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Myocardial Viability in Patients With ChronicCoronary Artery Disease

Comparison of 99mTc-Sestamibi With ThalliumReinjection and [18F]Fluorodeoxyglucose

Vasken Dilsizian, MD; James A. Arrighi, MD; Jean G. Diodati, MD; Arshed A. Quyyumi, MD;Karim Alavi; Stephen L. Bacharach, PhD; Jose A. Marin-Neto, MD;

Peter T. Katsiyiannis, MD; Robert 0. Bonow, MD

Background 99"Tc-sestamibi and thallium imaging havesimilar accuracy when used for diagnostic purposes, butwhether sestamibi provides accurate information regardingmyocardial viability in patients with chronic coronary arterydisease has not been established. Since there is minimalredistribution of sestamibi over time, it may overestimatenonviable myocardium in patients with left ventricular dys-function, in whom blood flow may be reduced at rest.Methods and Results We studied 54 patients with chronic

coronary artery disease with a mean ejection fraction of34±14%. Patients underwent stress/redistribution/reinjectionthallium tomography and, within a mean of 5 days, same-dayrest/stress sestamibi imaging using the same exercise protocoland with patients achieving the same exercise duration. Of the111 reversible thallium defects on either the redistribution orreinjection study, 40 (36%) were determined to be irreversibleon the rest/stress sestamibi study, whereas only 3 of 63irreversible thallium defects despite reinjection (5%) wereclassified to be reversible by sestamibi imaging. The concor-dance regarding reversibility of myocardial defects betweenthallium stress/redistribution/reinjection and same day rest/stress sestamibi studies was 75%. A subgroup of 25 patientsalso underwent positron emission tomography (PET) studieswith '5O-labeled water and [18F]fluorodeoxyglucose (FDG) atrest after an oral glucose load. As in the overall group of 54patients, there was concordance between thallium and sesta-mibi imaging regarding defect reversibility in 51 of 73 regions(70%). In the remaining 22 discordant regions (30%), 18(82%) appeared irreversible by sestamibi imaging but were

TNhe substance 9'Tc-sestamibi is a lipid-soluble,cationic perfusion tracer that is taken up in themyocardium in proportion to blood flow in a

manner parallel to that observed with microspheres andthallium, although with a somewhat lower myocardialextraction fraction than thallium.1-4 Unlike thallium,sestamibi uptake is not dependent on active transport,5,6and there is minimal myocardial redistribution of sesta-mibi over time.2,4,7 Therefore, the only informationregarding tissue viability to be obtained from sestamibiis thought to be related purely to the level of myocardial

Received July 6, 1993; revision accepted November 6, 1993.From the Cardiology Branch, National Heart, Lung, and Blood

Institute, and the Department of Nuclear Medicine, NationalInstitutes of Health, Bethesda, Md.Correspondence to Vasken Dilsizian, MD, National Institutes

of Health, Building 10, Room 7B-15, Bethesda, MD 20892.

reversible by thallium imaging. Myocardial viability was con-firmed in 17 of 18 regions, as evidenced by normal FDG uptake(10 regions) or FDG/blood flow mismatch (7 regions) on PET.These regions were present in 16 of the 25 patients studied(64%). We then explored methods to improve the sestamibiresults. First, when the 18 discordant regions with irreversiblesestamibi defects were further analyzed according to theseverity of defects, 14 (78%) demonstrated only mild-to-moderate reduction in sestamibi activity (51% to 85% ofnormal activity), suggestive of predominantly viable myocar-dium, and the overall concordance between thallium andsestamibi studies increased to 93%. Second, when an addi-tional 4-hour redistribution image was acquired in 18 patientsafter the injection of sestamibi at rest, 6 of 16 discordantirreversible regions (38%) on the rest/stress sestamibi studybecame reversible, thereby increasing the concordance be-tween thallium and sestamibi studies to 82%.

Conclusions These data indicate that same-day rest/stresssestamibi imaging will incorrectly identify 36% of myocardialregions as being irreversibly impaired and nonviable comparedwith both thallium redistribution/reinjection and PET. How-ever, the identification of reversible and viable myocardiumcan be greatly enhanced with sestamibi if an additional redis-tribution image is acquired after the rest sestamibi injection orif the severity of reduction in sestamibi activity within irrevers-ible defects is considered. (Circulation. 1994;89:578-587.)Key Words * scintigraphy * tomography * coronary

disease * myocardium * ischemia

blood flow, not to washout kinetics. Animal studies withsestamibi have demonstrated that the uptake and reten-tion of sestamibi require intact cell membrane andmitochondrial processes.8-10 However, whether the up-take of sestamibi can be used as a clinical marker ofmyocardial viability has not been established.From a theoretical standpoint, the minimal redistri-

bution of sestamibi might result in underestimation ofischemic but viable myocardium, especially in patientswith reduced regional perfusion at rest, in whom initialtracer delivery will be reduced. However, the perfor-mance of sestamibi compared with thallium for identi-fying viable myocardium has not been fully explored,especially in relation to clinical gold standards of myo-cardial viability, such as preserved glucose metabolismassessed by positron emission tomography (PET). In thepresent study, we determined whether alterations in

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membrane function (measured by serial thallium imag-ing) or the level of myocardial glucose metabolism(measured by PET) are better discriminators of viablemyocardium than abnormalities in relative myocardialflow reserve (measured by sestamibi). In addition, wedetermined whether redistribution of sestamibi afterinjection at rest can be detected clinically in patientswith chronic ischemic coronary artery disease andwhether this provides additional insight into myocardialviability beyond that obtained by rest/stress sestamibiimaging.

