Technetium-99m Teboroxime Regional Myocardial Washout in Subjects With and

Without Coronary Artery Disease Terrance Chua, MD, Hosen Kiat, MD, Guido Germane, PhD, Walter Palmas, MD,

Kent Takemoto, MD, John Friedman, MD, and Daniel S. Berman, MD

The aim of this study was to test the hypothesis that regional myocardial washout of technetium SSm teboroxime is slowed in the presence of coronary stenosis. Washout was assessed in 33 catheterized patients and in 13 with a low likeli- hood of coronary artery disease, using a triple de tector camera and dynamic si~e-photon emi* sion computed t-y, with serial l-minute acquisitions after iflection of 20 to 25 mCi of teboroxime at the third minute of adenoshm-irr duced hyperemia. Washout was measured as the percent change in counts between the first, 880 ond and third minutes after i~ection, as mea sured in 6 short-axis myocardiil regions of iti- est. Myocardial regions were classified as is- chemic (250% diameter stenosis and no prior myocardial infarct), infarcted, -I (no signili- cant coronary stenosis) or “low likelihood” (fVom the 13 patients with a low likelihood of coronary artery disease). Teboroxime washout was signs cantly (p <O.OOl) slowed in the ischemic myocar dium (12.7 f 6.3%) compared with the normal (16.5 rl: 6.7%), low-likelihood (17.6 f 6.1%) and irr farcted (17.6 f 4.4%) zones. There was regional vslliability in washout rates (% washout/min), with the anterior wall having the lowest (13.6 f 3.4%/ min) and ths inferior wall the highest (20.7 + 7.9%/ min) values. In regard to individual coronary ten+ tories, 21 of 41 ischemic, noninfarcted territories (51%) had abnormal washout compared with 3 of 43 -aI territories (7%) (p q 0.601). In conch+ sion, regional washout of teboroxhne is dete& ably slowed in ischemic, noninfarcted myocardi- urn. The clinical value of washout analysis in teboroxime singlephoton emission computed te mography warrants further investigation.

(Am J Cardiol1993;72:72*734)

From the Departments of Medicine (Division of Cardiology) and Imag- ing (Division of Nuclear Medicine), Cedars-Sinai Medical Center, Los Angeles, California; and the Department of Medicine, and the Division of Nuclear Medicine and Biophysics, Department of Radiological Sci- ences, UCLA School of Medicine, Los Angeles, California. This work was supported in part by a grant from Squibb Pharmaceuticals, Los An- geles, and a grant from Medco Research Inc., Los Angeles, California. Manuscript received November 25, 1992; revised manuscript received April 9, 1993, and accepted April 12.

Address for reprints: Hosen Kiat, MD, Department of Nuclear Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048.

T echnetium-99m (Tc-99m) teboroxime (Cardiotec, Squibb) is a myocardial perfusion compound with high first-pass extraction and rapid myocardial

clearance.‘~ Transport of teboroxime is diffusional in nature because of its neutral, lipophilic properties. As a result, the rate of washout of teboroxime from a specific myocardial region would be expected to be dependent on the blood flow to that region; this has been shown to be the case in animal studies.5 We hypothesized that the presence of significant, flow-limiting coronary stenoses would result in differences in the regional washout rates of Tc-99m teboroxime in patients with coronary artery disease (CAD), and that these differences could be de- tected with dynamic single-photon emission computer- ized tomography (SPECT) using a rapid acquisition pro- tocol and adenosine-induced hyperemia. The aim of this study was to measure myocardial teboroxime washout rates using dynamic SPECT, and to compare differential rates in normal, ischemic and infarcted myocardia.

METHODS Study e The study cohort comprised 46 pa-

tients: 33 with coronary angiography within 3 months of teboroxime SPECT, and 13 with a low likelihood of CAD based on age, gender, risk factors, symptom clas- sification and electrocardiogram, as determined by the system of Diamond et alc8 using the computer program CADENZA. The pretest likelihood of CAD in these pa- tients was 7.9 f 3.0% (range 3.3 to 13.9%). All patients were referred to our laboratory for myocardial perfusion imaging using pharmacologic stress between January and December 1991. Twenty-two patients had history of myocardial infarction. Patients with asthma, uncontrolled cardiac failure, second- or third-degree heart block, hy- potension (190 mm Hg systolic), or prior angioplasty or bypass surgery were excluded from the study. All pa- tients were required to abstain from xanthine derivatives and oral dipyridamole for 248 hours, and caffeine for 24 hours before examination, and signed a consent form ap- proved by the institutional review board of the medical center.

