nostic accuracy to 201TlSPECT for detection of significantcoronary artery disease (4). Serial 99mTc@teboroxime imaging after pharmacologic or atrial pacing stress wouldextend the clinical diagnostic utility of this new imagingagent to include patients unable to exercise. Post-reperfusion 9emTc@teboroxime imaging during interventional procedures would theoretically permit the earlier detection ofischemic myocardium in an acute care setting.

Myocardial uptake of 99mTc..teboroxime is rapid, withhigh extraction fraction over a wide range of flows (5) anddiagnostic quality cardiac visualization within 2 mm ofinjection (5,6). In animal studies, tracer clearance is closelyrelated to myocardial blood flow (5). Preliminary clinicalstudies (2) indicate that serial dynamic myocardial perfusion imaging may be achievable with this agent.

The goal ofthe present study was to compare the kineticbehavior of 99mTcteboroxime in normal and post-stenotic

myocardium in response to occlusive (“supply―),rapidpacing (“demand―),and pharmacologic (“hyperemic―)stress in the intact pre-instrumented canine model. Thisanimal model simulates relevant clinical situations andpermits the serial acquisition of detailed hemodynamicdata to correlate with the in vivo myocardial kinetics ofthis new perfusion agent.

The hypothesis that post-stenotic e9mTc@teboroximemyocardial clearance varies with different types of ischemic cardiac stress was tested. In addition, the corollaryof whether rapid differential myocardial clearance of99mTcteboroxime predisposes early tracer “redistribution―in post-stenotic myocardium was also examined.

METHODS

.@ nI@___@

Theclearancekineticsof the perfusiontracere9mTc@teborox@ime were evaluated in post-stenotic and normal myocardiumusingdynamicplanargammacameraimagingin pre-instrumenteddogsinthecontrolstate(n = 9) andfollowingtotalocclusion (2 mm), pharmacologic stress with adenosine [80and 160 @@g/kg/min]or dipyridamole,and rapidatrial pacing(220/mm).Technetium-99m-teboroximeclearancein normalmyocardium was accelerated by adenosine and by dipyndamolecomparedto the controlstate (8.9±1.1 and9.3 ±1.9mm versus 11.9 ±1.8 mm; p < 0.05). Post-stenotic 99r@@Tc@teboroxime clearance half-time was most significantly prolonged compared to nonoccluded contralateral perfusionzonesby 160 @g/kg/minadenosinestress(11.2 ±3.7 versus6.3 ±1.5 mm)andbycompletecoronaryocclusion(12.1 ±3.3 versus 6.6 ±1.2 mm; both p < 0.05). Differentialtracerclearancefrompost-stenoticversusnonoccludedzonesproduced quantitative evidence of relative defect “redistribution―in71% ofmaximalstressstudiesat a meanof8.8 ±2.5 mmpostinjection.Sensitivity,specificity,anddiagnosticaccuracyof prolonged regional 99mTcteberoxime clearance rates forpost-stenotic perfusion abnormalities were 62%, 100% and81% inmaximalstressstudies.Futureclinicaltrialsofexerciseandnonexercisestress @“Tc-teboroximeimagingshouldconsider these kinetic characteristics and examine the correlatesof perfusiondefect“redistribution.―

J NucI Med 1991; 32:2000—2008

echnetium-99m-teboroxime (methyl-boron [1-]-tris[1 ,2-cyclohexane dione dioxime (l-)]-N',N' “,N' ‘‘‘,N'‘‘‘‘)chlorotechnetium is a rapidly cleared myocardial perfusion agent currently being evaluated in exercisc-rest protocols in patients with suspected ischemicheart disease (1—3).These early clinical trials of exercise99mTcteboroxime imaging have shown comparable diag

ReceivedOct.26,1990;revisionacceptedJan.29,1991.For reprintscontact: D. Douglas Miller, MD, Departmentof Medicine,

Divisionof Cardiology,St. LouisUniversityMedicalCenter,3635VistaAve.,St.Louis,MO 63110-0250

.@ .. . .@

PreparationKits containing vials of lyophilized 99mTc@teboroxime were

supplied by Squibb Diagnostic Division, Princeton, NJ. Technetium-99m-sodium pertechnetate was obtained from eSMofl9mTcgenerators that were eluted within 24 hr of radiopharmaceutical

preparation. Radionuclide purity, aluminum ion content, andpH were determined prior to use.

2000 TheJournalof NuclearMedicine•Vol.32 •No. 10 •October1991

Demonstration of Differential Post-StenoticMyocardial Technetium-9 9m-TeboroximeClearance Kinetics After ExperimentalIschemia and Hyperemic StressRichard E. Stewart, Betty Heyl, Robert A. O'Rourke, Ralph Blumhardt, and D. Douglas Miller

Department ofMedicine, Division ofCardiology, and Department ofRadiology, Division ofNuclear Medicine, University ofTexas Health Science Center, San Antonio, Texas

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Each vial was reconstitutedwith 1 ml of [@mTc]sodiumpertechnetate, containing approximately 2—4mCi of radioactivity.The radiochemicalpurity wasdetermined utilizing 1.3x 11cmWhatman 31ET chromatographystripsand two individualmobilefacesolventsystems.Chromatographicresultsindicatedthat

the sum ofthe free‘@mTcand reduced/hydrolyzed @mTc@teborox@ime was routinely less than 10%, while the mean radiochemicalpurity averaged greater than 95%.

