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regions. One of the major causes of false-negative test
results is an inadequate exercise level in the absence of
symptoms (1). In exercise ECG studies 39%—50%of ab
normalities occur at heart rates in excess of 85% of the
maximally predicted heart rate and the highest level ac
counts for a quarterofdetected ST-segment abnormalities
(2,3). Sensitivity of the 201'fl test in detecting coronary artery disease (CAD) is lower when exercise tolerance is decreased due either to beta-blockade or physical impair
ment (4—6).
Myocardial oxygen demand is mainly determined by
the heart rate. An increase of the oxygen demand with the
level ofexercise enhances coronary blood flow disparity in
the presence of significant CAD. More distinct, regional
differences in coronary flow will lead to a better spatial
contrast using 2o―flscintigraphy (7).
Exercisetesting may be interruptedat a lower heart rate
because the patient reaches diagnostic criteria, such as
severe angina, tachyarrhythmias or ischemic ST-segment
depression. In most cases, reversibleperfusion defects will
be visible. Despite the fact that 20'Tl is injected when a
definite exercise endpoint is reached, it may be that in
some cases the images are not diagnostic. This may be due
to a false-positive exercise criterium or small branches
CAD but also to the fact that 201'flis injected at a submax
imal exercise level.
While it is known that dipyridamole increases the sen
sitivity of 201'flexercise in detecting ischemia in asympto
matic patients (8), little has been reported regarding the
contribution of dipyridamole in detecting ischemia in
symptomatic patients with known CAD who exercise sub
maximally. In this report, the hypothesis was tested that
in those selected cases 201'flscintigraphy after dipyridamole
with low-level exercise could offer additional diagnostic
power to the test. A greater degree of coronary vasodila
tation may be produced and subsequently disparity in
This study was undertakento establishthe additionalvalue of @°i1imagingafterdipyridamolein combinationwithlow levelexercisein15 symptomaticpatientswithnon-diagnostic 20111scans, who exercised submaximally. Most patients had angina,ST-segmentdepressionandevenexertionalhypoten @ slon and were referred for stress testing for determining thefunctionalsignificanceof knowncoronaryarterydisease.
Six patientswith a normalexercise @°i1test andone patient
with an apical defect only were found to have 37 segments (of 105 segments)with reversibleperfusiondefectsafter dipyridamoleinfusion.One patient showing two reversible defects after exercise had five reversible segments after
dipyridamole.Sevenpatients with fixed defects in 28 sag
mentsafterexerciseandtwo with smallareasof borderzone
Ischemia in seven additional (sub)segments, demonstrated fixed in defects in only ninesegmentsbut reversibledefects in 40 segments after dipyridamole. Quantitative analysis re suItedin 24.8±28.5(meanvalue)samplepointsbelow— s.d. of the meannormaluptakeafterexercise,whichin creased to 72 ±26.5 after dipyridamole infusion (p < 0.005). The washout analysis resulted in a mean value of 5.5 ±8. sample points below —2s.d. after exercise, increasing to 33. ±22.1 after dipyridamole(p < 0.005). ThaJlium-201myocar dial perfusion imaging after dipyridamole combined with low level upright bicyde exercise may unmask scintigraphic evi dance for ischemia in symptomatic patients who would 0th erwise have non-diagnosticimagingstudiesduringsubmaxi malexercise.
J NuclMed 1991;32:2071—
yocardial perfusion scintigraphy with 201'fl can de
termine the presence, localization and extent of ischemic
ReceivedJan.23,1991;revisionacceptedJun.26,1991. For reprints contact: J. Fred Verzljibergen, MD, Dept. of Nuclear Medicine, St.AntoniusHospital,P.O.Box2500, 3430 EMNieuwegein,TheNetherlands
MyocardialPerfusionImagingwithDipyridamoleandExerciseThallium-201•Verzijlbergenetal 2071
Inadequate Exercise Leads to Suboptimal
Imaging. Thallium-201 Myocardial Perfusion
Imaging After Dipyridamole Combined with
Low-Level Exercise Unmasks Ischemia in
Symptomatic Patients with Non-Diagnostic
Thallium-20 1 Scans Who Exercise Submaximally
J. Fred Verzijlbergen,Paul HMJ Vermeersch,Gert-JanLaarman,and CarlAPL Ascoop
Departments ofNuclear Medicine and Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands; and Department ofCardiology, Onse Lieve Veouwe Gasthuis, Amsterdam, The Netherlands
ICharacteristics TABLE
of Clinical and Hemodynamic Results in 15 TestsPatient SymptomaticPatientswithNon-diagnostic201@fl levelno. Exercise Age(yr) Gender HR(%) (W/m)
Thallium-20i Tests 1900
Exercise201Tibicycletests @°‘Ti-DP combined with
@ exercise
Non-diagnostic201Tiscans Diagnostic201Tiscans in patients who exercise submaximally i 105(99%) 15 (1%)
FIGURE1. PatientpopulationstudiedbetweenFebruary1987andOctober1989.