Clinical study pmtocd: The clinical protocol used is summarized in Figure 1. Two separate intravenous lines were inserted. The patient was positioned under the tri- ple detector gamma camera (Prism 3000, Picker Jnter- national) before commencement of pharmacologic stress. Adenosine (Adenoscan, Medco) was infused at 0.14 m&$nin for 4 minutes. Teboroxime (20 to 25 mCi) was injected at the third minute of adenosine infusion. Approximately 15 minutes later, a second dose of tebo- roxime (20 to 25 mCi) constituting the resting dose was

728 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72 SEPTEMBER 15, 1993

injected. Sequential l-minute SPECT files (referred to as frames, each comprising a set of planar views over 360”) were obtained over 25 minutes using a low-energy high- resolution collimator, with the detector rotating continu- ously in alternating directions.

Image wngr For visual interpretation, stress raw (planar) projection data images from the second- and third-minute frames after injection of teboroxime were summed before reconstruction. Raw projection data at rest from the second- to fifth-minute frame after injection at rest were also summed. Based on previously reported results of phantom experiments and patient studies,9J0 all clinical studies were then prefiltered with a low-pass filter (Butterworth, order 5, cutoff 0.215) be- fore ramp-filtered backprojection; this was performed because the relatively low counts collected in l-minute SPECT acquisitions result in images that without smooth- ing would be too noisy to enable consistent region-of- interest placement. Image reconstruction used the 180” data from the 45” left posterior oblique to 45” right an- terior oblique projection without attenuation correction.

To determine regional teboroxime washout rates, raw projection data from each l-minute frame obtained after stress teboroxime injection were reconstructed to pro- duce sequential l-minute SPECT images in standard short-axis, and vertical and horizontal long-axis views. Exact spatial alignment of the sequential images was en- sured by reconstructing and reorienting all frames si- multaneously in batch mode, so that identical values for slice selection and ventricle long-axis tilt would apply to all frames for the same patient. Using a modification of existing software (PIXIETM) on the PRISM 3000 pro- cessing station, 6 predeIined regions of interest of equal size were generated and positioned over the myocardi- urn in the consecutive short-axis images by 1 operator to measure the regional variation of activity over time. The washout rate of teboroxime (%/min) was calculat- ed for each region based on the average percent change in counts/min over the 3-minute time interval, beginning 1 minute after injection of teboroxime: (1) WOl = (counts in minute 1 - counts in minute 2)/counts in minute 1 X 100; (2) W02 = (counts in minute 2 - counts in minute 3)/counts in minute 2 X 100; (3) washout rate = (WOl + WO2)/2.

REST SPECT FILE

Minutes after teboroxime injection

FIWRE 1. Study protocol used in evaluation of re@nal myowdiil washout oftedmdu~ (w9anl) teborox- ime. Each iminute frame of si ngk#oton emis8iom comput- ed tomogpaphic (SPECT) acqulsitiom is represented by box.

Note that minutes 1, 2 and 3 are defined as the I- minute frames that begin 1, 2 and 3 minutes, respective- ly, after injection of teboroxime (Figure 1). An earlier frame, beginning immediately after injection of teborox- ime, was not used, because it contained blood pool activity. Later frames were also not used, because adeno- sine-induced hyperemia subsides within 3 minutes after termination of infusion,’ ’ and blood 0ow and washout rates would be expected to return to baseline by that time. In view of the limited number of data points avail- able for washout calculation, the averaging method was used in preference to linear fitting.

Washout data at rest (calculated as in equations 1 to 3) were available in 15 patients (8 with prior infarct). In this subgroup of patients, the ratio of stress to rest washout rate was also calculated.

Definitions of myocafdial regions and abnormal washout: Each of 6 short-axis myocardial regions (Fig- ure 2) were assigned to 1 of the 3 major coronary arter- ies. Anterior and anteroseptal regions were assigned to the left anterior descending artery, high lateral and in- ferolateral regions to the left circumflex artery, and in- ferior and inferoseptal regions to the right coronary ar- tery. Each region was also classified as follows: (1) Re- gions supplied by coronary arteries (~50% stenosis) were defined as “normal.” (2) Regions supplied by cor- onary arteries with stenosis 250% were defined as “in- farct” if there was electrocardiographic evidence of myocardial infarction, a nonreversible defect (present on the stress and rest perfusion images) in that specific re- gion, and absent wall motion in the vascular territory of the supplying artery on contrast left ventriculography at angiography. (3) Regions supplied by coronary arteries with stenosis 250% were defined as “ischemic” if they did not fulEl1 the criteria for infarct. (4) All regions from patients with a low likelihood of CAD were deEned as “low likelihood.” For the purpose of this study, washout in a myocardial region was deEned as normal if it was within the range of washout values for the same region in low-likelihood patients and as abnormal if it was less than the lowest value in this range.

