and dobutamine. Previous studies show that the diagnosticaccuracyof thalliumimagingwith each of these three pharmacologic agents is equivalent to that of exercise thallium

imaging (7—12). The mechanism of dipyridamole-induced

coronaiy vasodilation is an increased level of endogenousadenosine due to a decreased cellular reuptake mechanism(10,13). Compared to dipyridamole, adenosine has a morerapidonset of action and a shorter half-life (7,10). Dobutamine is a p1-specific agonist which causes increases inheart rate and contractility. Dobutamine is useful in patients who have asthma, severe obstructive pulmonary dis.ease, high-grade atrioventricular block, arterial hypotension or those receiving methyixanthine derivatives ordipyridamole (9,14). The three pharmacologic agents andexercise have also been used with the newer technetiumlabeled imaging agents and two-dimensional echocardiography.

The thalliumkinetics with pharmacologicstress testingmay be different from those with exercise (15—19).Thepurpose of this investigation was therefore to examine themyocardial and extracardiac thallium uptake and clearanceusing standard doses of intravenous dipyridamole, adenosine and dobutamine and compare the results to maximal

exercise in healthy subjects.

MATERIALSAND METhODS

Study SubjectsThe study subjects consisted of 15 healthy male volunteers

aged 23—30yr. These subjects were nonsmokers and took nocardiac medicationswith no history of cardiovasculardisease orother systemic illness. All had normal physical examinations,electrocardiograms and chest x-rays. The protocol was approvedby theinstitutionalreviewboardof theUniversityHospitalandeach subjectsigned a writtenconsent formpriorto the study. Theanticipatedwhole-body and renaldosimetry for the four thalliumtests were 1.2 rem and 8 rem, respectively.

Study ProtocolAll 15volunteersunderwent @°‘Tlmyocardialperfusionscm

tigraphyfourtimes; treadmillexercise testing, adenosine infusion,dipyridamole infusion and dobutamine infusion. The sequence ofthe tests was variable.All subjects fastedovernightpriorto stress

Thereare currentlyfourcommontypesofstressusedwiththailium-201imaginginthediagnosisofcoronaryarterydiseaseandriskassessment.The objectiveofthisstudywastoexaminethethalliumbiokineticsduringexercise,adenosine,dipyndamoleand dobutamine stress tesbng in 15 healthy volunteers. Mathods: Eachsubjectunderwentplanar @°@Tlimagingduringmaximaltreadmillexercisetesting,adenosineinfusion(140j@g/kg/mmfor6 mm),dipyndamoleinfusion(142 @g/kg/minfor4 mm)and dobutamine infusion (40 @@g/kg/min).Results: Absolutemyocardialthalliumactivttywasgreaterafterpharmacologictestingthanexercise,(p < 0.001 each).Thus,the activitywas 505counts/pixelwithadenosine,491 counts/pixelwithdipyndamole,517 counts/pixelwfthdobutamineand409 counts/pixelwithexerase.Themyocardialthalliumdearancewaslowerwfthpharmacologictesting than exercise;9.7%/hr with adenosine,9.9%/hr with dipyridamole,11.3%/hr with dobutamineand13%/hrwithexercise(p < 0.01each).Thethalliumuptakeandclearancein the lungandliverwerealsogreaterwithpharmacologic stress testing than exercise (p < 0.05). ConclusIons:Thus, thalliumblokinelicsare differentdunngpharmacologicstress testing with adenosine, dipyndamole and dobutaminethan during exercise.Diagnosticcriteriafor quantitativeanalysisof myocardialperfusionimagingmustthereforebe specfficforthe typeof stressused.

Key Words: adenosine;dipyrida.mole;dobutamine;exercise;thallium-201

J NucIMed1994;35:535-MI

xercise 20l@ imaging has been widely used in thediagnosis of coronary artery disease and risk assessment

(1—4).Inpatientswithexerciselimitations,pharmacologicstress testing has been accepted as an alternative methodto exercise testing (5—8).There are three pharmacologicagents that are currently used; dipyndamole, adenosine

ReceivedApr.23,1993;revisionacceptedAug.9, 1993.Forcorrespondenceor reprintsconta@tJaekyeongHeo,MD,PhMadeIPhIa

Heat Institute, Presbyterian Medical Center, 51 N. 39th St, PhiI@eIphia, PA19104.