MethodsPatient Selection

This was a prospective study involving 54 patients withchronic coronary artery disease who were referred for exercisethallium scintigraphy. Patients were eligible for this study ifthey demonstrated at least one irreversible perfusion defect onstandard stress/redistribution thallium imaging. The patientsranged in age from 36 to 79 years (mean, 63 years); there were49 men and 5 women. All patients underwent a historyand physical examination, chest radiograph, ECG, thalliumand 'Tc-sestamibi single photon emission computed tomog-raphy (SPECT) imaging, and coronary arteriography. Thirty-three patients also underwent PET imaging to assess regionalmyocardial glucose utilization. Coronary artery disease wasdefined as >50% reduction in luminal diameter of at least onemajor epicardial coronary artery as determined by coronaryangiography. ECG Q waves were assigned to one of fourmyocardial regions as follows: leads II, III, and aVF represent-ing the inferior region, V, and V2 representing the septalregion, V2 through Vs representing the anterior region, and I,aVL, Vs, and V6 representing the lateral region. All cardiacmedications were withdrawn before exercise studies in 31 of 54patients (57%). In the remaining 43% of the patients, theseverity of anginal symptoms precluded discontinuation ofmedical therapy. We studied only patients with chronic stablecoronary artery disease; no patient with recent acute myocar-dial infarction or unstable angina was included in the study.

Thallium SPECT ImagingAll patients underwent exercise thallium SPECT as previ-

ously described." After an overnight fast, patients were exer-cised on a treadmill, and 2 mCi thallium was injected at peakexercise. SPECT thallium images were obtained with a wide-field-of-view rotating gamma camera equipped with a low-energy, medium-resolution, high-sensitivity, parallel-hole col-limator (Apex 415, APC-3, Elscint Co, Boston, Mass) centeredon the 68-keV photo peak with a 20% window. The camerawas rotated over a 1800 arc in an elliptical orbit about thepatient's thorax at 60 increments for 30 seconds each. Redis-tribution images were acquired 3 to 4 hours after exercise.Immediately after redistribution, a 1-mCi additional thalliumdose was administered at rest, and reinjection images wereacquired 10 to 15 minutes thereafter.

99mTc Sestamibi ImagingWithin a mean of 5 days after the stress/redistribution

thallium study, patients demonstrating persistent thalliumdefects after conventional redistribution images were asked toreturn for a same-day rest/stress sestamibi study using 10 mCiof sestamibi at rest and 30 mCi at peak exercise.'2 SPECTsestamibi data were acquired 45 to 60 minutes after the doseadministered at rest and 60 minutes after the stress dose. Inthe first 29 patients, all technical factors for acquiring the data,such as the camera, camera angle and window settings, colli-mator distance from the chest wall, as well as the collimatoritself, were kept identical for both the thallium and sestamibistudies. However, when the data in the first 29 patients

appeared to be clearly in favor of thallium for identifyingreversible defects, the next 25 sestamibi patient studies wereacquired with a high-resolution collimator (while the otherparameters were maintained the same) to optimize the reso-lution of the sestamibi images with depth. An additional4-hour redistribution study after injection of sestamibi at restwas acquired in 18 of the last 25 patients before the stressstudy was performed. The reconstructed short- and long-axisimages of both thallium and sestamibi were read blindly, witheach segment graded as either normal, reversible, or irrevers-ible. Short-axis tomograms from the three sets of thalliumimages (stress, redistribution, reinjection) and three sets ofsestamibi images (rest, redistribution, stress) were also ana-lyzed objectively, by use of a semiautomatic quantitativecircumferential profile, as previously described."

Qualitative SPECT AnalysisThe distribution of thallium and sestamibi uptake was

analyzed qualitatively in the three standard orthogonal tomo-graphic imaging planes as follows: the septal, apical, andlateral regions in the horizontal long-axis view; the anterior,apical, and inferior regions in the vertical long-axis view; andthe anterior, septal, inferior, and lateral regions in the short-axis view. Thallium stress, redistribution, and reinjection im-ages and sestamibi rest, redistribution, and stress images wereall normalized to the region with the maximal myocardialactivity on the corresponding stress images. Four consecutiverepresentative slices of each view were displayed simultane-ously for interpretation. The images were graded by twoexperienced, blinded observers on a five-point scale from 0,markedly reduced/absent activity, to 2, definitely reduced, and4, normal. Differences were resolved by consensus. The gradeassigned to a given region was the lowest regional score fromall tomographic slices and views. A region was determined tobe irreversible if the assigned regional grade was abnormal andremained the same abnormal grade on subsequent images.Similarly, a region was determined to be reversible if theassigned abnormal regional grade increased or normalized onsubsequent images. In regions in which both reversible andirreversible defects were observed in the same vascular terri-tory, the region was assigned to be partially reversible. Sincethe presence of any reversibility implies myocardial ischemiaand viability, partially reversible defects were therefore con-sidered to be reversible defects in this analysis. A thalliumdefect that reversed on 3- to 4-hour redistribution images wasconsidered to represent ischemic and viable myocardium,independent of the changes in relative thallium activity thatoccurred after reinjection. Consequently, the determination ofwhether a myocardial region was viable required that anabnormal region identified on exercise images be reversible oneither the 3- to 4-hour redistribution or the reinjection study.