Hemodynamic Data Acquisition and AnalysisHealthy mongreldogs (15—20kg) were surgjcailypre-mnstru

mented for chronic physiologic monitoring using a previously

reported method (7). High fidelityleft ventricular(LV)pressure(LV end-diastolic pressure), the first derivative of LV pressure[dP/dt], aorticpressure,the minor axisLVdimension,apicalandbasal regional segment lengths and a surface ECG were recorded

on internallygrounded an eight channel forced ink pen oscillograph [Beckman Instruments, Inc., Fullerton, CA] at a paperspeed of 25 mm/sec. An average of 15 to 20 consecutive cardiaccycles were recorded for on- or ofiline analysis using software

developedin our laboratory.Percent regionalLV systolicshortening [%SS]was calculated according to a previous publishedmethod (7,8).These parameterswere used to establishthe presence and define the time of peak LV hemodynamic stress.

Experimental ProtocolAll animals wereanesthetizedwith intravenouspentobarbital

[30 mg/kg] in the right lateral decubitus position for the durationofthe studies. All nine dogs (five pre-instrumented with coronaryartery occluders and four pre-instrumented without occluders)underwentimagingwith 10±1mCi of @mTc-teboroximeunderbaseline conditions (without occluders inflated). Experimentalstress runs were carried out in random order in each of the fiveoccluded dogs after either 5 mm of partial [90%] single-vesselcoronary artery occlusion or 2 mm ofcomplete [100%] occlusion.A minimum interval of 48 hr was allowed between serial studiesto permit full hemodynamicrecovery.Followingpartial (90%)coronary occlusion, the dogs underwent the following pharmacologic stress: 80 @g/kg/minor 160 @zg/kg/minadenosine (Sigma,Inc., St. Louis, MO) intravenouslyfor 3 mm, or dipyridamole(Boehringer Ingelheim, Ridgefield, CT) 0. 14 mg/kg/mm intravenously over 4 mm (total dose = 0.56 mg/kg).

“Demand―ischemia was achieved with partial occlusion andatrial pacing at 220 bpm. Technetium-99m-teboroxime was administered as an intravenous bolus (flushed with 10 ml of normalsaline) at the point of peak stress as defined by online LVhemodynamics. This occurred at 2 ± 1 mm following the onset

of adenosine infusion and at 7 ±I mm followinginitiation ofdipyridamole infusion. Experimental runs were also performedas described above without coronary artery occlusion.

Image Acquisition and AnalysisImage acquisition was performed using a Searle MEDX-37

gamma camera fitted with a low-energyall-purposecollimatorand interfaced with a Medisys A2 computer (matrix = 64 x 64byte: zoom = 1.69). A 20% automatic photopeak window was

set around 140 keV. All images were acquired in the 50°leftanterior obliquecamera position. Imageacquisitionwas startedat the time of injection and consisted of 40 frames (30 sec perframe) followed by 2 frames of 5 mm per frame. Total imagingtime per study was 30 mm. Animals were repositioned for serialimaging studies by placing the thoracotomy incision scar at the

FIGURE 1. ROlsforanalysisof myocardial,blood-poolandlung activity are demonstratedat 1.5 mmpostinjection.MyocardialROls were set in theanteroseptaland posterolateralregions(whiteboxes),distant from the apicalinstrumentation“dimple.―Two lungROlswereplacedat the samelevelas the myocardialROls, wellabove the splanchnicactivity.Blood-pool ROls were placedin the central ventricularcavity(LV)and in the ascending aorta(Aorta).

level of the midpoint of the camera-collimator surface (determined by cross-hatched markings).

Twenty-fivepixel regions of interests (ROl) were drawn bytwo independent observers in the post-stenotic and nonoccluded(normal) myocardium corresponding to the anteroseptal andposterior myocardial walls (Fig. 1).Background ROIs were placedover two lung regions at the level of the LV chamber, and theLV cavity and ventricular outflow tract. All regionswere fixedfor the duration of studies, but could be adjusted for animalmotion. Care was taken to minimize the contribution of hepatobilary activity to the inferoposterior wall using adjustments incamera position guided by an activity source before e9mTc@tebo@roxime injection. Systematicprospectiveevaluation of the contribution ofall four backgroundROIsto myocardialactivitywasperformedin representativecontroland stressstudies.An averageof the LV outflow tract and one lung region produced optimumcorrection for both early (0—2mm) blood-pool and later (2—11mm) lung background activity adjacent to the myocardial ROIs.Data fromeachindividualimageframeweredecay-correctedandbackground-subtractedusinga methodsimilarto thosepreviouslyreported for analysisof dynamic myocardialradioisotopeclearance with serial planar imaging (9,10).

Technetium-99mtime-activitycurveswere initiallyexpressedas raw mean counts/pixel/30-secframe and fitted to the biexponential equation: Y = ae@―+ be@212(@ reference 31 ). Tracerclearance half-times [t,, in minutes] were derived by linear regression of the natural logarithmic transformation of the decay corrected and background subtracted @mTcraw myocardial timeactivity curves acquired during the first 1 1 mm of each study,

according to the standard equation: t,@= ln2/X1 (4,5).Relative “redistribution,―the apparent normalization of@mTc@

teboroxime activity in post-stenotic myocardial defects, was assessedqualitativelyand quantitatively.Serialplanar images(30-sec studies x 20 mm) were visually scored by two observersblinded to both the study and experimental protocol for qualitative reduction of defect size (i.e., “redistribution―)(1 1). Quantitative “redistribution―(“R―)was prospectively defined as thepoint at which the log transformed 1—11-mm time-activity curves[post-stenotic zone (curve A—C)versus normal zone (curve B—D)] reached @40%of their initial (time = 1 mm) count densitydifference (Fig. 2) (12):

“R'@_) ((CA1I@y :@0.40

where“R―= quantitative “redistribution―,A ln post-stenoticmyocardial counts (time 1 mm), B = ln normal zone counts

2001Post-Stenotic @“Tc-TeboroximeKinetics•Stewartet al

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5 10 15

Time (minutes)2520 30

Tc-99m TEBOROXIME IMAGING:@.ADENOSINE(l6Ojig/kg/min)STRESSUUiU)0

Ui

-JUi

U)I-z0C) .C 0 I 2 4 5 6 8 0

-J TIME (MIN)