Visual interpretation: Stress and rest SPECT im- ages were interpreted side by side by 2 observers who were unaware of the clinical data, as well as the results

REGIONS OF INTEREST

ANT:R’oR

ANTEROSEPTAL HlGH LATERAL

INFEROSEPTAL +

INFEROLATERAL

INFEklOR

SUMMED SHORT AXIS SLICES

FIGURE 2. Myocardial regions of interest used in measure ment of washout.

REGIONAL TEBOROXIME WASHOUT 729

'p401

OiGR SUBGROUPS

ISCHEYIC INFARCT NORMAL LOW REGIONS REGIONS REGIONS LIKELIHOOD

FlGURE 3. Mean stress washout rates from ischemic, irr Perot, nonal and low-likelihood mgions.

of coronary angiography. The left ventricular myocardi- urn was scored using a 20-segment model described pre- viously,*2~13 with scores ranging from 0 (normal) to 4 (absent tracer uptake).

Coronary angiography: Cardiac catheterization was performed by the standard Judkins technique. Coronary angiograms were interpreted by 2 experienced observers who were unaware of the results of the teboroxime study. Significant CAD was defined as 250% stenosis in a major epicardial artery.

Statistical analysis: Comparisons of proportions were obtained using the &i-square statistics. All contin- uous measures were summarized as mean value + SD and were compared using Student’s t test. The alpha level of significance was set at 0.05. To determine the differences in regional washout rate, analysis of variance for multiple measures was performed using the New- man-Keuls procedure. All computations were obtained with the True Epistat statistical software (Richardson, Texas). For each patient subset analyzed, sensitivity was defined as the number of regions with 250% stenosis showing abnormal washout or visual perfusion defects, divided by the total number of regions with 250% steno- sis, whereas specificity was defined as the number of re- gions with normal coronary arteries (~50% stenosis) having normal washout or normal perfusion by visual

analysis, divided by the total number of regions with normal coronary arteries.

RESULTS The mean washout rate of teboroxime from ischemic

regions was significantly slower than that from normal or low-likelihood regions (Figure 3). Teboroxime wash- out was also considerably slower in ischemic than in in- farct regions. There was no significant difference in washout rates between normal, low-likelihood and in- farct regions. In the subgroup of 15 patients with both stress and rest washout rate measurements, the mean stress-rest ratios in normal regions (n = 22) and in re- gions with ~50% stenosis and no prior infarct (n = 8) were 1.98 + 2.32 and 1.94 + 2.36, respectively (p = NS). In regions with 250% stenosis and no infarct (n = 36), and those with prior infarct (n = 24), the ratios were 0.88 f 1.52 and 0.84 + 0.88, respectively (p = NS). Although there appeared to be a trend for the washout ratios of the latter 2 groups to be lower than those of the first 2 groups, the differences were not significant in these small study subgroups.

Figure 4 shows the mean rates of teboroxime wash- out as a function of anatomic location for ischemic and low-likelihood myocardial regions. For both low-likeli- hood and ischemic myocardial regions, the rate of te- boroxime washout had regional variability. For each an- atomic location, the mean teboroxime washout rates from ischemic regions appeared to be lower than those from low-likelihood regions; this difference was signifi- cant for anterior, anteroseptal and high lateral regions.

Detection of disease by washout analysis: Of 56 stenotic (250% diameter stenosis) arteries, 21 (38%) were associated with abnormal washout in 21 region supplied by the artery. In contrast, only 3 of 43 territo- ries (7%) supplied by normal vessels had regions with abnormal washout (p <O.OOl). Of 41 vascular territories with no prior myocardial infarct and supplied by stenot- ic vessels, 21 (51%) included 21 region with abnormally slow washout. In 33 catheterized patients, the sensitivi- ty and specitkity for detection of stenotic arteries (250%)

