Quantitative comparison of thallium-201 scintigraphy after exercise and dipyridamole in coronary artery disease

Quantitative Comparison of Thallium=201 Scintigraphy After Exercise and Dipyridamole in Coronary Artery Disease Shalendra Kumar Varma, MD, Denny D. Watson, PhD, and George A. Beller, MD

Data comparing myocardial thallium-201 imaging after exercise and intravenous dipyrklamok! infusion in the same patients are scarce. Accordingly, this study is a segment-by-segment quan6tative analysis of regional uptake and washout of thalgurn-201 after dipyrklamole (0.66 mg/kg) and symptom-limited exercise tesHng in 21 patients (aser58*99yearr)withdreapainaudied2.5f 1.0 weeks apart. Thallium-201 activity in 9 myocardial segmds was measured in initial and delayed ante&r and 45” left anterior oblique views, pmducing 164 pairs of segments in the dishfbution of 63 coronary suppty regions for dim comparison. The number of segments with normal thallhm201 uptake and the number of numerically significant defects wee rimWar with exercise and dipyrklamele (76 vs 73%, 24 VI 27%, respectively, ~not~).Aslightlyhigherpropor tion of *bution defects was found after dipytidamole infusion compered to exercise (17 vs lo%, p
From the Cardiology Division, Department of Internal Medicine, University of Virginia Health SciencesCenter, Charlottesville, Virginia. Thii study was supported in part by grant ROl HL-26205 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda,Maryland. Manuscript received October 28, 1988; revisedmanuscript receivedand acceptedJuly 10,1989. Addressfor reprints: GeorgeA. Beller, MD, Box 158,University of Virginia Health SciencesCenter, Charlottesville, Virginia 22908.

I

ntravenousinfusion of dipyridamole hasbeensuggested as an alternative to physical exercisefor myocardial perfusion imaging with thallium-201.1-3 It has beenreported that the sensitivity and specificity of dipyridamole-thallium-201 imaging for coronary artery diseasedetection is comparableor evensuperior to the sensitivity of thallium-201 scintigraphy after exercise.4 However, a direct comparison of segmental thallium uptake and washout after exerciseand intravenous dipyridamole in the samepatients who have no limitation to exercisetesting has not been reported. Since both exercise and dipyridamole induce heterogeneity in blood flow at the time of tracer administration, we hypothesized that the pattern of thallium-201 uptake on the initial imagesshould be similar.5-8Accordingly, we undertook this study to systemically compare the similarities and differences in uptake and washout of thallium-201 in consecutivepatients who rendered informed consent to undergo both procedures. None had any apparent limitations to performing an exercise test. MEW005 Patient bdection: The study population consistedof 21 patients who were referred for diagnostic evaluation of chest pain and gave informed consent to undergo thallium-201 scintigraphy after both exerciseand an intravenous dipyridamole infusion. The chest pain was classified as typical angina in 15 patients and atypical angina in 6 patients. Eighty-six percent were men and 14% were women with a mean age of 58 f 9.2 (standard deviation) years. Criteria for exclusion included a history of significant valvular disease,unstable angina, myocardial infarction within 6 months, known chronic obstructive pulmonary disease,asthma and chronic aminophylline use. All patients were studied while taking their prescribed drug regimens and no medication changesoccurred between the 2 studies. Graded exezeise te& All patients initially underwent a symptom-limited exercise test using the Bruce protocol. The test was terminated when symptoms (chest pain, angina, dyspnea or fatigue) prevented further exercise. Exercise and dipyridamole-thallium

scintigraphy:

Dipyridamole-thallium-201 scintigraphy was performed at 2.5 f 1 weeks after exercise scintigraphy. All patients were placed in a supine position for the imaging procedure.Dipyridamole was then infused intravenously at a dose of 0.56 mg/kg. This was followed 3 minutes

THE AMERICAN JOURNAL OF CARDIOLOGY OCTOBER 15.1989

871

45 LA;)

ANT

&

/ /

/

/ --

!

