical studies referenced above involve exercise stress. At present, few quantitative, comparative studies of patients undergoing pharmacological stress imaging with ^99mTc-tetrofosmin have been reported. In one recent study, Cuocolo et al²⁵ reported that exercise-induced defects on ^99mTc-tetrofosmin imaging were more severe than on adenosine stress images when exercise and vasodilator images acquired in the same patients were compared. More recently, preliminary data from Raggi et al²⁶ suggest that more reversible or partially reversible perfusion defects were identified on dipyridamole ²⁰¹Tl SPECT images than on dipyridamole ^99mTc-tetrofosmin images (89 versus 55) when 340 interpretable scan segments were analyzed in 26 patients. This difference was seen in myocardial regions perfused by vessels with 50% to 70% stenoses on quantitative angiography. The initial postdipyridamole defect magnitude of these reversible defects was significantly greater on the ²⁰¹Tl SPECT images than on the corresponding ^99mTc-tetrofosmin images. In contrast, the detection rate for myocardial scar and the defect magnitude in nonreversible defects were comparable for the two imaging agents.

Conclusions
^99mTc-tetrofosmin uptake during adenosine-induced hyperemic flow underestimated the flow disparity between stenotic and normal perfusion beds in dogs with critical and mild stenoses. The degree of underestimation was greater than seen with ²⁰¹Tl uptake patterns in the same dogs. The clinical implication of these experimental observations for vasodilator SPECT imaging remains to be definitively determined, because such variables as greater redistribution, more scatter, and greater attenuation with ²⁰¹Tl could offset its advantage with respect to extraction kinetics with high-flow states. Few clinical studies are available that directly compare ²⁰¹Tl and ^99mTc-tetrofosmin uptake during vasodilator stress in the absence of prior infarction, although, as mentioned previously, some of the clinical imaging studies published to date show high sensitivity and specificity for stress imaging with ^99mTc-tetrofosmin for detection of coronary artery disease and identifying coronary stenoses. In some studies, the detection rate of reversible ischemia and defect magnitude on stress-induced perfusion abnormalities is greater for ²⁰¹Tl compared with ^99mTc-tetrofosmin for both exercise and vasodilator stress. Additional clinical research is needed that uses larger numbers of patients and quantitative SPECT imaging to properly assess the influence on clinical imaging studies of the experimental findings reported in these canine models of severe and mild coronary stenoses.

	Selected Abbreviations and Acronyms

 

EF = extraction fraction LAD = left anterior descending coronary artery LCx = left circumflex coronary artery SPECT = single-photon emission computed tomography 99mTc-tetrofosmin = technetium-99m-1,2-bis[bis(2- ethoxyethyl)phosphino]ethane

	Acknowledgments

 
This study was supported in part by a Grant-in-Aid from the American Heart Association, Virginia Affiliate, and a grant from Amersham International, Inc. We recognize the superb editorial assistance provided by Jerry Curtis in the preparation of this manuscript.

Received February 6, 1997; revision received April 25, 1997; accepted May 3, 1997.

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