Compansonof 20111Imaging Bioldneticsâ€Lee et al. 535

Biokinetics of Thallium—201in Normal Subjects:Comparison Between Adenosine , Dipyridamole,Dobutamine and ExerciseJaetae Lee, Shung C. Chae, Kyubo Lee, Jaekyeong Heo and Abdulmassih S. Iskandrian

Departments ofNuclear Medicine and Cardiology, Kyungjxxk National University School ofMedicine, Taegu, Korea; andthe PhiladelphiaHeart Institute, PresbyterianMedical Center, Philadelphia,Pennsylvania

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testing. The mean time intervalbetween two consecutive studieswas 15 days (range7—32days).

Stress Thallium Imaging ProtocolsThe heartrate, blood pressure and a 12-leadelectrocardiogram

were continuously monitored throughoutthe procedure. A doseof 2 mCi(74MBq)of 201'flwas injectedduringeach test. The doseof the thalliumwas precisely determined with a dose calibrator(Capintec CRC-12, Ramsey, NJ) by measuring the radioactivity inthe syringe before and after administration.

Exercise Thallium ImagingThe subjects performed symptom-limited maximal treadmill

exercise testingusing the Bruce protocol. All subjects achieved atleast 85% of the maximum predicted heart rate and the test@wasstopped because of exhaustion. None had angina or ST segmentdepression duringthe test. At peak exercise, @°‘Tlwas injectedand the subjects continued to exercise for one additionalminute.Imaging was begun within 10 mm of the termination of the exercisc.

Adenosine Thallium ImagingAdenosine (adenosine powder, Sigma, St. Louis, MO) was

dissolved in 0.9% NaCl and preparedfor intravenoususe by thepharmacyof the UniversityHospitalin a concentrationof 3 mg/ml. Adenosine was administeredintravenouslyusing an infusionpumpata rateof 140 @g/kg/minfor6 mm.At theendof thethirdminute,2OFflwas injectedandimagingwas begunwithin10mmafter thalliuminjection.

Dipyridamole Thallium ImagingDipyridamole was given intravenously at a rate of 142 @g/kg/

mmfor4 mm.Threeminutesafterthe infusionwas completed,201T1was injected intravenously and imaging was begun within 10mm after thalliuminjection. Supplementalexercise was not usedin this protocol.

Dobutamine Thallium ImagingDobutamine was infused at an initial rate of 5 @g/kg/minfor 3

mm. The infusion was increased at 3-mm intervals until a maximalinfusion of 40 @gfkg/minwas reached. Thallium-201 was injected1 mm after the start of the maximal tolerable dose and infusionwas continued for two additional minutes. Imaging was begunwithin 10 mm of thalliuminjection.

Planar Thallium ImagingThallium-201myocardialperfusion imagingwas performedin

theanterior,45°leftanteriorobliqueand75°leftanteriorobliqueviews. The images were recorded for 8 mm in each view using asingle-crystal gamma camera equipped with a parallel-hole collimator and interfacedwith a computer system (Microdelta, Sicmens, HoffmanEstates, IL). A 20%energywindow was centeredat 68—80keV and a 10%window on the 167 keV peaks of 201'fl.All images were stored in a computer disk in a 128 x 128matrix.Delayed images were obtained in a similar fashion, 3—4hr later.

Quantitatlon of Thallium Uptake and ClearanceRegionsof interest(ROts)wereassignedoverthemyocardium,

the lung and the liver in both initial and delayed images. Sixmyocardial regions were examined; anterior and inferior segmentsin the anterior projection, septum and posterolateral segments inthe 45°LAO projectionandanteriorandinferoposteriorsegmentsin the 75°LAO projection. The mean counts per pixel from a ROlin these areas was determined (Fig. 1).The thallium clearance was

0

FiGURE 1. ROlassignmentin the anterior projection (lung,antenorwall, infenorwall andliver).

measured as follows: (initialcounts —delayed counts)/the initialcounts. This was then divided by the time between the initial anddelayedimagingtoyieldaclearancerateperhour.Theexacttimebetween the initial and delayed images was recorded in eachsubject.

Statistical AnalysIsData were expressed as mean ±standarddeviation when ap

propriate, and were compared using analysis of variance, Student's t-test and chi-squareanalysis using the SPSSIPCstatisticalsoftware program (SPSS Inc., Chicago, IL). A p value of <0.05

was considered statistically significant.