Quantitative SPECT AnalysisFor each patient, an operator-defined region of interest was

drawn around the left ventricular activity of each of fourconsecutive, 10.3-mm-thick, short-axis slices on the thalliumstress images and the corresponding thallium redistributionand reinjection tomograms and the sestamibi rest, redistribu-tion, and stress tomograms. The myocardial activity was sub-divided into eight sectors, each emanating from the center ofthe tomograms. All eight sectors were of equal arc and wereconstructed beginning at the 3 o'clock position (mid lateralwall) and proceeding counterclockwise. The sectors were thengrouped into four myocardial regions; anterior, septal, infe-rior, and lateral. The apical myocardial activity was deter-mined from the first, most apical tomogram. Assessment ofregional thallium activity on the stress images was carried outwith reference to mean thallium activity determined forgroups of normal male and female subjects." Similarly, re-gional sestamibi activity on the stress images was assessed withreference to mean sestamibi activity determined for groups of

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normal male and female subjects. The myocardial region withthe maximum mean counts per pixel on the thallium stress andsestamibi stress studies was normalized to the value for thecorresponding region for normal subjects of the same sex, andthis was used as a normal reference region for that patient.The same corresponding regions in the redistribution andreinjection thallium studies and rest and redistribution sesta-mibi studies were identified and used as the reference regionsfor those studies. The activity of thallium or sestamibi in allother myocardial regions was then expressed as a percent ofthe activity measured in that reference region for each of thethallium stress, redistribution, and reinjection and sestamibirest, redistribution, and stress sestamibi image series. A myo-cardial region was considered abnormal in a patient withcoronary artery disease if the thallium or sestamibi uptake onthe stress image was greater than 2 SD below the meanobserved in the same region for normal volunteers of the samesex. On the basis of previous reproducibility measurements inour laboratory,'3 a region with reduced activity on the stressstudy was considered reversibly ischemic if the increase ofnormalized thallium or sestamibi activity exceeded 10% on thesubsequent images for that region. Alternatively, a region withreduced activity on the stress study was considered irreversiblyabnormal if the normalized thallium or sestamibi activity didnot increase more than 10% on subsequent images for thatregion. These irreversible defects were then subgrouped onthe basis of severity of reduction in tracer activityl3'14: mild tomoderate (51% to 85% of peak activity) and severe (c50% ofpeak) defects. Since there are no data in the literature thatcompare the severity of sestamibi defect to established mark-ers of myocardial viability in patients with chronic ischemic leftventricular dysfunction, we arbitrarily chose to apply the samecriteria of mild to moderate and severe reduction in traceractivity to the sestamibi studies.

Positron Emission TomographyThirty-three patients underwent PET studies within a mean

of 10 days from the SPECT studies, of whom 25 had techni-cally adequate "0-labeled water (["O]H20) and FDG data toassess regional myocardial perfusion and exogenous glucoseutilization. Imaging was performed with a whole-body PETcamera producing 21 contiguous tomograms spaced 5.1 mmapart with a slice thickness of 13 mm and an in-plane resolu-tion of 6.5 mm. Images were obtained perpendicular to thelong axis of the body to create a series of transaxial tomograms.All patients were pretreated with 50 g oral glucose 1 hourbefore the study after an overnight fast. After a 20-minutetransmission scan to correct for attenuation, two separatebolus injections of 12 to 15 mCi of ["O]H2O were administeredintravenously 12 minutes apart. Like most PET scanners, ourscanner is unable to accurately handle the bolus phase of aninjection of more than 15 to 20 mCi when the heart is in thefield of view. Each study was analyzed separately, and the flowvalues were averaged together. This resulted in average flowvalues with SDs comparable to those that would have beenobtained from a single 30- to 40-mCi injection. The twoseparate bolus injections of ["O]H2O were followed by theadministration of 5 mCi of FDG 15 minutes later. DynamicPET data were acquired continuously for 5 minutes after each["O]H2O injection and for 60 to 75 minutes after the FDGinjection. The data acquired at 30 minutes after FDG injec-tion, corresponding to the final 30 to 45 minutes of dataacquisition, were reconstructed to create tomographic imagesof regional myocardial FDG uptake.

Regional Myocardial FDG Uptake. To compare relative re-gional myocardial FDG uptake with thallium and sestamibiactivities objectively, the acquired transaxial FDG images foreach patient were reconstructed in the short-axis view with thesame slice thickness as was used for the thallium studies (10.3mm). For each patient, short-axis tomograms from the threesets of thallium images (stress, redistribution, reinjection) and

the corresponding three sets of sestamibi images (rest, redis-tribution, stress) were visually aligned with the FDG tomo-grams for direct comparison. Myocardial regions of interestrepresenting the apical, anterior, lateral, septal, and inferiormyocardium were assessed by circumferential profile analysison each of the thallium, sestamibi, and FDG short-axis tomo-grams. Thallium, sestamibi and FDG activities were thencomputed within each region. In each patient, the myocardialregion with the maximum counts on the exercise study wasused as the normal reference region for that patient. Themyocardial region on the FDG series that corresponded to thenormal reference region on the thallium stress image serieswas used as the normal reference region for relative FDGuptake. FDG uptake in all other myocardial regions wasexpressed as a percent of the activity in this reference region.

Regional Myocardial Blood Flow. Absolute regional myocar-dial blood flow was computed from the dynamic ["O]H20data, as previously described.'4 The FDG image series wasreviewed for each patient to identify the appropriate tomo-graphic levels in which the left ventricular cavity was welldefined. An average of four such tomographic levels wereidentified per patient. Left ventricular cavity regions of inter-est were manually constructed on these FDG tomograms andwere then applied directly to the corresponding tomographic["O]H20 data to derive a composite ventricular blood pooltime-activity curve of the tracer. This ventricular time-activitycurve was then used as the ["O]H20 arterial input function.Previous studies have demonstrated that the blood pool time-activity curve computed in this manner accurately representsinstantaneous arterial concentrations of ['O]H20.1516 By useof the ["O]H20 arterial input function, the myocardial["O]H2O time-activity curve, and an assumed partition coef-ficient for ["O]H20 of 0.92, absolute regional myocardialblood flow was computed by a modification of the methods ofIida et al'7 and Herrero et all8 that automatically accounts forpartial volume and spill-over effects. This water model alsoprovides a partial volume correction factor that could in theorybe used to provide partial volume correction for FDG. How-ever, this correction factor also introduces additional statisticalfluctuations in the FDG values. In addition, correction of theFDG data for partial volume effects would create difficulties inthe comparison of the FDG data to the thallium and sestamibidata, which are also subject to partial volume effects. Thus, weelected not to correct the FDG data for partial volume. To thebest of our knowledge, all previous viability studies using FDGhave also not performed this correction.Regional FDG Uptake Relative to Blood Flow. Regional FDG