coronary flow with less restriction due to ischemic symp
toms at the moment of 2OVflinjection.
PATIENTSAND METhODS Between February 1987 and October 1989, 1900 patients were
referredto the department of nuclear medicinefor exercise2o'@fl
testing for the detection or evaluation of CAD. In the same period, 780 patients underwent @°‘Tlmyocardial perfusion im
agingafter dipyridamolecombinedwith low-levelexercise(9). A
20―nbicycleexercisetest wasusedunlessit wasknownor suspected that the patient would not be able to reach a sufficient
exerciseleveldue to peripheralartery disease,orthopedic prob
lems, emphysema, etc. If the patient was unable to reach at least 85% of the age-predicted heart rate without achieving one or
moreof the criteriato terminate,injectionof 20,'flwasdeferred
and the test was extended with dipyridamole (9). The study group was composed of 15 patients who had a non
@ diagnostic2o―fl after a submaximalexercisetest whichwas
interruptedbecause of accepted criteria (Fig. 1). Dipyridamole 20―flimaging was performed 7—10days after exercise 201'fl.Pa tient characteristics are given in Table 1.
Exercise Electrocardiography A calibratedbicycle ergometerin the uprightposition was used in a symptom-limited exercise test. The initial external load was
60 W for 3 mm. Thereaftertheloadwasincreasedevery3 mm
by 30 W until one of the following termination criteria was fulfilled:severe angina pectoris, an ischemic ST-segment depres sion ofat least 0.2 mV (leads CM5 and CC5), dyspnea, sustained ventricular tachyarrhythmiasor exertional hypotension (Table 2). In all patients,drugssuchasbeta-blockingagentsandcalcium antagonists were discontinued 24 hr before the test and digitalis
derivativeswerewithheldfor2 wk.Anti-anginalmedicationwas
replaced with short-acting nitrates. Patients were requested to
inform our department in caseof progressiveangina.
Thallium-201ImagingProtocol
At the highest achievable level of exercise, 2.5 mCi (92 MBq) 20'Tlwereinjected intravenouslyand exercisewascontinued for another minute. Imagingwas performedin the anterior, 30°and
70. left anterioroblique(LAO) view for 10 mm/projection,
beginning within 5 mm after cessation ofexercise. Redistribution scintigrams were obtained after 4 hr. The patients' physical
activities were restricted between the two recordings and the
patients were allowed to drink one cup of coffee but were to refrainfrom eating (10). All studies were performedon a Toshiba GCA 50, a small field ofview gamma camera, with a low-energy, all-purpose parallel-hole collimator. A 20% symmetrical energy window centered on the 80 keV photopeak was used. There was a minimum of 400,000 counts per image obtained. The camera was interfaced to a Medical Data Systems (MDS-A2) computer with dedicated nuclear medicine software.
Dipyridamole Infusion with Low-Level Exercise In all patients beta-blocking agents, calcium antagonists and aminophylline derivatives were discontinued at least 24 hr before the test. Patients were asked to refrainfrom drinking caffeinated beverages after midnight of the day before the study. AfterintravenousadministrationofO.l4 mg dipyndamole per kilogrambody weight per minute for 4 mm and flushing the line during the fifth minute, the patient was exercised for 4 mm at a
158M6490W/3269F8460W/3348M78120W/3449F7090W/2557M6090W/
HR(%)= percentageof age-relatedpeakheartrateachievedwith @°1Tlinjection. W/m = exercise level in Watts during a given time period in minutes.
2072 TheJournalof NuclearMedicine•Vol.32 •No.11 •November
Note:a stripedareadepictsa reversibledefectanda closedareadepictsa fixeddefect. DP/EXCMPI = Dipyndamolein com@nationwithlow-levelexercisemyocardialperfusionimaging;EXC MPI = myocardialperfusion imagingafterexercise LAD= left anteriordescendingLCX= left circumflexartery andRCA= nghtcoronaryartery.