11C

a)0.ECo

U)1

0)

C

0C-)

C-J

9

.6 AdenosineDipyridomole

— Baseline

0 NON-OCCLUDED

. OCCLUDED

2

FIGURE 2. LOgtransformedmyocardialclearancedata froma studyof severepartialcoronarystenosisduringadenosine[160@zg/kg/min]stress. The approachof the normalzone (curve B—D)and post-stenoticzone (curveA—C)clearancecurves at pointC—D to within 40% of their initial 1-mm difference at point A—Boccurs at 5 mm (6 mm postinjection).These curves intersect at8 mm postinjection. Quantitative relative “redistribution―wasaccompanied by qualitativepartial “fill-in―of the anteroseptalperfusiondefect. The myocardialclearance half-timein the nonoccludedzonewas 4.9 mmas comparedto 10.5 mmin the poststenoticzone.

(time 1 mm), C = In post-stenotic myocardial counts (time 11mm), and D = In normal zone counts (time 11 mm).

The choice of 11 mm (10 mm following the 0—1mm clearanceof blood pool) was based on careful analysis of the raw datawhich routinely demonstrated a “breakpoint―between early andlate washout at <1 1—12mm postinjection (see Fig. 4). Myocardialactivity beyond 11 mm postinjection was too low (27%—34%of1 mm postinjection), and clearance too statistically variable (latetl/, = 20 ± 2—33 ± 4 mm) to permit further assessment of SSmTc..

teboroxime clearance.

Statistical AnalysisData are expressed as mean ± I s.d. Paired samples were

compared using the Students t-test. A probability value of <0.05was considered significant. Linear regression was calculated bythe least squares method. Blood clearance data (Fig. 3) were fitto a biexponentialfunction usingthe RS/l softwarepackage“fitfunction―(Bolt, Baranek and Newman, Cambridge, MA).

RESULTS

Hemodynamic ResponseTable 1 lists the hemodynamic responses at baseline

and after peak pharmacologic and pacing stress. The peakstress triple product (heart rate x LV systolic pressure x+dP/dtmax) did not increase significantly after adenosineand dipyridamole infusion, consistent with previous studies of these pharmacologic stress agents on canine LVperformance (13). There was a significant increase incardiac index (7. 1 ±1.0 to 13.9 ±4.6 1/min/m2; p < 0.05)and triple product (43,578 ±14,460 to 84,979 ±35,431units; p < 0.05) during pacing stress. The left ventricularend-diastolic pressure (LVEDP) increased only duringcomplete occlusion (7 ±4 to 21 ±13 mmHg; p < 0.05).

FIGURE 3. Systemicarterialbloodclearanceof @“Tc-teboroxime was evaluated in the subset of 3 dogs instrumented forDopplercoronary artery blood flow determination.Tracer clearance was biexponentialunder baselineconditions (k1= 1.29 ±.05,k2= 0.025±.004)andfollowingpharmacologicstresswithhigh-doseadenosine(k1= 1.68 ±.07, k2 = 0.031 ±.003 anddipyndamole(k1= 1.82 ±.09, k2 = 0.043 ±.004). Early blood99mTcteberoximeclearancekineticswere comparableand significantlydifferentfrom control followingdipyndamoleand adenosinestresses.

Regional Contractile FunctionThe LV percent systolic shortening (%SS), an index of

regional contractile function (13), is given in Table 2 forthe post-stenotic and nonoccluded vascular beds. Totalcoronary occlusion, and partial occlusion with high-doseadenosine (160 @g/kg/min),dipyridamole or rapid atrialpacing transiently decreased post-stenotic LV contractileperformance (all p < 0.05), which returned to normal at10 mm post-stress. Low-dose adenosine (80 @ig/kg/min)plus stenosis did not depress post-stenotic LV contractilefunction.

Coronary blood flow was not directly measured in thepresence of flow limiting stenoses. However, previouslyreported data from our laboratory (19) demonstrate asignificant reduction in radiolabeled microsphere regionalmyocardial blood flows with severe (90%) partial stenosisalone (1.4—0.9ml/min/g), partial stenosis and rapid atrialpacing (0.6 ml/min/g), and complete occlusion (0.2 ml/min/g; all p < 0.05).

Technetium-99m-Teboroxime Myocardial ClearanceKinetics

Table 3A summarizes the early (1—11 mm) clearancehalf-times of 99mTcteboroxime at control and under thevaried stress conditions. Mean early 99mTc..teboroximeclearance was delayed in ischemic post-stenotic zones compared to contralateral normal myocardial zones under allconditions of pharmacologic and pacing stress (p < 0.05),but was most prolonged after the infusion of 160 @g/kg/mm (1 1.2 ±3.7 versus 6.3 ±1.5 mm; p < 0.05) (Fig. 4).There was also a significant difference in post-stenotic

2002 The Journal of Nuclear Medicine•Vol.32 •No. 10 •October1991

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I. PharmacologicStress(n=5)0.3

Adenosine0.6 AdenosineDipyndamoleBaselinePeak

stressBaseline Peakstress BaselinePeakstressHR125±26157±24136±43

172±28146±24174±18LVPsystolic123 ±141 22 ±121 38 ±20 140±12 126 ±181 34±22LVEDP5.6

±3.28.4 ±7.47.0 ±4.4 6.8 ±9.5 5.8 ±3.34.4 ±12.8+dP/dL,@3,177±1,0773,475 ±1,2323,614 ±954 4,443±973 3,540±9654,706 ±1,137Triple

product53,373 ±37,1 2668,788 ±35,76075,290 ±44,046 110,125 ±39,000 83,558±40,8411 15,983±47,174Cardiacindex7.5 ±1.08.9 ±1.37.8 ±1.8 9.8±2.1 7.9±1.612.0 ±4.6-II.