uptake was then interpreted in relation to regional myocardialblood flow assessed by ["O]H20. Three groups of myocardialregions were identified: (1) normal (normal blood flow asso-ciated with normal FDG uptake), (2) mismatch (reducedmyocardial blood flow with FDG:blood flow ratio .110% ofthat of the normal reference region), and (3) match (reducedFDG uptake and FDG:blood flow ratio < 10% of that of thereference region). As previously described,'9 a region could bedefined as showing mismatch if FDG activity was normal,increased, or less than normal, as long as FDG activity wasdisproportionately increased relative to the reduced regionalblood flow. The cutoff for the FDG:blood flow ratio of 110%was derived from previously published data obtained in normalvolunteers in whom FDG:blood flow ratio values ranged from1.02 to 1.12 mg/g per minute,20 which is similar to the 1.20cutoff value used by Vanoverschelde et al.2' Although the. 110% cutoff value has not been correlated with measures offunctional recovery, we have previously shown, using the.110% cutoff value to define mismatch, that myocardialregions with FDG:blood flow mismatch have regional systolicwall thickening by gated magnetic resonance imaging that issimilar to that of regions with normal FDG uptake and that issignificantly greater than regions with FDG:blood flow match.This offers further support to the reliability of this objective

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method to calculate FDG:blood flow mismatch for identifyingviable myocardium.

Radionuclide AngiographyGated blood pool cardiac scintigraphy was performed to

assess left ventricular ejection fraction at rest, using red bloodcells labeled in vivo with 20 to 25 mCi of 9'Tc-pertechnetate.Imaging was done within a mean of 13 days from the SPECTstudies with a conventional Anger camera equipped with ahigh-sensitivity parallel-hole collimator, as previously de-scribed.22 The left ventricular ejection fraction was derived bycomputer analysis of the scintigraphic data, and regional wallmotion was assessed qualitatively by two experienced observ-ers from the images displayed in cineangiographic format.22The lower limit of normal for resting ejection fraction by ourtechnique is 45%.

Coronary ArteriographyCardiac catheterization was performed with the percutane-

ous femoral technique. Coronary artery stenosis and graftpatency were assessed by experienced cardiologists withoutknowledge of exercise thallium or sestamibi results. Twelvepatients had marked narrowing of one vessel, 14 of two vessels,and 28 of three vessels. In patients with bypass grafts, a vesselwas considered patent if there was no significant narrowingwithin the graft or in the native coronary artery distal to thegraft anastomosis.

Statistical AnalysisData are presented as mean±SD. Group comparisons be-

tween thallium stress/redistribution/reinjection and sestamibirest/stress images and differences between thallium and ses-tamibi studies with respect to exercise duration, anginal symp-toms, and ischemic ECG changes were performed by either X 2analysis or paired t test. Differences between the entire groupand the subgroup of patients who underwent PET studies withrespect to exercise duration, rate-pressure product, symptomsof angina, left ventricular function, and wall motion abnormal-ities were analyzed by either two-tailed unpaired t test or 2

analysis.

ResultsCharacterization of PatientsAmong the 54 patients studied, there was no signifi-

cant difference between the thallium and sestamibistudies with respect to exercise duration on treadmilltesting (5.3±2.6 versus 5.6±2.5 minutes, P=NS), thepercent of patients with anginal symptoms, or ischemicECG changes. Furthermore, when the characteristics ofthe 25 patients who underwent PET studies were com-pared with the entire group of 54 patients, exerciseduration on treadmill testing (5.6±2.5 versus 5.5±2.4minutes, P=NS), rate-pressure product achieved duringexercise (22±6x 10 versus 21±6x 10, P=NS), and thepercent of patients with anginal symptoms were thesame in both groups. There were also no differencesbetween the two groups with respect to the left ventric-ular ejection fraction or wall motion abnormality at rest.Left ventricular ejection fraction in the 54 patientsranged from 8% to 66% (mean, 34±14%) and wasbelow the normal range in 42 patients. In the subgroupof 25 patients who underwent PET studies, left ventric-ular ejection fraction ranged from 8% to 64% (mean,30±12%) and was below the normal range in 23patients.When patients who were studied on cardiac medica-

tions were compared with those who were off medicaltherapy, as anticipated, there were differences in exercise

Thallium-201

Stress E

AbnormalRegions

Reinjection : 1[Normalized or Irreversible

Improved

Tc-99m Sestamibi

Same Day 4Rest-Stress

Reversible Irreversible ReversibleFIG 1. Flow diagram displaying the prevalence of reversible andirreversible thallium perfusion defects by stress/redistribution/reinjection and same-day rest/stress sestamibi studies in the 54patients studied.

duration (4.3±1.2 versus 6.2±2.8 minutes, P<.002) andrate-pressure product (19±6x103 versus 24±5x103,P=.001) between the two groups. However, the numberof perfusion defects on stress images was the same inboth groups (3±1 versus 3±1, P=NS).