30 - m LOW LIKELIHOOD

ii? q ISCHEMIC

Li p q 0.03 z s p = 0.0 I

$ 20- !? B e F d + 10 - 2 5

z

O- ANTERIOR HIGH INFERO- INFERIOR INFERO- ANTERO-

LATERAL LATERAL SEPTAL SEPTAL

730 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72 SEPTEMBER 15,1993

FlGuRE4.Mean!stmsllwashoutratesby aMtomii location fram low4ikelihood and ischsmic regions. In low-likelihood patien@ !?igniRcant (p cO.01) overall variability in m@onal washout rates was pmsent,withantdorandhi@lateralre gkns having dowest washout, and infbrb or wall the hi@est. Similar patbm in dii femncesforregkmalwashoutrateswas ohsewed in ischemk #oup. MM tube roxime washout rates fram ischemic re gions were lower thm fnrm low4ik& hoodmgkmsinantdor,antemseptal andhighlateral~*p=NSversus correrponding ischemic #oups.

by blinded visual evaluation of the perfusion SPECT im- ages were 71% (40 of 56) and 86% (37 of 43), respec- tively. Seven arteries were associated with abnormal washout, but were normal by visual assessment (no per- fusion defect); of these, 5 had significant coronary steno- sis (250%). Thus, the combination of washout and per- fusion assessment (abnormality assumed if either one is abnormal) resulted in a sensitivity of 80% (45 of 56) and a specificity of 81% (35 of 43) compared with 71 and 86%, respectively, for visual assessment alone (p = NS for both sensitivity and specificity comparisons). Two case examples with abnormal regional washout, 1 with and the other without matching perfusion defect, are shown in Figures 5 and 6, respectively.

DISCUSSION This study showed that the regional washout of te-

boroxime is detectably slowed in ischemic, noninfarcted myocardium after adenosine-induced hyperemia. Using a triple detector camera and sequential l-minute SPECT acquisitions, we assessed the rate of change of counts in 6 myocardial regions over the 3-minute interval begin- ning immediately after termination of adenosine infusion (i.e., 1 minute after injection of teboroxime). Washout rate was quantified for each region of interest based on the average percent change over the 3-minute time in- terval beginning 1 minute after injection of teboroxime. We measured washout after adenosine infusion, rather than at rest, because differences in washout rates would be expected to increase at maximal coronary hyperemia. A 4-minute (rather than 6-minute) infusion of adenosine was used mainly because it resulted in better image quality, as determined in our initial work with teborox- ime,‘O which documented very rapid reduction in myo- cardial count rates when the adenosine infusion was continued for the “standard” 3 minutes after injection.

It should be noted that maximal hyperemia is achieved within 2 minutes of beginning intravenous adenosine,” and that patient discomfort and motion due to the side effects of adenosine may increase with longer infusion duration. We did not assess washout at >3 minutes from termination of adenosine infusion, because coronary flow returns to baseline within 2 to 3 minutes of stop- ping the drug infusion. t 1 Data from the first minute after injection of teboroxime were also not analyzed owing to the frequent presence of blood pool activity. Although most teboroxime is cleared after the tirst minute, and 90% is cleared from the blood within 3 minutes of in- jection,’ t to minimize spillover from residual blood pool activity, all myocardial regions of interest were stopped short of the endocardial left ventricular surface.t4

In myocardial regions supplied by coronary arteries with significant stenoses (250%), but without prior myo- cardial infarction, measured rates of teboroxime washout after adenosine-induced hyperemia were significantly lower than those in corresponding regions supplied by normal arteries and in regions in patients without an- giography but with a low likelihood of CAD.

The relation between blood flow and teboroxime clearance is consistent with the neutral, lipophilic prop- erties of teboroxime, and the diffusional nature of its up- take and transp~rt.‘-~J~-‘~ Therefore, teboroxime myo- cardial clearance should increase as blood flow increases and would be relatively reduced in regions of low blood flow due to limiting stenoses. The difference in tracer myocardial clearance between the hypoperfused regions (supplied by stenotic vessels) and normally perfused myocardium is accentuated by adenosine-induced hy- peremia, as reflected from the present results that re- vealed slow washout in the noninfarcted regions sup- plied by stenotic arteries. In addition, in the subgroup of patients with both stress and rest washout data, stress

STRESS TEBO

REST TEBO

FlWRE 5. Case example of abnormal washout. Stress (top) and rest (&Mom] teboroxhne (TEBO) stud&s fram a patient with 3-vessel disease, showing 3 shorhxis (/ei? to HgM, apex to base) and 1 vertical long-axis (fm ti#t) view. In addRion to perR~sioa defects in anterior and infe#ulateral walls, there is transient hchemic dilatatktn of the left vehicle. Washout rates in anterior and inferabteral walls were abnormal (2 and S%/min, respectively) compared with those in Ming bw4ikelihood rwgions.