RESULTS

Hemodynamic ResponsesThe exercise durationin the 15healthy subjectswas 12.9

±1.7 mm and the workload was 12.1 ±1.3 METS (Table1). The baseline measurements of heart rate, blood pressure and double product were comparable with the fourinterventions. Maximum heart rate was higher with exercisc than with pharmacologic testing. Similarly, the peakheart rate was higher with dobutamme than with adenosmeanddipyridamole.Therewas no differencein the heartrateresponse between adenosme and dipyridamole. The systolic blood pressure increased duringexercise and dobutamine infusion, but did not significantly change duringadenosine or dipyridamole infusion. The double product

was significantly higher during exercise than dobutamine.

Side Effects During PharmaCOlOgICStress TestingThere were no serious side effects. No subject required

a specific antidote for reversal of side effects duringany ofthe pharmacologic stress tests. Premature termination ofthe dobutamine before achieving the maximum dose occurred in one subject. The infusion was terminated at a rate

of 30 /hg/kgbecause of ventricular prematurebeats. Thisarrhythmiasubsided without treatmentwithin 3 mm afterthe infusion was discontinued. Common side effects arelisted in Table 2. Most patients graded the side effects asmild and transient. First degree atriovent.ricularblock appeared in one subject during adenosine infusion. More

subjects preferredadenosine than dipyridamoleor dobutamine (60% versus 27% versus 13%, p < 0.05). Moresubjects reported that dobutamine was the most intolerableagent, followed by adenosine and dipyridamole (67%versus 20%versus 13%,p < 0.05).

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ExerciseMenosineD@yridamoleDobutammneHeart

rate(bpm)Baseline64±763±864±1162±8Peak186±12*t79±1982±1192±29*p-value

<0.001<0.001<0.001<0.001Systolicbloodpressure(mmHg)Baseline

109±11112±7115±10110±10Peak162±14k109±10111±10175±2rp-value

<0.001NSNS<0.001DIaStOlICbloodpressure(mmHg)Baseline

67±970±971±869±8Peak83±865±570±981±16p-value

<0.001<0.05NS<0.01Doubleproduct(x10@)Baseline

70±1071±1273±1568±8Peak301±25*187±2591±16154±25*p-value

<0.001<0.001<0.001<0.001*p

< 0.001exerciseversusadenosineanddipyridamole.tp< 0.01 exerciseversusdobutamine.*p< 0.001 dobutamineversusadenosineanddipyridamole.‘p< 0.001 exerciseversusdobutamine.

Therewerenosignificantdifferencesbetweenadenosineanddipyridamole.

MenosineDipyridamoleDobutamineChestpains1075Flushing883Headaches584cioeing532D@ness2011°AVblock100Epigastricpain110Dyspnea610Palpitations005Facial

numbness003Nausea003Anxiety002Arrhythmias001CMIs003Any

symptom13 (87%)12 (80%)1 1 (73%)

TABLE 1HemodynamicResponsesin 15 HealthySubjects

Myocardial and Extracardiac Thallium UptakeThese results are shown in Table 3. None of the normal

subjects had perfusion abnormalities during any of the fourinterventions (Fig. 2). The myocardial thallium activity

was higher duringpharmacologictesting than exercise. Inthe anteriorprojection, the mean activity was 409 counts!pixel with exercise, 506 counts/pixel with adenosine, 491counts/pixel with dipyridamole and 517 counts/pixel withdobutamine (p < 0.001 versus exercise, each) (Fig. 3).There were no differences between the three pharmacologic agents. The extracardiac activity in the lung and liverwas higher during pharmacologic testing than exercise (Table 3).

TABLE 2Side Effectsof PharmacologicInterventionsin 15 Healthy

Subjects

Myocardial and ExtracardiaCThallium ClearanceThese results are shown in Table 4. The myocardial

thallium clearance was lower with adenosine, dipyridamoleand dobutaminethan exercise (Fig. 4). Also, lung thalliumclearance was higher with adenosine and dipyridamolethan exercise. The thallium clearance during dobutamineinfusion was intermediate between exercise and adenosineor dipyridamole.Finally, the liver thalliumclearance rateswere higherwith adenosine, dipyridamoleand dobutaminethan with exercise but again, there were no differencesamong the three pharmacologicagents (Fig. 4).