Qualitative Analysis of Thallium andSestamibi ImagesDuring thalliimn stress testing, perfusion defects de-

veloped in 174 myocardial regions, of which 111 werereversible and 63 (36%) were irreversible on redistribu-tion/reinjection images. Of the 111 reversible thalliumdefects, 40 (36%) were determined to be irreversible onthe rest/stress sestamibi study. In contrast, only 3 of 63irreversible thallium defects (5%) were classified to bereversible by sestamibi imaging (Fig 1). Hence, whenregions were classified as reversible or irreversible,same-day rest/stress sestamibi and stress/redistribution/reinjection imaging provided concordant informationregarding defect reversibility and myocardial viability in131 regions (75%), with 71 (54%) identified as revers-ible and 60 (46%) identified as irreversible. However,sestamibi misidentified ischemic myocardium as nonvi-able in 40 of 174 abnormal regions (23%), representing23 of the 54 patients (43%), compared with thallium.When data from the patients in whom a medium-

resolution collimator was used for acquiring sestamibiimages were compared with data obtained from ahigh-resolution collimator, the results for defect revers-ibility in the two patient groups were similar. Amongthe 29 patients in whom medium-resolution collimationwas used, 19 of 57 regions (33%) that were identified tobe reversible by thallium imaging were irreversible onrest/stress sestamibi images. Similarly, among the 25patients studied with a high-resolution collimator, 21 of54 regions (39%) identified to be reversible by thalliumredistribution-reinjection imaging were irreversible bysestamibi imaging.

Analysis of Perfusion Defects in Regions With ECGQ Waves and Wall Motion AbnormalitiesOf the 54 patients studied, a total of 100 asynergic

myocardial regions were identified, of which 42 were in

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Reversibility of Defects

1825%

23

32%

Normal or IrreversibleReversible

Rest-StressTc-99m Sestamibi

c

09

.E0

R &A X

z501-

Normal orMiid-Moderate

Severe

Severity of Defects

n =73

5170%

2%

45%

1723%

Normal or SevereMld-Modate I

Rest-S

Tc-99m Sestemibi

FIG 2. Diagram showing concordance and discor-dance between thallium stress/redistribution/rein-jection and sestamibi rest/stress images in 25patients who also underwent PET studies. Data onreversibility of defects (normal/reversible or irre-versible) are shown on the left, and severity ofdefects (normal/mild-to-moderate or severe) isshown on the right. Eighteen of 22 discordantregions between thallium and sestamibi studiesare reversible by thallium redistribution/reinjectionstudies. Myocardial viability was confirmed in 17 of18 regions by PET.

the apical region and the remaining 58 were either inthe anterior, septal, inferior, or lateral regions. Sincethere is no ECG correlate of the apical region, thalliumand sestamibi perfusion defects in relation to presenceor absence of ECG Q waves were assessed in the 58asynergic regions. Twenty-one of the 58 asynergic re-

gions were classified as hypokinetic and 37 as akinetic or

dyskinetic.Hypokinetic Regions. Among the 21 hypokinetic re-

gions, 8 had associated Q waves and 13 did not. Of the8 regions with Q waves, there was concordance of databetween thallium and sestamibi regarding myocardialreversibility or irreversibility in 5 regions (63%). In theremaining 3 regions (37%) with discordant results, all 3were reversible by thallium redistribution/reinjectionstudies but irreversible on the sestamibi rest/stressstudies. Of the 13 non-Q-wave hypokinetic regions,there was concordance of data regarding myocardialreversibility or irreversibility in 12 regions (92%), andthe remaining 1 region was reversible by thallium alone.Because hypokinetic regions indicate the presence ofviable myocardium, it is in akinetic or dyskinetic regionsthat viability is a clinical concern. Thus, we directed our

attention to the 37 regions that were judged to beakinetic or dyskinetic by radionuclide angiography.Akinetic orDyskinetic Regions. Among the 37 akinetic/

dyskinetic regions, 24 had associated Q waves and 13did not. Of the 24 regions with Q waves, there wasconcordance of data between thallium and sestamibiwith respect to myocardial reversibility or irreversibilityin 19 regions (79%). In the remaining 5 regions (21%)with discordant results, 4 were reversible by thalliumand 1 by sestamibi studies. Of the 13 non-Q-waveakinetic/dyskinetic regions, there was concordance ofdata regarding myocardial reversibility or irreversibilityin 10 regions (77%). In the remaining 3 regions (23%)with discordant results, all 3 were reversible by thalliumredistribution/reinjection studies but irreversible on thesestamibi rest/stress studies.

Comparison of Quantitative Thallium andSestamibi Results With PETTo investigate the apparent discordance between

thallium and sestamibi imaging regarding myocardialviability, and also to verify the concordance of the twoimaging protocols, regional blood flow and metabolicFDG data were analyzed in the subset of 25 patients.Among the 25 patients, 73 regions were identified to beabnormal on the stress thallium study. As in the findingsobtained in the overall group of 54 patients, when the

results of thallium and sestamibi images were com-

pared, there was discordance of data regarding myocar-dial reversibility or irreversibility in the 22 regions(30%), with 18 regions (82%) identified as reversible bythallium redistribution/reinjection studies but irrevers-ible on the sestamibi rest/stress studies. Myocardialviability was confirmed in 17 of 18 regions, as evidencedby normal FDG uptake (10 regions) or FDG:blood flowmismatch (7 regions) on PET. These regions were

present in 16 of the 25 patients studied (64%).In the remaining 51 regions (70%) with concordant

results between the thallium and sestamibi studies, 28(55%) were identified as reversible and 23 (45%) iden-tified as irreversible (Fig 2). Myocardial viability wasconfirmed in 26 of 28 regions (93%), as evidenced bynormal FDG uptake (12 regions) or FDG:blood flowmismatch (14 regions) on PET. Of the 23 regions thatwere irreversible both by thallium and sestamibi, only 14(61%) were confirmed to be nonviable by PET.The apparent discordance between PET, thallium,

and sestamibi imaging resulted when all irreversibledefects were grouped together, without considering theseverity of the reduction in tracer activity within thedefect. We therefore determined whether a quantitativeanalysis in which the severity of the irreversible thalliumand sestamibi defects was accounted for would improvethe concordance between the PET, thallium, and sesta-mibi results.