PacingStress(n=5)Baseline

PeakstressHR

LVPsystolicLVEDP+dP/dt.@@@TripleproductCardiacindex106±20

209±9―120±16 119±216.8 ±3.3 24 ±7.0

3370 ±748 3327 ±97143,580 ±14,468 84,978 ±35,432―

7.1 ±1.0 13.9 ±4.6―Ill.

TotalOcclusion(n =6)Baseline

Peakstress

124 ±19

C p < 0.05 versusbaseline.LVP

= LVPpressure(mmHg),LVEDP= LV end-diastolicpressure(mmHg),+dP/dt,,,, = first derivativeof LVP(mmHg/sec),andcardiacindex=I/min/m2.clearance

half-time between pacing stress (7.3 ±1.2 mm) Quantitative post-stenotic counts ratio analysis conand complete occlusion (12. 1 ±3.3 mm; p < 0.05). firmed optimal defect visualization at 5 mmpostinjectionTechnetium-99m-teboroxime

clearance in nonoccluded (Table 3B). Lung:heart @mTc@teboroximeactivity ratios5zonesdiffered significantly from the control value (1 1.9 ± mm postinjection did not differ under variedexperimental1

.8 mm, p < 0.05) under all cardiac stress conditions. stressconditions.TABLE

2PercentSystolic ShorteningDataPost-Stenoticbed NonoccludedbedExperimental

conditions Baseline Peak 10 mm postinjection Baseline Peak 10 mmpostinjectionNo

occlusionControl(n= 9) 13.3%±3.9% — — 13.0%±3.4% ——0.6

Adenosine(n= 4) 12.7%±5.2% 12.4%±6.0% 12.3%±2.9 10.0%±4.2% 10.2%±4.0% 10.5%±1.8%Dipyndamole(n = 4) 11.0% ±5.9% 11.5% ±6.5% 9.7% ±4.9% 16.2% ±1.9% 20.8% ±7.8% 13.8% ±4.3%Total

occlusion(n = 6) 15.5% ±4.3% 10.4 ±3.9%― 14.2% ±3.4% — ——Partialocclusion (n =5)+

Adenosine(0.3) 10.4% ±4.8% 8.0% ±3.7% 12.2% ±4.6% 11.6% ±4.1% 11.6% ±4.2% 10.6% ±3.5%+Adenosine(0.6) 11.2% ±4.7% 7.6% ±3.2%― 13.1% ±5.9% 10.6% ±4.1% 11.9% ±5.0% 10.0% ±3.9%+Dipyridamole 12.2% ±3.6% 8.6% ±4.8%― 11.5% ±5.8% 15.4% ±4.0% 19.1% ±7.6% 15.0% ±4.0%+Pacing (220/mm) 12.3% ±5.7% 8.1% ±4.7%― 13.0% ±3.5% 12.8% ±2.7% 13.9% ±5.5% 13.9% ±4.7%C

p < 0.05 vs. baseline and 1 0' post-values.

HRLVPsystolicLVEDP+dP/dL,TripleproductCardiac index

164±20108 ±17

21.2±13.2―2,389 ±759

38,031 ±16,0946.6 ±2.0

124 ±119.6 ±3.3

3,108 ±32747,866±8,208

7.6 ±1.8

Post-Stenotic @“Tc-TeboroximeKinetics•Stewartet al 2003

TABLE 1Hemodynamic Data

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TABLE3ATechnetium-99m-TeboroximeImaging Data in ResponsetoPharmacologic

and lschemicStressMyocardial

clearancehalf-timen(mm)

9* 11.9±1.8

TABLE3BTechnetium-99m-TeboroximeImagingData in Response to

Pharmacologic and lschemicStressMyocardial

Poststenotic:normalzonecountsratio

distribution―was present in 7 1% of maximal stress studies[15/21]: 60% after pacing stress, 60% after pharmacologicstress with adenosine 160 @g/kg/min,80% after dipyridamole stress and 83% after complete occlusion (n = 5/6studies), and in 17/26 (65%) of all studies. Concordancebetween “redistribution―scoring by quantitative curveanalysis and blinded expert qualitative scoring was 60%.

DISCUSSION

The current study utilized widely available dynamicplanar gamma camera imaging in a validated pre-instrumented chronic dog model of severe coronary stenosis,with pacing and varied hyperemic stresses. The followingobservations were made:

1. Technetium-99m-teboroxime clearance is significantly delayed in ischemic myocardium distal tosevere (90%) stenoses following rapid atrial pacing,adenosine and dipyridamole stresses as compared tothe contralateral nonoccluded zone.

2. Increased cardiac work (i.e., triple product), highdose adenosine (160 @zg/kg/min)and dipyridamoleinfusion accelerate 99mTc@teboroximeclearance fromnonoccluded zones compared to control data fromthe same perfusion beds.

3. High-dose adenosine stress and complete (100%) occlusion with reperfusion caused the greatest prolongation of teboroxime clearance compared to nonoccluded zones.

4. Differentialpost-stenoticversusnonoccludedzone

ControlNoocclusionAdenosine(0.6)Dipyndamole

Partialocclusion

Adenosine(0.3)Adenosine(0.6)DipyridamolePacingComplete occlusion

C p < 0.05 between post-stenotic and normal zone half-time.

t p < 0.05 vs. control half-time.

SFive pre-instrumented and four uninstrumented control dogs.

SSix experimental runs in five dogs.