DISCUSSION

Thallium-201 Imaging With Adenosine, Dlpyrldamoleand Dobutamine

Adenosine is a potent vasodilator in most vascular bedswith the exception of the kidney (20,21). The coronaryvasodilation is thought to be due to activation of purine A2receptors. Wilson et al. and Rossen et a]. reported a max

imalor near maximalcoronary hyperemiawith an intravenous dose of 140 @tgfk@min(22,23). The primarymechanism of action of dipyridamole is by inhibiting the cellularreuptakeof endogenous adenosine andthus, increasingtheinterstitial adenosine concentration (7,24). The dipyridamole dose used in the United States with thalliumimagingis142 @*gfkg/minfor 4 mm although higher doses are used inEurope, especially with echocardiography(25). Rossen etal. compared the hemodynamic effects of adenosine anddipyridamole and showed that the decrease in coronaryvascular resistance was greater with adenosine but theincrease in coronary blood flow velocity was similar withboth agents (23). Dobutamine is a synthetic sympathomi

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ExerciseAdenosineDipyridamoleDobutamineAnterolateral408

±58501 ±94@477 ±103@501±78Interior410±54510±96504±113@544±81tPosterolateral387

±47508 ±99@493 ±95537 ±92@Septum389±52531±109*518±108*5,%@99*Anterior340

±42497 ±9545@ ±75*4@ ±89@Inf-Post362±39524 ±94@503 ±77*526 ±75*Lung115±14192±21*191±25*183±20*Liver109±20442±76k440±79*504±46@*p

< 0.001versusexercise.tp< 0.01 versusexercise.*p< 0.05versusexercise.mt-Post

= inferior-posterior.

TABLE 3ThalliumActivityin SixMyocardial,LungandLiverROls(meancounts/pixel)in 15HealthySubjects

metic amine with predominant p1-agonist activity resultingin increased myocardial contractility and myocardialoxygen consumption(26,27). At higherdoses (>20 @gfkg/min),dobutamine produces a f@and alpha-adrenergiceffect resulting in increases in heart rate and blood pressure. Thepharmacokinetic profile of dobutamine is favorable; thetissue half-time is about 2 mm and the mean duration ofaction is less than 10 mm. Doses of up to 40 p@gfkg/min have

been used safely for imagingpurposes (9).

Hemodynamic ResponsesThe hemodynamic responses in this study were similar

to those reportedby others (26—29).Dobutamineincreasedthe heart rate, blood pressure and double product (28).Adenosine and dipyridamole caused much smaller increases in heart rate and double product and an insignificant decrease in blood pressure. The double product washigher during exercise than any of the pharmacologicagents. Mannering et al. compared the effects of 20 @gfkg/min of dobutamineto exercise in patients 3 wk after myocardial infarction (29). They suggested that ischemia produced by dobutamine is predominantly caused by anincrease in inotropicity rather than an increase in heart rateas it occurs with exercise.

Side EffeCtsSide effects were frequent during pharmacologic stress

testing, butwere well toleratedand short-lived. No specific

FIGURE 2. Examples ofmyocardialimagesin the antenor projectionduring exercise(left upper quadrant), adenosine(rightupper),dipyridamole(left lower) and dobutamine(rightlower).

antidote was needed in any of the subjects. In only onesubject was maximal dobutamine dose not achieved because of ventricular arrhythmias. Dobutamine has beenknown to increase the risk of ventricular tachyarrhythmias, especially at higher doses, because of acceleration ofdiastolic depolarizations(30). The incidence of side effectswas not significantly different among the three agents.

Thirteensubjects had at least one symptom duringadenosine infusion, 12 during dipyridamole infusion and 11 during dobutamine infusion. These results are similar to thoseseen in patients with suspected coronary artery disease.Although the sample size is small, more patients preferredadenosine than dipyridamoleor dobutamine. In fact, morepatients ranked dobutamine as the most intolerable pharmacologic agent. These results are different from thoseobserved by Martinet a!. which showed that most patientspreferreddobutaminethanadenosineor dipyridamole(28).Several studies have reported the use of mild exercisealong with dipyridamole(31—35).Comparedto dipyridamole alone, therewas a significantincrease in peak heartrateandblood pressure associated with supplementalexercise.