/

LA D/RCA

\ \

\

/

RCA myoeanlrl-Mintochm8ex;RCA=dghtcommy

872

LCX

LA

\. \ RCA

I -- --GJI

LAD

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64

a-Y;--

\

\

later with approximately 2.0 mCi of thallium-201. A similar dose of thallium-201 was administered during exercisescintigraphy in a manner previously described.9 Be acan analysis: In addition to conventional scintigraphic imaging, quantitation of regional myocardial thallium-201 activity was undertaken by methodspreviously described.6After quantitative analysis, 4 quantitative profiles on the anterior image and 5 scan segmentsin the 4Y left anterior oblique projection were examined (Figure 1). Redistribution and abnormal thallium-201 washout were designated by quantitative criteria.lO We also attempted to identify the vesselresponsible for a regional perfusion abnormality. The 9 myocardial scan segmentswere divided into 3 coronary supply regions (Figure 2). Defects in 1 or more scan segmentsin a particular coronary supply region caused the supply region to be designated as abnormal. Becausethere were 21 patients, a direct comparison of 63 coronary supply regions was possible.Two observersindependently interpreted all initial and delayed thallium201 images, with differences resolved by a third observer. Car&e eatheterizatios~ In 15 of 21 (71%) patients, selectivecoronary angiography and biplane left ventriculography was performed. Caliper-measuredstenosesof 250% in the 3 major coronary arteries were considered significant. Statistiesr Data were analyzed with the assistanceof commercially available computer software (RS/l). The

PREVALENCE

OF NORMAL

TABLE I Peak Myocardial Thallium-201 Uptake After Exercise or Intravenous Dipyridamole Peak Thallium-201 Uptake (counts/mCi injected Thallium-201)

Anterior view LAO view

Exercise

Dipyridamole

p Value

127 f 50 113f44

16Of60 148*53

o.ooD2

o.coo1

LAO = letl anterior oblique.

significance of differences between proportions was evaluated with the 2-tailed Fisher’s exact test. RESULTS

Hemodynamie data: The patients exercised to a workload of 7.4 f 2.4 METS and achieved84 f 15%of their age-predicted maximal heart rate. The relatively low heart rate achievedcould be attributed to concomitant P-blocker (66%) and calcium-antagonist (76%) treatment. After infusion of intravenous dipyridamole, there was an increasein the heart rate by a mean of 17 f 5 beats/min and a decreasein systolic blood pressure byameanof17f6mmHg. Peak thallium counter The peak thallium-201 activity collected after 8 minutes on the initial anterior and 45” left anterior oblique projections was calculated for 13 patients after both intravenous dipyridamole and ex-

PREVALENCE

SESMENTS

OF ASNORUAL

SEGCIENTS

50

100

40 m 4-l

p-o.

038

27%

IVOP

THE AMERICAN

JOURNAL

OF CARDIOLOGY

OCTOBER 15,1989

873

lWALUUM-2Dl

SClNllGRAPHY

AFI’ER EXERCBE AND DIPYRIDAMDLE

ercise. These peak counts were indexed to the dose (in mCi) of thallium-201 injected. As shown in Table I, the peak counts of thallium-201 were significantly higher after dipyridamole infusion. Quantitative

segment-by-mment

comparison:

There were 189 pairs of scan segmentsavailable for direct comparison. As shown in Figure 3, 76% of these segmentsdemonstrated normal uptake of thallium-201 after exercise. This was not statistically different from the 73% of these same 189 scan segmentsthat demonstrated normal uptake of thallium-201 after dipyridamole infusion. The number and fraction of scan segments that representeddefects were also similar (24 vs 27%). Figure 4 shows a segment-by-segment,comparison of thallium-201 uptake after exercise and intravenous dipyridamole. One-hundred twenty-nine scan segments demonstrated normal thallium-201 uptake after both exerciseand intravenous dipyridamole and 36 scan segmentsdemonstrated concordant abnormal thallium201 uptake. Thus, 165 of 189 scan segmentsor 87% showed concordance with respect to thallium-201 up take. Twenty-four scan segments showed discordant thallium-201 uptake (i.e., thallium-201 uptake was abnormal after either exercise or dipyridamole, but not both). In an attempt to determine whether the discordant findings in the 24 segmentswere evidenceof diseasein different vascular territories, we performed a vesselregion-by-vessel region comparison of thallium-201 uptake after exercise and intravenous dipyridamole. The uptake of thallium-201 in paired scintigraphic vascular regions after exercise or intravenous dipyridamole was in agreement in 61 of 63 (97%) of the coronary supply regions (Figure 5). Thus, when discordant segmental findings between dipyridamole and an exercise scintigram were observed, they usually involved segments