Quantitative Analysis of Sestamibi Activity in Irrevers-ible Defects. Of the 23 regions that were concordantlyirreversible by both thallium stress/redistribution/rein-jection and sestamibi rest/stress studies, 6 (26%) hadmild-to-moderate reduction in sestamibi activity(68±14%) and 17 (74%) had severely reduced sestamibiactivity (31±13%). Among the regions with mild-to-moderate irreversible sestamibi defects, thallium activ-ity was also only moderately reduced in 5 regions(63±10%), and PET identified all 5 to be viable. Incontrast, among the 17 regions with severe irreversiblesestamibi defects, thallium activity was also severelyreduced (35±7%), and only 4 of 17 regions (23%) hadevidence for viability by PET.Among the 22 regions in which the thallium and

sestamibi studies were discordant (17 of which wereviable by both PET and thallium), the majority (17, or77%) had only mild-to-moderate reduction in sestamibiactivity. The relative sestamibi activity within thesemild-to-moderate discordant regions was 63±5%, whichwas similar to that observed in the mild-to-moderateconcordant regions (68±14%, P=NS). Thus, the sever-

iNormal orReversibie

Irreversibie

c

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n = 73

2838%

45%

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Thallium-201

Stress LI

AbnormalRegions

Redistribution- 39 | 6Reinjection

Normalized or IrreversibleImproved

Tc-99m Sestamibi

Same DayRest-Stress

Reversible

Rest-Redistribution-Stress

Reversible

I N-,1

41Irreversible I

IrreversibleFIG 3. Diagram showing enhanced detection of reversibledefects by redistribution of sestamibi after injection of thetracer at rest. The prevalence of reversible and irreversibleperfusion defects with and without sestamibi redistribution iscompared with thallium stress/redistribution/reinjection studiesin 18 patients.

ity of sestamibi activity within irreversible defects ap-pears to provide valuable information regarding myo-cardial viability. When regions with irreversiblesestamibi uptake were reclassified as viable if the mag-nitude of the reduction of sestamibi activity was onlymild-to-moderate, sestamibi imaging underestimated vi-able myocardium in only 4 of 18 regions (22%) com-pared with thallium reinjection and FDG PET. This

increased the overall concordance between thalliumand sestamibi studies to 93% (Fig 2).

Rest/Redistribution/Stress Sestamibi Imaging. A sub-group of 18 patients had an additional 4-hour redistri-bution study acquired after the injection of sestamibi atrest. A total of 55 regions were abnormal on the stressthallium studies in these patients. As with the totalgroup, when thallium stress/redistribution/reinjectionand sestamibi rest/stress images were classified as re-versible or irreversible, the two imaging methods pro-vided concordant information regarding defect revers-ibility and myocardial viability in 39 of the 55 regions(71%), with discordance in 16 regions. All 16 discordantregions were identified to be reversible by thalliumstress/redistribution/reinjection imaging but irreversibleby rest/stress sestamibi imaging. However, this discor-dance rate was reduced by examining the sestamibiredistribution data. The 4-hour sestamibi redistributionimages identified 6 of the 16 defects (38%) that wereirreversible on the initial sestamibi rest study to bereversible and viable (Fig 3). Such redistribution wasobserved in 4 of 18 patients (22%). Two patient exam-ples in whom irreversible sestamibi defects on rest/stress protocol were identified to be reversible onsestamibi redistribution images are shown in Figs 4 and5. Thus, the inclusion of 4-hour redistribution data afterthe rest sestamibi injection increased the concordancebetween thallium and sestamibi in identifying reversibil-ity of defects to 82%.

DiscussionIn the past two decades, thallium scintigraphy has

played an important role in detecting coronary arterydisease and differentiating viable from infarcted myo-cardium.23 Since the uptake of thallium by myocardialcells is an active process, thallium scintigraphy has aunique potential for assessing regional blood flow andmyocardial viability. Normal thallium uptake duringstress and reversible thallium abnormalities on stress/3-to 4-hour redistribution images have been shown to be

Thallium-201RD RI

Tc-99m SestamibiS R

FIG 4. Tomograms from a patient with reversible thallium defects and irreversible defects on rest/stress sestamibi imaging. The patientperformed the same level of exercise with both thallium (6 minutes 33 seconds) and sestamibi (6 minutes 16 seconds) studies. Twoconsecutive short-axis tomograms are displayed for thallium stress (S), redistribution (RD), and reinjection (RI) with correspondingsestamibi tomograms of stress, rest (R), and redistribution. Thallium SPECT images reveal extensive inferior and septal perfusiondefects during stress, which are reversible on redistribution images and reinjection studies. Same day rest/stress sestamibi images,performed 3 days after the thallium study, show extensive inferior and septal perfusion defects, with partial reversibility in the upperseptum but irreversibility in the lower septum and inferior regions. Sestamibi redistribution images acquired 4 hours after injection of thetracer at rest show partial reversibility in the lower septum and inferior regions.