FiGURE3. Averagecountdensftiesfromthemyocardium,lungand liverduringexercise,adenosine,dipyridamoleanddobutaminestress testing. @p< 0.001, tp < 0.01 and tp < 0.05 versus exercise,respectively.

0 Exercise0 Adenosine

@ Dipyndamole

UDobutamine0.U)

C

$4

The Journalof NuclearMedicineâ€Vol.35 â€No. 4 â€April1994538

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Anterolateral12.9±1.09.8±1.r9.7±2.2*11.0±1.9Inferior13.0±1.39.7 ±1.7k10.1 ±2.3@11.6 ±1.7@Posterolateral12.4±1.110.3 ±l5@10.4 ±2.3@11.3 ±1.5*Septum1

2.0 ±1.010.3 ±1.9@10.5 ±2.31 1.4±1.6@Anterior11.7±1.211.0±1.910.8±1.911.3±1.8mt-Post1

1.7 ±1.210.7 ±I .61 1.0±I .61 1.5 ±1.3Lung7.9±1.79.8 ±1.2@10.4 ±1.2@8.7 ±1.5Liver—3.0±5.512±2.6k12.5±3.r11.5±1.7@‘p

< 0.001versusexercise.tp.@0.01 versusexercise.*p< 0.05versusexercise.mt-Post

= inferIor-posterior.

TABLE 4ThalliumClearancefromCardiacandExtracardiacROIs

Menosine DipyrldarnoleExercise Dobutamine

Noncardiac side effects were less with combined exerciseand dipyridamole.

Myocardlal Thallium UptakeMyocardial uptake of 20111 in normal subjects was

greater after pharmacologic testing than exercise. The av

erage myocardial activity was 1.3 times greater with adenosine, 1.2 times greater with dipyridamole and 1.4 timesgreater with dobutamine (see Table 3 and Fig. 3). There

were no significant differences in the myocardial activityamong the three pharmacologic agents. The myocardialthallium uptake depends on flow, extraction and clearance.Based on Saperstein's fractionationprinciple, myocardialthallium activity is related to coronary blood flow as apercent of the cardiac output (36). The ratio of the coro

nary blood flow-to-cardiac output is greater during adenosine or dipyridamole infusion than exercise because theincrease in coronary blood flow is more, while the increasein cardiac output is less (10). The similarmyocardial thalhum activities with adenosine and dipyridamole,however,do not necessarily prove that the coronary blood flow wasalso similarbecause the extractionfractionof @°‘Tltends to

FiGURE 4. Thallium-201washoutfromthe myocardium,lungand liverafter exercise,adenosine,dipyridamoleand dobutaminestresstesting.*p < 0.001and tp < 0.01versusexercise,respecthialy.

level off at a flow rate above 2.5 times the baseline flowlevel (1).

Previous studies have shown a higher myocardial-tobackground ratio resulting in visually superior thallium images when dipyridamole protocol was supplemented withlow-level exercise (31—35).Brown et al. found a 68% increase in coronary sinus flow with supplementationof anisometric handgrip as compared with dipyridamole alone

(32).However,Rossenetal.demonstratednosignificantchange in coronary flow reserve as measured with a coronary Doppler catheter (33). They suggested that their results differed from Brown et al. because of limitationsintrinsic to coronary sinus thermodilution technique. Furthermore, they proposed that the addition of an isometric

handgrip to dipyridamole testing might well improve theaccuracy of the technique as a result of factors other thana change in coronary flow such as increase in double product, and adrenergicstimulation.

Dobutamine produced hemodynamic changes similar toexercise. In patientswith and without coronary arterydisease, dobutamine results in a dose-dependent increase in

coronary blood flow, cardiac output and left ventricularcontractilityand, to a lesser extent, in heartrate and meanarterial blood pressure (37—40).Meyer et al. (41) andStephen et al. (39) reportedthat duringinfusion of dobutamine at a rate of 8—10@tg/kg/min,patients with a normalcoronary angiogram had a 130%—150%increase in coronary perfusion. Also dobutamine produced a twofold increase in cardiac output at a dose of 32 p.gfkg/minin dogsand patients with coronary artery disease (41,42).