55

8.9 ±1.19.3 ±1.9 DiagnosticAccuracyfor Detectionof Abnormal @Tc

Post-Stenotic zone Normal zone Teboroxime Clearance5 10 6 + 2 5― 7 0 + 1 9@ If normal 99mTcteboroxime clearance is defined as <2

5 11:2 ; 3:7― 6.3@ 1:S@ s.d. above the nonoccluded group mean, then the5 8.6 ±2.1 “ 5.8 ±1.4@ sensitivity of regional tracer clearance half-time5 7.3 ±1.2― 5.6 ±1.l@ determinations for detecting post-stenotic perfusion

abnormalities in low- and high-dose adenosine6@ 121+33―.—. .—. dipyridamole,pacing,stress,andtotalocclusionstudies

was 25%, 60%, 60%, 60%, and 66%, respectively. Overallsensitivity was 54% (14/26) including low-dose adenosinestudies and 62% (13/21) excluding these sub-maximaladenosine studies. Six additional studies demonstratedvisual evidence of relative “redistribution―but did nothave regional clearance half-time values exceeding 2 s.d.above the mean. When combined with quantitativeclearance data, qualitative scoring improved sensitivity to60%,80%,100%,60%and66%intheabovestudygroups;and 73% overall.

None of the 26 nonoccluded zones demonstrated half___________________ time clearance rates exceeding 2 s.d. above the mean,

n 5 mm io mm producing no false-positives and a specificity of 100%-@: 0.87 ±0.08 0.89 ±0.1 1 using this criteria. The diagnostic accuracy was 77% for

all types of stress in 52 segments and 81% in maximal5 0.87 ±0.10 0.89 ±0.10 stress studies analyzed for the presence ofabnormal 99mTc@5 0.89 ±0.09 0.89 ±0.10 teboroxime clearance.

ControlNoocclusionAdenosine(0.6)DipyridamolePartialocclusionAdenosine(0.3)Adenosine(0.6)DipyridamolePacingCompleteocclusion

5 0.70±0.135 0.65±0.12―5 0.73± 0.16'5 0.70±0.17

0.73±0.180.71±0.170.74 ±0.070.73 ±0.22

6* 0.82±0.09 0.91±23

C p < 0.05 vs. corresponding “no occlusion― counts ratio.

t Five pre-instrumented and four uninstrumented control dogs.

* Six experimental runs in five dogs.

Qualitative Versus Quantitative Analysis of @“TcTeboroxime Myocardial Redistribution

Two independent observers qualitatively graded myocardial visualization as good to excellent in 28 of 35 (80%)of all studies, and defect visualization as present in 22/26(85%) of stressstudies (Fig. 5). Figure 6 is an example ofa post-stenotic myocardial perfusion defect with qualitative relative “redistribution―of @mTc@teboroximeactivity.The corresponding clearance curves are shown in Figure2, with the curves reaching s40% of their original logtransformed count density difference within 10 mm ofinjection. Using this quantitative definition, relative “re

2004 The Journalof NuclearMedicine•Vol. 32 •No. 10 •October1991

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S 10 15 20

FIGURE 4. (A) Typical myocardialclearancekineticdata (0—30mm)following

@“Tc-teboroximeinjection(10 mCi i.v.)during high-dose adenosine stress. Thepost-stenotic zone (closed circles) andcontralateralnonocciudedzone (opencirdes) data are derivedfromfixedROls inthe anteroseptaland posterolateralmyocardium.The raw kinetic data [upper left]andlogtransformeddata[upperright]withcorrespondingregression curves areshown (r = 0.9). In this study, the earlydearance half-time in the nonoccludedzone was 5 mmas comparedto 11 mminthe post-stenotic (“occluded―)perfusionbed.(B)Representativemyocardialclearance kinetic data (0—30mm)following injectionof @“Tc-teboroxime(10 mCi i.v.) infixed myocardial ROls in the occluded anteroseptal (dosed circles) and nonoccluded posterolateral(opencircles)perfusion beds followingtotal (100%)occlusionof the left anterior descending coronaryartery.The raw clearancedata [lower left]and log transformeddata [lower right] aredisplayed,withregressionofthelogtransformed data (r = 0.9). The post-stenoticclearance half-time was delayed versusnonoccludedperfusionzones(11.5 vs 6.0mm).

A200

@ 150

@ 100

°so

120

100

@80

@60

t 40

20

—0-- No@Occk@ded-.-Occ@@d@d

6

5

25 30 1

4—,,—.No@Occluded

-@- Occluded

0 5 10 15 20 25 30 S 10 15 20 25 30

Tjme @nutes

99mTcteboroxime myocardial clearance results inquantitative “redistribution―of activity into poststenotic myocardium in 60%—83%(7 1% ±12%) ofstudies at an average of 8.8 ±2.5 mm followinginjection, with qualitative evidence of defect “redistribution―in 60% ofthese studies.

5. Sensitivity,specificity,and diagnosticaccuracyoftracer half-time clearance data for detecting poststenotic perfusion abnormalities were 62%, 100%and 81% after maximal stress. These data acquiredin a close-chested animal model may be extrapolated,with caution, to the clinical use of @mTc@teboroximemyocardial perfusion imaging.

Myocardial Imaging ConsiderationsMyocardial Tracer Uptake. The peak myocardial uptake

ofintravenously injected @mTc@teboroximeis 2.3% ±0.8%of the injected dose (1), and is theoretically related tocoronary blood flow (relative to cardiac output) and extraction fraction. In perfused hearts, myocardial extractionof this agent consistently exceeds that of either 2OVflor

@mTc-sestamibi(mean E max = 0.76 ±.09 versus 0.62 ±0.09versus0.30±.10; p < 0.01)(20). Themyocardialextraction (E max = 0.72 ±0.09) remains constant over awide range of flows (5,20). Coronary blood flow was notdirectly measured during the stress-occlusion imagingstudies, although Doppler flow probe studies in a subgroupofanimals confirmed significant coronary hyperemia comparable to previous studies (14—18) in response to highdose adenosine (coronary flow reserve = 2.0) and dipyri

damole (coronary flow reserve = 2.6) infusion. The ratioof increased coronary blood flow to cardiac output (1.6—4.4) favoredmyocardialtraceruptakeduringpharmacologic coronary vasodilation. Differences in the regionaluptake of99mTc@teboroxime following these varied stressesshould therefore have been primarily dependent uponchanges in regional myocardial blood flow.