within the samevascular region. As an example, a scintigram after exercisein patient 8 demonstrateda defect in the upper septum with normal uptake in the lower septum. After dipyridamole, a defect in the lower sep turn was noted, but the upper septum was normal. This resulted in classification of the upper and lower septum as 2 discordant segments.However, the left anterior descending artery supply region was classified as abnormal after both exerciseand dipyridamole. Interestingly, 33 of 189 (17%) scan segmentsdemonstrated redistribution defectsafter dipyridamole compared to 19 of 189 (10%) segmentswith redistribution defectsafter exercise (p <0.04) (Figure 3). Thus, 33 of 52 (63%) defects noted after dipyridamole infusion demonstrated redistribution compared to 19 of 44 (43%) defects noted after exercise (p = 0.06). ccmelationwitll comnary angiography: Fifteen of the 21 patients underwent coronary angiography. Fourteen of 15 patients had at least 1 coronary stenosisof 150%, and 10 had multivessel disease.Of the 45 major epicardial vesselsavailable for assessment(15 patients X 3 vessels),26 had a stenosisof 250% and 19 had no significant lesions.As shown in Table II, all 19 vascular regions subservedby angiographically normal coronary arteries were correctly identified as normal by both exercise and dipyridamole thallium-201 scintigraphy. Of the 26 vascular regions perfused by stenotic vesselsin these 15 patients, initial thallium-201 images with exercise and dipyridamole showedthe same 16 of 26 vascular zonesto be hypoperfused Thus, thallium-201 scintigrams after exercise or intravenous dipyridamole demonstrated identical results in these 15 patients. Sixty-one percent of the coronary supply regions perfused by stenotic coronary vesselsshowed an abnormal thallium201 scan nattern with both exerciseand intravenous dipyridamoie protocols.

EXERCISE NORMAL

ABNORMAL

NORMAL

129

8

ABNORMAL

16

36

DIPYRIDAMOLE

I

AGREEMENT

IN 165/189

FIGURE 4. A ssgment-by-segmed amnpadmef--2oluptakeafterexerdseendinbwcmour~~sWenpementofecmmgmentsshewedcamdentnonruler~~e.

874

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64

= 87.5%

Quantitative clearance of fhallii: The clearance between the initial and delayed images was calculated by measuring the difference between thallium activity on the initial and delayed views, dividing it by the thallium-201 activity in the initial views and multiplying by 100. While there was a 21% decreasein thallium-201 activity betweenthe initial and delayed imagesafter exercise, there was only a 12% reduction in thallium-201 activity after dipyridamole (p
IA

I

-

of Thallium-201 Uptake/Coronary for 45 Vascular Regions (15 Patients)

Exercise Dipyridamole

Normal

Abnormal

19/19 (100%) 19/19 (100%)

16/26 (61%) 16/26 (61%)

I

taken. Few patients have undergonethallium-201 imaging after dipyridamole infusion and exercise within a short period of time. In a study by Gould et a1,1475%of patients who had a perfusion defect after exercise also had a defect after oral administration of dipyridamole. The interpretation of scintiscanswas qualitative and no segmentalcomparisonof imageswas made. In a preliminary report of a select group of patients who failed to reach 85% of age-predictedmaximal heart rate or who achieved a low workload during exercise thallium, 21 patients underwent thallium-201 scintigraphy after dipyridamole.t5 Six of the 21 patients demonstratedredistribution defects.However, this was a very select population with limited exercise capacity; one would expect dipyridamole to unmask areas of potential ischemia not manifested at a low exercise workload. In an earlier study comparing distribution of thallium-201 after either exerciseor dipyridamole, Josephsonet all6 found a similar sensitivity and specificity for diagnosing coronary artery diseaseamong 38 patients. This was, however, a qualitative analysis limited to 5 myocardial regions. Furthermore, no comparison of washout patterns of thallium-201 in these patients was reported. In the present study, we systematically quantitated the initial distribution of thallium-201 and subsequent thallium201 washout on scintiscansobtained after exerciseand dipyridamole in the same patients.