Our thalliumdata suggest that the increase in coronaryblood flow was probably greater than the increase in cardiac output with dobutamine at a dose of 40 @tg/kg/min.Itis, however, possible that because of a greater increase inmyocardial oxygen demand, the thallium extraction withdobutamine may differ from that from dipyridamole andadenosine, and further studies are necessary to measurethe coronary flow and cardiac output during these interventions. Weich et al. found a logarithmic decrease in

0 Exercise0 Menosine

@ Dipyridamole

I Dobutamine0

Compansonof 201T1Imaging Blokinebcsâ€Lee et al. 539

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thallium uptake when coronary blood flow was increasedin excess of oxygen demand (43).

Myocardiai Thallium ClearanceThe myocardial thallium clearance was slower with

pharmacologicinterventionsthanexercise (see Table4 andFig. 4). There were no significantdifferences between thethreepharmacologicagents. Of note, in the 75°left anterioroblique projection, the differences between the pharmacologic interventions and exercise was not visible. This projection is the last projection to be obtained almost 20 minafter completion of the exercise.

The myocardial clearance with exercise was slightlylower than that observed in the anteriorand 45°left anterior oblique projection. Myocardial clearance with dobutamine was slightly but insignificantly higher than that ofdipyridamole and adenosine, and was somewhat intermediate between the clearance rates of these two agents andexercise. Lower myocardialthaffiumclearance with pharmacologic intervention rather than exercise, despite ahigher initial thallium activity, may be due to a lower gradient (myocardium to blood pool). The lower gradient isprobably related to higher blood pool activity caused by ahigher liver clearance as shown in this study (see below).Previous studies have also suggested differences in clearance rates in rest, pharmacologic and exercise thaffiumstudies. Even in exercise studies the clearance is lower inpatients with submaximal than maximal stress(15—17,44,45).

Extracardiac Thallium Activity and ClearanceThe lung and liver thallium activities were higher with

pharmacologicinterventionsthan exercise, but againtherewere no significantdifferences between the three pharmacologic agents (see Table 4 and Fig. 4). The differences inregional thalliumactivity between pharmacologictests andexercise are probably related to differences in regionalblood flows (46). With exercise, the increase in oxygendelivery to exercising muscle is mediated by increases incardiac output, oxygen extraction and redistributionof thecardiac output from the liver and splanchnic tissue to theexercising muscles. In contrast with pharmacologicvasodilatation with adenosine and dipyridamole, there are noimportant changes in regional flow distribution.

The lung uptake of thallium after pharmacologic testswas also greaterthanafterexercise. This may be relatedtoa slower pulmonary transit time caused by a lower heartrate facilitating thallium extraction. A decrease in pulmonary vascular resistance may also enhance lung thalliumuptake. This decrease has been observed with adenosineandwith dobutamine(47). The lungthalliumclearancewasfaster with adenosine and dipyridamole than with exercise.Also, the liver clearance rate of thallium was higher withadenosine, dipyridamole and dobutamine than with exercisc. These differences might be due to higher thalliumactivity in the lung and liver in the initial images withpharmacologic agents than with exercise (see Tables 3 and

4 and Figs. 3 and 4).

In conclusion, there are important differences in themyocardial and extracardiac uptake and clearance of 201'flbetween pharmacologic stress testing and exercise testing.

These differences suggest the need for stress-specific normal files when quantitativeanalysis is used to examine themyocardial perfusion. In a previous study, we observedthat if the ifie obtained duringexercise is used with adenosine studies, the defect size is overestimated (48). Finally,the differences in cardiac and extracardiacactivities combined with differences in clearance rates are importantparameters that may affect the accuracy of quantitative

analysis when interpolative background subtraction methods are used.

ACKNOWLEDGMENTS

The authorsthankCarliseWilliamsandSusanKelchnerfortheirexpert secretarialassistancein the preparationof thismanuscript. Presented in part at the 42nd Annual Scientific Session ofthe AmericanCollege of Cardiology, March 14—18,1993in Anaheim, California.

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1994;35:535-541.J Nucl Med.   Jaetae Lee, Shung C. Chae, Kyubo Lee, Jaekyeong Heo and Abdulmassih S. Iskandrian  Dipyridamole, Dobutamine and ExerciseBiokinetics of Thallium-201 in Normal Subjects: Comparison Between Adenosine,

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