FlWRE5.Caseexanpleof&nomne I washout. Stress and ti teboroxime (TEBO) studii fmm p&ii with disease of left ~and~~in%art~ealmageformatisidentiealtothatin~re5.Arevsrdble~canbe~in the infeator wall, but the anterior wall was scomd as normal by visual a ssessment. However, washoet in the anterior wall was also abnamal (9%/min).

REGIONAL TEBOROXIME WASHOUT 731

washout was almost twice as great as rest washout in normal regions (mean stress-rest washout ratio 1.98), whereas this was not true in regions with >50% steno- sis (ratio 0.84). In the relatively small cohort studied, however, these tindings were not statistically significant. A larger population may be warranted to further evalu- ate the clinical potential of stress-rest washout ratios in detection of hypoperfused myocardium.

The tindings of this clinical study are in agreement with previous work in animals by Stewart et aL5 show- ing that the rate of myocardial washout of teboroxime is intluenced by regional blood flow; using dynamic planar imaging, adenosine stress and complete coronary occlu- sion in a dog model, that group showed that the pres- ence of a critical coronary stenosis results in a significant reduction in washout rates compared with those in nor- mal perfusion zones. In other studies of animals*8 and humans19 using planar imaging, this effect of reduced blood flow on teboroxime clearance has been implied by the observation of “redistribution” of teboroxime. Re- versibility of initial perfusion defects after 1 injection of tracer would then be explained as the result of differen- tial washout, with slower clearance in regions of reduced flow (Figure 7). However, the evaluation of regional teboroxime washout rates using dynamic SPECT, and the demonstration of slow washout in ischemic myo- cardium were not previously reported in humans.

ma#pkrinfarctonwashoutrate:Thewashout rate of teboroxime was not slowed in the presence of a significant stenosis if the region supplied by the stenosed artery was previously infarcted. Washout rates from in- farcted regions were significantly higher than those from ischemic, noninfarcted regions, and were not different than those from normal and low-likelihood regions. There are several possible explanations for this tinding. Uptake of teboroxime needs viable tissue, so the activ- ity measured in previously infarcted regions may repre- sent teboroxime passing through the interstitium, or pho- tons scattered from the adjacent tissue, rather than teboroxime uptake by myocardial cells. Therefore, the relatively high rate of washout measured may reflect a rapid passage of nonextracted teboroxime through the

interstitium, or the change in scatter from normal adja- cent myocardium with time, rather than the true myo- cardial washout rate. Further work in an animal model appears to be indicated to explore the kinetics of tebo- roxime clearance in infarcted tissue to further evaluate the potential of washout analysis in differentiating in- farcted from ischemic myocardium.

Rc@aml variabilii of washout rate In this study, washout rates were shown to have regional variability. As we previously stated, patients with a low likelihood of CAD were used as a surrogate for a normal patient population, because of the small number of patients with normal coronary arteries on angiography. In these pa- tients, there was a significant (p ~0.01) overall difference in regional washout, with the anterior and high lateral regions having the slowest washout, and the inferior wall the highest. In patients with CAD, a similar pattern was also noted in the ischemic, noninfarct regions for corresponding anatomic locations. A possible explana- tion for this regional variation in washout rates is the ef- fect of hepatic teboroxime uptake on the measured ac- tivity in the inferior myocardial wall. Liver uptake of teboroxime is avid, peaking 6 minutes after injection of teboroxime, and may interfere with visual assessment of the inferior wa11.2s23 A paradoxical reduction in counts in the inferior wall can then occur when hepatic uptake is particularly intense, because the filtered backprojec- tion reconstruction process causes count cancellation in a band immediately outside the liver boundary.24 Be- cause hepatic activity increases with time in the period under study, the degree of reduction of counts in the ad- jacent inferior myocardial wall would also increase with time. This would result in an apparently faster washout from the inferior than from the anterior wall, which is at a greater distance from the liver. Hepatic activity would also be expected to increase the variability of measured washout rates from the inferior wall, because the intensity of liver uptake varies among patients. This latter hypothesis is consistent with the results of the low- likelihood patient studies, where the standard deviation of washout rates from the inferior and inferolateral wall was greater than that from the anterior and high lateral

STRESS TEBO

2-3 MIN

FlGURE 7. Case example of effect of washout on defect sevetity. This example shows effect of dii ml tiil washout rates on teboroxims (TEBO) defect seve6ty over time. Shorhxis images reconstructed by summing S to 3mi inute (top) and 2- to &ninute(boitom)stressdatadata~ in this patient with disease of lefl anterior desoendingawd~coronayalter iss.Pehsiandefectsin wteroseptal ad inferior walls, prominent in 2- to hinute ie am barely debchbleinthe2- to84ninateimagesprobablyduetoslowwashoutinankmweptd (3%/min) and inferior (3%/min) walls.

