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Dipyridamole's Role in Detecting Ischemia in Thallium-201 Imaging, Lecture notes of Medicine

The use of dipyridamole in enhancing the sensitivity of Thallium-201 myocardial perfusion imaging in detecting ischemia, particularly in symptomatic patients with known coronary artery disease who exercise submaximally. The study reveals that dipyridamole can unmask scintigraphic evidence for ischemia in such patients, leading to more accurate diagnosis and better treatment planning.

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  • How does dipyridamole affect the sensitivity of Thallium-201 myocardial perfusion imaging in detecting ischemia?

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bg1
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 heartrate.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 interrupted at 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 @°i1imagingafterdipyridamoleincombinationwithlow
levelexercisein15symptomaticpatientswithnon-diagnostic
20111scans, who exercised submaximally. Most patients had
angina,ST-segmentdepressionand evenexertionalhypoten
slon andwere referred for stress@ testing for determining
thefunctionalsignificanceofknowncoronaryarterydisease.
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.Sevenpatientswith fixed defects in 28 sag
mentsafterexerciseandtwo with smallareasof borderzone
Ischemia in seven additional (sub)segments, demonstrated
fixed in defects in onlynine segmentsbut reversibledefects
in 40 segments after dipyridamole. Quantitative analysis re
suItedin 24.8±28.5(meanvalue)samplepointsbelow—2
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 ±8.1
sample points below —2s.d. after exercise, increasing to 33.3
±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—2078
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.Box2500,3430EMNieuwegein,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-Jan Laarman,and Carl APLAscoop
Departments ofNuclear Medicine and Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands; and
Department ofCardiology, Onse Lieve Veouwe Gasthuis, Amsterdam, The Netherlands
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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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(continued from p. 2063)

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  1. Strauss HW, Fischman AJ. Cardiovascular nuclear medicine: The next step. JNuclMed 1989;30:l 123—1128.

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?

  1. hepatic adenoma
  2. cavernous hemangioma
  3. simple hepatic cyst
  4. metastasis
  5. 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

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