Myocardial Clearance Kinetics. Canine studies havedemonstrated differential washout rates of @mTc@teborox@ime during baseline conditions and coronary hyperemiawithin 4 mm ofinjection using a modified SPECT camerasystem (5). This differential clearance effect is observed inboth early (t½ 2.3 ±0.6 versus 1.5 ±0.6 mm) and lateU',,= 20±9versus34±9mm)phasesof@mTc@teboroximewashout. In a study utilizing serial planar imaging (4),postexercise 99mTcteboroxime washout in both normaland CAD patients was faster than that occurring at rest.In CAD patients, late phase washout half-time followingrest injection equalled 50 ±17 mm versus 31 ±10 mm innormal subjects(p < 0.01). Thus, the myocardial clearanceof 99mTcteboroxime occurs at different rates during coronary hyperemia and varied levels ofcardiac work and maybe delayed under conditions of chronic myocardial ischemia.

We made no attempt to perform compartmental analysis on these dynamic 30-sec images that do not possess thetemporal resolution of our serial blood sampling data.Cardiac Na(Tl) probe studies of myocardial clearance ofthis agent following intracoronary injection demonstrate abiexponential washout pattern with a 2-mm fast compo

2005Post-Stenotic @Tc-TeboroximeKinetics •Stewart et al

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ditions and following dipyridamole stress (mean t,, = 21±4 versus 12 ±4 mm) (5). Differences in clearancekinetics following intracoronary and intravenous injectionare due in part to tracer recirculation and continuedreuptake postinjection following intravenous dosing.

Blood Clearance Kinetics. Previous animal studies (5,23) have demonstrated rapid blood clearance of 99mTc@teboroxime after intravenous injection, with no differencein baseline and dipyridamole blood kinetics. In previousclinical studies, rest injection blood levels decrease from39% of the injected doseat 90 secto only 9.5% at 15 mm(1). Residual blood 99mTc@teboroximeactivity in dogs atrest and after dipyridamole stress averages 8% ±3% ofpeak at 2 mm and 4% ±2% at 5 mm (5). Blood-poolclearance data were acquired in the current study throughout imaging (30 mm) to examine the input function atbaseline and following adenosine and dipyridamole stress.These data indicated rapid biexponential blood-pool clearance of the agent under each experimental condition andconfirmed that blood-pool background activity did notsignificantly affect myocardial imaging beyond 2 mm postinjection (Fig. 3). Early blood 99mTc@teboroximeclearancekinetics were comparable and significantly different fromcontrol following dipyridamole and adenosine stresses.

Experimental LimitationsCoronary Stenosis Model. The severe (>90%) partial

coronary stenoses utilized in these studies (19) predictablyreduced the coronary flow reserve to markedly abnormallevels, although a range of abnormality was possible (14,18). In contrast to human angioplasty (24), in awake oranesthetized animals coronary flow increases in nonoccluded perfusion beds during contralateral coronary arteryocclusion (25). No attempt was made in the current studyto utilize pharmacologic neuronal blockade, thus the potential existed for reflex contralateral hyperemia with single coronary artery occlusion in these studies. Coronaryflow in the contralateral unoccluded bed remains unchanged during pacing “demand―stress compared to control conditions ( 1.4—1.5 ml/min/g) in our model (19).

Pharmacologic Stress. Both pharmacologic agents utilized in the current study have profound, dose-dependenteffects on coronary blood flow, which plateau at the highestdoses administered (15—18)and preferentially alter subendocardial perfusion (15,16). Despite reflex changes insystemic blood pressure (27) and cardiac index (29), intravenous vasodilator administration does not alter intrinsicleft ventricular function in normal individuals (28) or dogs(13).

In the current study, near-maximal vasodilatation wasachieved by both high-dose adenosine and dipyridamoleat similar doses to those in previous studies (13,27—29)without associated significant global or regional LV functional effects in the absence of coronary occlusion. Poststenotic reactive hyperemia may have accelerated clearance in these beds (30), potentially reducing the differences

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2006 The Journal of Nuclear Medicine•Vol.32 •No. 10 •October 1991

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FIGURE5. (A)Pairedimagesfollowinginjectionof @“Tc-teboroxime(10 mCii.v.)dunngdipyridamoleStreSSwithoutstenosis[upper left], and dipyndamolestress with partial LAD occlusion[uppernghtl. The dipyndamolebaselinestudy demonstratesexcellentcardiacvisualizationwith some residualblood-poolactivity(1mmpostinjection)anda smalldefectat theapicalsiteof instrumentation.The stressimageillustratesa myocardialperfusiondefect in the anteroseptalwall. (B) A paired imagesetfollowinginjectionof @“Tc-teboroxime(10mCii.v.)inthecontrolstate[lowerleftjwithoutstressor coronarystenosis,andduringpacingstresswithpartialLADstenosis[lowerright].Myocardialvisualizationis excellent,with a smallapicaldefect due to instrumentation in the “baseline―study. Pacing stress plus partialstenosis produced a transient anteroseptalwall motion abnormality in the LAD territory.

nent and a variable (20—78mm) slow component (1,5).Preliminary kinetic studies using high temporal resolutionprobe analysis of regional myocardial @mTc@teboroximeactivity in a canine occlusion model have confirmed bioexponential tracer clearance and differential washout in normal versus ischemic tissues (31). Low counts and statistical“noise―of the late (>1 1 mm) counts made any determination of a late compartment size impossible. The reduction from 1-mm postinjection peak average counts at 15—20 mm following injection was 70% ±30% (residual meanactivity = 30% ±3%). This deterioration of count rateswas visually confirmed on inspection of these images.