S RD

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T.htall:ium-201 .Tc99m Sestamib*iS RD RI S R RD

UEEFIn 5. Tomograms showing concordance between thallium reinjection and sestamibi redistribution imaging. Two consecutiveshort-axis tomograms are displayed for thallium stress (S), redistribution (RD), and reinjection (RI) with corresponding sestamibitomograms of stress, rest (R), and redistribution. Thallium stress/redistribution images reveal partially reversible inferior and fixedanterolateral defects that improve after reinjection of thallium at rest. Same-day rest/stress sestamibi images incorrectly identified theanterolateral region as being irreversibly impaired and nonviable and the inferolateral region to be only partially reversible compared withthallium redistribution/reinjection study. However, sestamibi redistribution images acquired 4 hours after injection of the tracer at restshow partial reversibility in the anterolateral region and complete reversibility of the inferolateral region comparable to the thalliumreinjection image.

accurate indicators of viable myocardium. However, asubstantial number of severely ischemic but viable myo-cardial regions may appear irreversible on standardstress/3- to 4-hour redistribution thallium scintigraphyand thus mimic infarcted myocardium. Recent studieshave shown that the identification of viable myocardiumin such irreversible thallium defects may be enhanced bythe reinjection of thallium at rest. Reinjection identifiesviability in up to 50% of defects that appear irreversibleat 3 to 4 hours11'314,24-34 and in 39% of defects thatappear irreversible at 24 hours.35 That myocardial re-gions identified by thallium reinjection represent viablemyocardium is supported by (1) improvement in bothregional perfusion and regional wall motion after revas-cularization,1"'25-27 (2) preserved metabolic activity byPET,'1429 (3) preserved regional systolic wall thickeningby gated nuclear magnetic resonance imaging,33,34 and(4) substantial regional augmentation of thallium (dif-ferential uptake >50%) after reinjection at rest.'3

Despite the excellent physiological characteristics ofthallium for imaging myocardial perfusion and viability,its low energy (68 to 80 keV) is suboptimal for scintil-lation camera imaging, since the radionuclide is readilyscattered and attenuated. Its relatively long half-life (73hours) limits the dose of thallium that may be adminis-tered, which further reduces image resolution. In con-trast, the higher emission energy of 140 keV for 'ETc(resulting in less attenuation) and significantly shorterhalf-life of 6 hours (permitting the administration of amuch higher dose of the tracer) are more optimal forgamma camera imaging.

9`"Tc-labeled sestamibi is a lipophilic perfusion tracerwhose uptake by the myocardium is distinct from that ofthallium. Unlike the transport of thallium, which (likepotassium) requires predominantly active transport sys-tems,36,37 the uptake of sestamibi is passive acrossmitochondrial membranes, but at equilibrium, sestamibiis retained within the mitochondria because of a largenegative transmembrane potential.38

Transcapillary transport and myocardial retention ofboth sestamibi and thallium are affected by the perfu-sion rate, capillary permeability, and the binding char-acteristics within the myocardium.8 9 Despite the differ-

ences in kinetics between sestamibi and thallium, theinitial regional myocardial uptake of the two tracers issimilar. This fact is supported by recent publishedreports from several large trials in humans that haveindicated that both agents have similar accuracy fordetecting coronary artery disease.39-42 With respect tothe assessment of myocardial viability, published re-ports to date have demonstrated an excellent correla-tion between rest sestamibi uptake and severity ofcoronary artery stenosis as well as a good generalcorrelation between sestamibi uptake and viability asassessed by wall motion.3,5 Among regions with onlymoderate reduction (50% to 67% of peak activity) insestamibi activity, 80% had improved sestamibi activityafter coronary artery bypass surgery. In contrast, only39% of regions with severe reduction (<50% of peak) insestamibi activity showed improvement in regional per-fusion postoperatively.5

In stunned but viable myocardium, in which coronaryflow has been restored by reperfusion, sestamibi uptakeshould be an accurate marker of cellular viability, andthis has been confirmed in several studies.610'43-48 Inexperimental models of stunned myocardium, the reten-tion of sestamibi has been comparable to that of thal-lium.'0'43 In contrast, in regions of necrotic myocardium,the retention of sestamibi is negligible and parallelsindices of viability, such as deoxyglucose uptake andhistochemical staining.'0 Furthermore, after acutereperfusion in animal models, a close correlation be-tween sestamibi autoradiograph images and pathologi-cal infarct size has been demonstrated,44'45 independentof regional blood flow.

In patients studied within the first week after throm-bolytic therapy for acute myocardial infarction, sesta-mibi defect size correlates significantly with regionalwall motion at the time of discharge,46 with late ejectionfraction measurements,46 and with peak release of cre-atine kinase.47 These confirmatory clinical studies sug-gest that sestamibi may be useful as a viability marker inthe setting of stunned myocardium after reperfusiontherapy for acute myocardial infaretion.The available data regarding the use of sestamibi for

identifying hibernating myocardium in patients with

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chronic coronary artery disease and left ventriculardysfunction are conflicting.5,32,49-51 Using conventionalplanar imaging and qualitative analysis in a small groupof coronary artery disease patients, Cuocolo and co-workers32 reported that 29% of reversible myocardialregions by thallium reinjection appeared irreversiblewhen a 2-day stress/rest sestamibi protocol was per-formed. If the mechanism of the thallium reinjectioneffect is merely that the reinjected thallium dose pro-vides a better assessment of resting myocardial perfu-sion than redistribution images, then thallium reinjec-tion results should be equivalent to results obtainedwhen sestamibi is injected at rest. It is likely that theperiod of thallium redistribution after exercise beforethe reinjected dose may be the key factor, with theimages after reinjection incorporating the metabolicinformation inherent in the redistribution data. Thus,thallium reinjection images are not merely measures ofresting blood flow.52 Uptake of thallium and sestamibi,like all other tracers, reflects both regional blood flowand myocardial extraction; these vary depending on theretention process involved for each individual tracer.However, despite the recognized metabolic or trans-membrane trapping of these tracers, the relation be-tween myocardial tracer uptake and blood flow is notsignificantly altered except during acute myocardialischemia, during conditions of extremely low pH, orduring hyperemic flow.We have previously shown that thallium reinjection