TABLE 3
Thallium-201MyocardialPerfusionImagingAfterExerciseandDipyndamoleInfusioninCombinationwithLow-Level
ExerciseandAngiographicFindings
PatientNo. EXCMPI DP/EXCMPI Coronary angiography
@Q::@:@
@c@9c@
LCX100%,LADdistal85%
LAD 70%
@@ c::@ fl RCA100%,LAD80% @::Iji1@'@‘i@W ‘@@b LCX distal 95%
c@c:@@@@QcLAD75%
c:@RJ@)(-;:D RCA 1 00%,LCXprox.50%anddistal100%, q@@7 @(/ll)' ‘@lllJ@ apical hypokinesia
@ c@/JIQ@ RCA75%
@@::@CLAD65%,LCXdistal100%
@ @:9C LAD100%,RCAdistal90%
@@ c@/1@ RCA 1 00%,LCX80%
@@@ RCA90%,inferiorwailhypokinesia
@ c@:::9C RCA90%,LCX80%
@@ c@_, LCX90%,LAD70%
@ t@ @o RCA 80%, LCX prox. 70%, distal 100%, apical hypokinesia
@ 4@ c@19 RCA 95%
@ @k:@ RCA 1 00%,LCX90%inferiorwallhypokines
ii
showed reversible perfusion defects in 37 out of 105 seg
ments after dipyndamole. The localization and extent of
the lesions afterdipyndamole was in close correlation with
the angiographicfindings (Fig. 2).
One patient (Patient 8) demonstrated only limited is
chemia in the LAD flow-region that could hardly explain
increased lung uptake and severe dyspnea during exercise.
After dipyridamole infusion the ischemic area extended
over five instead of two segments within the LAD flow
region, which was found to be occluded in combination
with jeopardized collaterals from the RCA.
Seven patients (Patients 9—15)had one or more fixed
2074 The Journal of Nuclear Medicine •Vol. 32 •No. 11 •November
FIGURE2. (A)Thallium-201myocardial
perfusion images of a 51-yr-cid male in whom a successfulPTCA procedurewas performed on the left circumflex and left descending anterior artery 6 mo before imaging (patient no. 7). Thallium-201ex ercisewas performedbecauseof progres sive anginapectons.Thallium-201was in jected at a heart rate of 74% of the pre dictedvaluein combmationwfth 1 mm ST segment elevation. Despite high lung-up take only a small fixed apical defect is
found(anterior)anda smallreversibleap
Icaldefect(LAO-70).(B)Afterdipyridamole infusion,an extensivereversibleperfusion @@ defect is found In the anterolateral and .@2A anteroseptalwall(arrows).Againexten sive lung-uptakeis noted. Coronaryby pass surgerywas performedon the enter olateraland diagonalbranchand LAD.
LQO-
defects, and two patients had fixed defects combined with
small concomitant areas ofischemia (Patients 13 and 14).
After dipyridamole infusion, the 28 fixed defects found
after exercise decreased to 9 fixed defects, but the 7 revers ible perfusion defects increased to 40 segments. Most fixed
defects correlated well with hypokinetic and akinetic seg
ments demonstrated with left ventricularangiography.
Quantitative analysis resulted in decreased uptake of
201'flin 372 sample points(mean 24.8 ±28.5) afterexercise
and in 1080 sample points (mean 72 ±26.5) after dipyri
damole (Table 4). Decreased washout was noted in 82
sample points (5.5 ±8.1) after exercise and in 500 sample
points (33.3 ±22.1) after dipyridamole. The differences
between both sets of results were of statistical significance (p < 0.005).
DISCUSSION
TestResufts
From a large series of patients referred for stress 2oI1@@
imaging, we studied 15 patients who failed to demonstrate
reversibleperfusion defects despite angina pectoris and/or
ischemic ST-segment changes at a submaximal exercise
level. After dipyridamole infusion, 7—10days later, the
amount of ischemic segments increased from 9 to 82. Six
patients lacking any perfusion defects after exercise and
LlU-?
U RifT
@ @ -
one patient with only a small apical defect exhibited 37
reversible hypoperfused segments after dipyridamole,
whereas the eighth patient revealed a much larger reversi
ble perfusion defect in the LAD region (from two to five
segments).