Image-derived myocardial activity clearance after intravenous injection is monoexponential during control con

aFIGURE 6. Serial @Tc-teboroximemyocardialimagesfollowinghigh-doseadenosinestresswithoutocclusion(A),andafterhigh-doseadenosinestresswithseverepartialLADstenosis1mm postinjection(B) and at 5 mm postinjection (C). The lattertwo imagesdemonstrate clear evidenceof relativedefect “redistnbution―phenomenoninthe anteroseptal perfusiondefect. Datafrom the same animal are quantitativelydisplayed in Figure 2.This “redistribution―phenomenonwas presentin 60% of highdose adenosineplus LAD stenosisstudies.

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observed between normal and post-stenotic clearance kinetics. Significant differences in teboroxime clearance werenoted, despite this potential but transient confoundingeffect.

Qualitative-Quantitative “Redistribution“Concordance.The 60% concordance between qualitative and quantitative relative “redistribution―for the different stresses studied represents the relationship between images that showedunequivocal evidence of “redistribution―by both analyticmethods. The rapid clearance of the 99mTc@teboroximefrom the canine myocardium made qualitative evaluationof perfusion defects beyond 5 mm difficult in 20% ofstudies due to low count rates. This resulted in lower ratesof qualitative “redistribution―(54%) as compared to themore rigorous quantitative curve analysis (7 1%). The approach of@mTc@teboroximecounts to within 40% of theiroriginal difference in the unoccluded and post-stenoticzones might not have been visually appreciated, even byexperienced observers (corresponding to a normal versusdefect zone counts ratio of 1.67).

Background Subtraction. Different background activitycontributions from the splanchnic and pulmonary regionsmay confound the evaluation of static planar images oftracers with significant hepatic uptake such as 99mTc@ses@tamibi (22,26), 20―fl(12), ‘231-phenylpentadecanoic acid(10) and meta-iodobenzyl guanidine (9). Planar 99mTc@sestamibi images differ from 20Tl images due to theirmarked subdiaphragmatic uptake (in liver, gallbladder,intestinal tract) and decreased low-photon energy scatter(22). These features are also noted in @mTc@teboroximeimages (4,5,30), which are characterized by spatially andtemporally inhomogeneous background activity. Bloodpool predominates early following injection (0—1mm),with a gradual increase in lung activity (low level) andsplanchnic activity (high level) by 5—10mm postinjection.To address this difficult problem in the current dynamicimaging study of 99mTcteboroxime kinetics, two background ROIs were placed at the level of the heart wellabove the diaphragm and secondary hepatic counts. Averaged activity in one blood pool and one lung ROl wereused to correct for spatially and temporally variable background effects in each image frame. Based on examinationof our raw time-activity data and previously reportedexperimental (31) and clinical data (4,5,23), an early (1—11 mm) myocardial washout rate was calculated.

The use oftwo blood-pool regions (aorta and LV cavity)caused oversubtraction of counts from early images, andinadequate background subtraction in later images. Theuse of lung only ROIs was insufficient for backgroundsubtraction of early images. A narrow range of early (5mm) lung-to-heart 99mTcteboroxime ratios followed disparate hemodynamic stresses. Correction for temporallyvariable background activity was prospectively performedprior to analysis ofmyocardial clearance kinetics followingcoronary hyperemic and ischemic stresses, revealing aperfusion defect in 85% of studies.

Interpolative background subtraction methods havebeen used to correct for high secondary lung and splanchnic counts in static planar 9vmTc@Sestamibistudies (22),but would be difficult to apply to the 40 frame dynamicplanar imaging protocol utilized here. There are no datato confirm whether splanchnic uptake of 99mTc@teborox@ime, a potential confounding effect in inferoapical perfusion beds (2,4), varies at different workloads or under theeffect of coronary hyperemia. A modified interpolativebackground subtraction technique will be required to optimize ischemia detection in standard static planar 99mTc..teboroxime images.

Standard rotational tomographic imaging reduces theproblem ofoverlying background activity, but depends ona relatively stable tracer concentration in the myocardiumover the acquisition time. The rapidly cleared 99mTc@tebo@roxime agent may be tomographically studied with multiple head camera systems that reduce imaging time.

Clinical ImplicationsThese data provide important insights into the clinical

potential for combining nonexercise cardiac stresses withmyocardial 99mTc..imagiflg.In a previous clinical study(15), 80% of 99mTcteboroximeperfusiondefectswerefound to be distal to high grade (>90%) stenoses similarto those in this experimental protocol. Our studies, performed under a variety of nonexercise maximal stressconditions, demonstrated comparable sensitivity (62%),high specificity (100%) and overall diagnostic accuracy of8 1% for detecting regional ischemia based on myocardialtracer clearance rates. By extrapolating these data to aclinical setting, optimum pharmacologic stress (dipyridamole 0.56 mg/kg or adenosine 160 sg/kg/min) or transesophageal pacing would have correctly identified 60% ofpost-stenotic zones, with no false-positive studies. Inclusion of additional studies with qualitatively graded visual“redistribution―increased sensitivity to 80%.