data provide a more accurate reflection of myocardialviability (as confirmed by FDG:blood flow mismatch byPET) than images obtained in the same patients imme-diately after a separate resting injection of thallium 1week later.52 These observations imply that perfusionagents that measure coronary blood flow alone may notprovide as complete or as accurate a measure of myo-cardial viability as an agent that redistributes, such asthallium. Since others have shown that sestamibi trackswith regional myocardial blood flow but does not redis-tribute appreciably compared with thallium, sestamibimay underestimate viable myocardium in regions withchronic reduction in blood flow. Our data with restingsestamibi images in the present paper support thisconcept. We identified a large number of myocardialregions that were classified as viable by the thalliumstress/redistribution/reinjection protocol but nonviableon the sestamibi rest/stress protocol. Viability of theseregions was confirmed by the PET data.Our data also identify two approaches that may be

used to maximize the ability of sestamibi to serve as amarker of viability. These surmount, in part, the limi-tations of sestamibi in relation to thallium for assessingviable myocardium. The first of these is the observationthat sestamibi will redistribute after a resting injectionin some patients with left ventricular dysfunction. Pre-vious studies suggest that sestamibi does redistribute incertain situations.4,7,53-55 After injection of sestamibi atpeak exercise, minimal but clinically relevant redistribu-tion of the tracer has been reported in ischemic myo-cardium of patients with coronary artery disease.53Recently, in a model of sustained low-flow ischemia,Sinusas et al54'55 have reported that sestamibi mayredistribute over 2.5 hours in a manner comparable tothallium. In the subgroup of our patients undergoing an

the tracer is injected at rest, sestamibi redistributionoccurred in 38% of the regions with perfusion defectson the initial rest image that were identified as viable onthe thallium and PET studies. Such redistribution wasobserved in 22% of patients and increased the overallconcordance between thallium and sestamibi imagingregarding defect reversibility to 82%. Thus, our dataindicate that 4-hour redistribution images (acquiredafter injection of sestamibi at rest) may provide addi-tional insight into myocardial viability in patients withchronic coronary artery disease beyond that obtained byqualitative rest/stress sestamibi imaging. It is also im-portant to note that, despite the acquisition of redistri-bution images, qualitative sestamibi imaging may stillunderestimate the presence of viable myocardium in18% of viable myocardial regions compared withthallium.The second approach that may be beneficial to en-

hance the performance of 9'9Tc-sestamibi for viabilityassessment is a quantitative analysis of regional sesta-mibi activity. Such quantitative methods have beenuseful in thallium imaging for identifying viable myo-cardium within apparently irreversible thallium de-fects.13'14'52 Among regions that were considered viableby thallium imaging and PET but possibly nonviable onthe basis of an irreversible defect on rest/stress images,78% had sestamibi activity that was >50% of theactivity in normal territories. If such mild-to-moderatesestamibi defects are considered to represent viablemyocardial tissue on the basis of sestamibi activityalone, and only severe reduction in activity (<50% ofnormal) is considered evidence of nonviability, then theoverall concordance between thallium and sestamibistudies increased to 93%.

Limitations of the StudyThe application of criteria for grading severity of

thallium defects to the sestamibi studies was arbitrary,and it may not have been optimal for sestamibi. It is alsoimportant to point out that thallium and sestamibiquantitative data are not truly "quantitative," for, un-like PET studies, attenuation correction cannot beperformed on SPECT studies. Furthermore, sinceSPECT does not correct for soft-tissue attenuation,there is regional heterogeneity of lower limits of normalfor both thallium and sestamibi that ranges from 70% inthe septum to 90% in the lateral wall. Thus, although itis possible to demonstrate values that fall outside thisnormal range, ie, "perfusion defect," it is not possible touse these normal profiles to quantify severity of defect,since the magnitude of heterogeneity of measuredtracer activity in normal subjects varies considerablyamong subjects. This is a limitation of SPECT imagingthat may be overcome by PET. However, despite theselimitations, the overall concordance between thalliumand sestamibi studies for the presence or absence ofviable myocardium by this quantitative approach islargely confirmed by PET.

ConclusionsIn summary, 9'9Tc-sestamibi has inherent limitations

in the identification of viable myocardium in patientswith chronic coronary artery disease and left ventriculardysfunction, in whom hibernating myocardium may

additional redistribution sestamibi study 4 hours after remain viable despite chronic reduction in regional

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blood flow. Rest/stress sestamibi imaging will incor-rectly identify up to 36% of myocardial regions as beingirreversibly impaired and nonviable compared with thal-lium redistribution/reinjection imaging and PET. Thus,if the clinical question to be addressed is one of thepresence or absence of exercise-induced ischemia andviability, then thallium imaging and PET appear to bepreferred techniques. However, two approaches can beused to improve the identification of reversible andviable myocardium with sestamibi. Despite a washoutrate from normal myocardium that is substantially lessthan that of thallium, sestamibi does exhibit redistribu-tion in some patients, and additional redistributionimages acquired after rest sestamibi injection greatlyenhance the identification of defect reversibility andviability. Alternatively, a quantitative analysis of re-

gional sestamibi activity after resting injections alsoenhances the detection of viable myocardium. Thus,either of these approaches or a combination of themmay be used to improve the performance of sestamibifor viability assessment.

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P T Katsiyiannis and R O BonowV Dilsizian, J A Arrighi, J G Diodati, A A Quyyumi, K Alavi, S L Bacharach, J A Marin-Neto,

99mTc-sestamibi with thallium reinjection and [18F]fluorodeoxyglucose.Myocardial viability in patients with chronic coronary artery disease. Comparison of

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1994 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.89.2.578

1994;89:578-587Circulation. 

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