In seven patients fixed defects were found, which were
not expected on the basis of any proof of sustained myo
cardial infarctions. Two of these patients had seven con
comitant reversible perfusion defects as well. After dipyr idamole infusion only 9 ofthe presumably found 28 fixed
defects remained fixed and the other 19 segments turned
out to be reversible.These fixed defects afterdipyridamole
infusion correlated well with akinetic and hypokinetic
segments found with left ventricular angiography. Addi
tionally, fourteen segments, which were assessed normal
afterexercise, showed reversibledefects afterdipyridamole.
Most patients were referred for stress 201'fltesting for
determining the localization and extent of known CAD.
All patients, but one, were symptomatic during exercise. Based on angiographic and/or clinical findings implicating
a high pre-test likelihood, it was reasonable to expect
reversible perfusion defects on the 201'flimages. The ob
vious lack of ischemic areas warranted additional dipyri
damole studies since in all patients 20―flwas injected at a
submaximal exercise level.
MyocardialPerfusionImagingwith Dipy@idamoleandExerciseThallium-201•Verzijlbergenat al (^2075)
and delayed images. Ingestion of glucose cannot ac
count for the different findings.
Mean percentage myocardial 201Tlwashout after di
pyridamole is only slightly lower than after exercise (12) in normally perfused myocardium. Slower than normal regional myocardial washout occurs in the ab sence ofCAD ifthe patient is injected at a submaximal
heart rate; the difference with 2OPflwashout after dipyr
idamole will increase in relation to the lower level of
heart rate. Not only will the submaximal exercise level
lead to a lower sensitivity in the detection ofCAD, slow
washout may hamper the fifing-in of hypoperfused
segments. Whether a thallium defect after the admin
istration of dipyridamole represents relative hypoper
fusion with limited ischemia compared to exercise
induced ischemia remains a tempting question. It may
be that ischemia is the main cause of slow ifiling-in. It
is obvious that further basic research is necessary to
better evaluate this observation. The observation that a
fixed defect after 3-4 hr does not necessarily demon
strate scar tissue necessitates delayed redistribution or
better reinjection of 1 mCi of 20―flat rest (32,33,36).
CONCLUSION
It has been proven that dipyridamole-201T1myocardial
imaging unmasks ischemia in nearly 30% of asymptomatic
submaximal tests. The present study indicates that dipyr
idamole with low-level exercise unmasks ischemia or a
larger area of ischemia in symptomatic patients with non
@ diagnostic 20―fl who exercised submaximally as well.
Fixed defects after exercise, not expected on the basis of
sustained myocardial infarction, turned out to be reversi
ble perfusion defects after dipyridamole infusion in most
cases. Dipyridamole-201T1 myocardial perfusion imaging
with low-level exercise more accurately reflected the sever
ity and extent of CAD and, most importantly, provoked
redistribution in viable myocardium with fixed defects
after exercise 201'flimaging in this subset of patients.
ACKNOWLEDGMENT
Weexpressourgratitudeforthe patientandskillfulassistance
of Mrs. J. Starink.
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A 43-yr-oldwoman with irritablebowelsyndromedeveloped
an episode of acute abdominalpain, which was not
characteristicof her prior symptoms.Youare shownboth a
hepaticsonogram(Fig.3)anda hepaticblood-poolscintigram
obtained with @Tc-labeledred blood cells (Fig. 4). Basedonthesonographicfindings(inFig.3)alone,which of thefollowingdiagnosesshouldbeconsidered?
- hepatic adenoma
- cavernous hemangioma
- simple hepatic cyst
- metastasis
- hepatocellular carcinoma
Truestatementsconcerningthefindingsinthispatient'slabel
edredbloodcellstudy(Fig.4)includewhichofthefollowing?
I I. Cavernoushemangiomaisthemostlikelydiagnosis.
12. SPECTisnecessaryfordefinitivediagnosis.
13. The likelihoodof hepatocellularcarcinomais ap
proximately 20%.
14. The likelihoodof metastasisis approximately20%.
L Poet R
L
1mm 5mm
Head Ant Feet
10 mm 15 mln
LongftudlnalScan Figure 3 (^) FIgure4A 20 mm
Poet
3 hr Figure4B
R
(continuedon p. 2125)
2078 TheJoumalofNuclearMedlclne^ •Vol.32^ •No. 11 •November
SELF-STUDY TEST
41