732 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72 SEPTEMBER 15,1993

wall. Increased attenuation of gamma rays in the inferi- or wall region may also result in greater washout vari- ability due to lower count statistics, but this cannot ex- plain the faster rate of washout, because the degree of attenuation for a given region does not change with time. Finally, there may be physiologic differences in the clearance of teboroxime from different anatomic regions of the heart, although we know of no mechanisms that would account for this. Although blood flow is not uni- form throughout the heart and varies from the endocar- dial to epicardial surface, there are no major differences between the anterior and inferior wall that would ac- count for different tracer washout rates. Irrespective of the mechanism, regional variability in measured washout rates should be considered if normal values for teborox- ime washout are to be developed.

AldpiSOfW4lShOUtrate*thOdOtOCtiOllOfCO~

nary artery disease: Although the main purpose of this study was to compare the rate of teboroxime washout in ischemic, normal and infarcted myocardial zones, we have also assessed the frequency of abnormal washout in vascular territories supplied by normal and stenotic vessels, as an indicator of its potential value in the de- tection of CAD. We found that abnormal washout was present in 51% of territories with no prior myocardial infarct supplied by stenotic arteries. In contrast, only 7% of normal territories had abnormal washout (p <O.OOl). Thus, washout measured by our technique has a 51% sensitivity for detection of diseased vessels supplying myocardium without prior infarct, with a specificity of 93%. These values are comparable to the results report- ed by Stewart et al5 using dynamic planar imaging in a dog model. However, the present results should be con- sidered to be preliminary because refinements in the methods for measuring washout (e.g., the use of washout polar maps, and the implementation of a correction al- gorithm for liver-induced artifacts), as well as the de- velopment of normal limits based on a large number of normal patients, are likely to improve the technique’s ac- curacy. In ~lanar,*~*“~ as well as SPECT,27 thallium-201 myocardial perfusion studies, analysis of washout (al- though over a much longer time frame) has been shown to improve the detection of CAD.

POtdid~rdeafW&3hOUttOperfu-

sion defect analysis: We also assessed the potential value of washout as an adjunct to visual assessment of perfusion. Abnormal washout was detected in several myocardial regions supplied by diseased vessels that were visually interpreted to have a normal perfusion pat- tern. There was a trend for washout analysis to increase the sensitivity for detection of abnormal vessels (from 71 to 80%); however, specificity, appeared to decrease (86 to 81%), although by a lesser degree. It should be stressed that the study cohort was small, and these dif- ferences are not statistically significant. Assessment of the potential clinical value of teboroxime washout will need a prospective study with a larger number of pa- tients, in addition to the optimization of measurement techniques, and the development of normal limits for teboroxime washout. Perhaps most importantly, analysis of the washout rate of teboroxime within a perfusion de-

fect may provide a method for differentiating viable from nonviable hypoperfused myocardium from a single injection. Of note, washout analysis following rest injec- tion is potentially also capable of such differentiation.

Study limitations In this study, washout was mea- sured in 6 short-axis regions of interest. A more sophis- ticated approach, using polar maps, would avoid exclu- sion of the apex and the potential for failure to detect small areas with abnormal washout due to the large re- gions of interest used. Furthermore, patients with a low (but not a very low) likelihood of CAD were used to develop normal limits. Due to the absence of treadmill electrocardiographic results in our study group, the like- lihood of CAD was 33 to 13.9% in patients rather than the ~5% that was previously considered to be low likeli- hood. Thus, some of these patients may well have had CAD. If a truly low likelihood population had been used, the washout normal limits may have been higher, providing a better threshold for separating the normal and abnormal washout values.

The washout as calculated in this study is affected by the transient change in coronary flow (because it is calculated after termination of adenosine infusion). If adenosine infusion had been continued throughout the time when washout rate was calculated, the difference between washout rate in normally perfused myocardium and in regions supplied by stenotic vessels would have likely been larger. Finally, the issue of the relative ad- vantages and disadvantages between technetium-te- boroxime and the other currently approved myocardial perfusion agents was not addressed.28-‘0

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