The potential clinical applicability of this analysis ofdynamic teboroxime clearance (disappearance) for evaluation of functional perfusion abnormalities in patientswith defined coronary anatomy is implied. Studies of99mTcteboroxime in coronary artery disease patients usingan exercise-rest imaging protocol have also demonstratedthat dynamic early (5—10mm) postexercise imaging detects “redistribution―in 82% of initial perfusion defects(2). Our description of early postinjection relative 99mTc..

teboroxime “redistribution―by qualitative and quantitative analysis in this study confirms these clinical observations and extends previous studies by demonstrating thisphenomenon during reperfusion after transient total occlusion and following nonexercise (pharmacologic andpacing) stresses. Further studies of maximal exercise andnonexercise stress will be required to determine whetherless severe stenoses produce comparable post-stress defectvisualization and relative “redistribution―to that observedin the current experimental study of severe coronary stenosis and occlusion-reperfusion.

Post-Stenotic @“Tc-TeboroximeKinetics •Stewart et al 2007

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ventricular performance in conscious dogs. Am J Physiol 1990:258(part2):H424—430.

14. Kirkeeide RL, Gould KL, Parsel L. Assessment of coronary stenoses bymyocardial perfusion imaging during pharmacologic coronary vasodilatation. VII. Validation ofcoronary flow reservea single integrated functionalmeasure of stenosis severity reflecting all its geometric dimensions. J AmCoilCardiol 1986:7:103—I13.

15. Gerwitz H, Gross SL, Williams DO, Most AS. Contracting effects ofnifedipine and adenosine on regional myocardial blood flow distributionand metabolism distal to severe coronary arterial stenosis: observations insedated, close-chest domestic swine. Circulation 1984:69:1048—1057.

16. Rembert JC, Boyd LM, Watkinson WP, Greenfield JC. Effect of adenosineon transmural myocardial blood flow distribution in the awake dog. Am JPhvsiol l980:239:H7—HI3.

17. Wilson RF, Christensen B, Zimmer S. Laxson D, White CW. Effects ofadenosine on the coronary circulation in humans. J Am Coil Cardiol1989:13:132A.

18. Wilson RF. White CF. Intracoronary papaverine: an ideal coronary vasodilator for studies of the coronary circulation in conscious humans. Circulation 1986;73:444—457.

19. Applegate Ri, Walsh RA, O'Rourke. Comparative effects of pacing-induced and flow-limited ischemia: the effect of severity versus type ofmyocardial ischemia on diagnostic function. Circulation 1990:8 1:I380—1392.

20. Leppo JA, Meerdink DJ. Comparative myocardial extraction of two technetium-labeled BATO derivatives (SQ302 17, SQ32014) and thallium. JNuclMed 1990:31:67—74.

2 1. Grunwald AM, Watson DD, Holzgrefe HH. Irving JF, BelIer GA. Myocardialthalliumkineticsin normalandischemicmyocardium.Circulation1989:64:610—618.

22. Koster K, Wackers FJT, Mattera JA, Fetterman RC. Quantitative analysisof planar technetium-99m-sestamibi myocardial perfusion images usingmodified background subtraction. J NuclMed 1990:31:1400—1408.

23. Narra RK, Nunn AD, Kuczynski BL, Feld 1, Wedeking P. Eckelman WC.A neutral technetium-99mcomplexfor myocardialimaging.J NuclMed1989:30:1830—1837.

24. FeldmanRL, Conti CR, PepineCJ. Regionalcoronaryversusflow responses to transient coronary artery occlusion in human beings. J Am CoilCardiol1983:2:1—10.

25. Joyce EE, Gregg DE. Coronary artery occlusion in the intact unanesthetizeddog: intercoronary reflexes. Am J Plivsiol 1967;2 13:64—70.

26. Kiat H, MaddahiJ. RoyL. FriedmanJ, BermanDS.Comparisonof Tc99m-methoxy-isobutyl with TI-201 imaging by planar and SPECT techniques for assessment of coronary diseases. Am Heart J 1989:1 17: 1—11.

27. Marchant E, Pichard A, Rodriguez JA, Casanegra P. Acute effect ofsystemic versus intracoronary dipyridamole on coronary circulation. Am JCardiol1986:57:1401—140.

28. Watt AH. Penny WJ, Singh H, Routledge PA. Henderson AH. Adenosinecarries transient dilatation ofcoronary arteries in man. BrJ Clin Pharmacol1987:24:665—668.

29. Biaggioni I. Olafsson B, Robertson RM, Hollister AS, Robertson D. Cardiovascular and respiratory effects of adenosine in conscious man. CirculationRes 1987:61:779—786.

30. Leppo JA, Okada RD. Strauss HW, Pohost GM. Effect of hyperaemia onthallium-20l redistribution in normal canine myocardium. CardiovascRes1985:19:679—685

3 I. Glover DK, Okada RD. Hebert CB. Tc-99m-teoboroxime (SQ3O,2l7,Cardiotec) kinetics in normal and ischemic canine myocardium. Circulalion 1990:82(suppl IIl):III—486.

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ACKNOWLEDGMENTS

The authors thank Dr. Adrian Nunn (Bristol-Meyers-SquibbInstitute) for his support, Mr. Daniel Escobedo for his experttechnical assistance, Ms. Debbie Helterbridle for secretarial assistance and Dr. Tuhin K. Chaudhuri and Mr. John Straw,Division of Nuclear Medicine, Audie L. Murphy Veterans Administration Hospital, for expert radiopharmacy support. Supported in part by the American Heart Association (Texas affiliate)grant-in-aid (88G-355) and by the Bristol-Meyers-Squibb Institute, Princeton, NJ. Presented in part at the American HeartAssociation 63rd Annual Scientific Sessions, Dallas, TX, November 1990.

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1991;32:2000-2008.J Nucl Med.   Richard E. Stewart, Betty Heyl, Robert A. O'Rourke, Ralph Blumhardt and D. Douglas Miller  Clearance Kinetics After Experimental Ischemia and Hyperemic StressDemonstration of Differential Post-Stenotic Myocardial Technetium-99m-Teboroxime

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