EXERCISE NORMAL

ABNORMAL

NORMAL

47

7

ABNORMAL

7

20

DIPYRIDAMOLE

AGREEMENT FlGlJRE5.AVFSSd~-VeSWlregioncomprvbon

IN 67163

ofthalml-2ol~nterewas97%

=

97%

concordruKcin6lof63V~

--

THE AMERICAN

JOURNAL

OF CARDIOLOGY

OCTOBER 15,1989

875

l’WUlUM-#)l

SCINTIGRAPHY AFI’ER EXERCISE AND DIPYRIDAMDLE

We have demonstrated that the peak thallium-201 counts in myocardial segmentsafter dipyridamole exceed those seen after exercise. This suggeststhat the degree of coronary vasodilation and the resultant increasein coronary blood flow was probably greater after dipyridamole than exercise. This lends support to prior work by Gould17in experimental models. We showed that the number of normal scan segments and number of scan segmentsshowing perfusion abnormalities observedafter exerciseand dipyridamole were similar. This suggeststhat the relative distribution of thallium-201 and the degree of myocardial blood flow heterogeneity is similar after exerciseand dipyridamole infusion in thii patient population. The prevalence of thallium-201 redistribution was slightly but significantly greater on dipyridamole than on exercise scans within abnormal vascular scan regions. The explanation for this difference is not readily apparent but could be attributed to a greater degreeof regional flow heteroge neity induced by dipyridamole compared to exercise. Perhaps differences in washout kinetics, which will be discussed,contributed to this finding. Although the initial relative distribution of thallium201 after exerciseor dipyridamole infusion appearssim-

25

< 0.0001 If

”

Ex

IVDP

FlDlIREB.lbdtllamdDl~lhe~ mdddeyedh8geeafterexer&edhMwneus~mele.Thedemmlce eftlIayn-2Dlw8s~dewer etterd@lidmhlhmefterexerdee.

876

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64

ilar, there were differences in subsequentrate of thallium-201 washout in areas showing normal thallium-201 uptake. Thallium-201 washout from normally perfused segmentswas significantly slower after intravenous dipyridamole than after exercise. Becausethe time interval when the delayed images were begun was kept constant in the 2 studies, the differences could not be explained by an alteration in the time of delayed image collections. This fmding supports the work of Ruddy et al,‘* who demonstrated a slower myocardial clearance of thallium-201 in normal volunteers after dipyridamole compared to clearance after exerciseimaging. Our data indicate that quantitative criteria that have been developed for exercise thallium-201 scintigraphy can be used for dipyridamole scintigraphy.19The high degree (97%) of concordant findings in detecting normally and abnormally perfused coronary supply regions of the major coronary arteries strongly supports a comparable initial distribution of thallium-201 under exercise and dipyridamole states. However, one must be wary of interpreting isolated washout abnormalities without defectselsewhereon dipyridamole thallium-201 scansas abnormal: thallium-201 clearance betweenthe initial and delayed images is slower after dipyridamole induced vasodilation comparedto exercisestresstesting. There are severallimitations to this study. First, only 21 patients participated. However, the high concordance rate observed among the 189 pairs of scan segments suggeststhat recruitment of a larger number of patients would probably not appreciably alter the results. Patients took their prescribed medications during this study. This should affect scintiscansobtained after both exercise and dipyridamole becausethere were no alterations in medication regimens between the 2 studies. Qualitative interpretation of coronary angiograms using caliper readings may not be an accurate measure of the degreeof coronary artery stenosis.This limitation should not affect study results because thallium-201 scintigraphy after exercise and dipyridamole was performed in the same patients within a short period of time. Whatever errors in under- or overestimating stenosis severity would be applied to both exerciseand dipyridamole scan comparisonsin an identical manner. In conclusion, our study shows that exerciseand dipyridamole thallium-201 imaging in the same patients is comparable in detecting and localizing scan segments with normal or abnormal myocardial perfusion. The 2 imaging protocols yielded comparable results in identifying coronary vessels with significant stenoses and identifying those vessels without significant coronary artery disease.Dipyridamole-thallium-201 scintigraphy can be substituted for exercise stress scintigraphy, and the sensitivity and specScity for coronary artery disease detection and prediction of extent of disease will be comparable. v We are indebted to the staff of the Noninvasive Laboratory of the University of Virginia Hospital for the performance of thallium scintiscans and for the superb secretarial assistanceof Jerry Curtis.

REFERENCES 1. Schrader J, Berne RM, Rubio R. Uptake and metabolism of adenosineby human erythmyte ghosts. Am J PhysioI 1972:223:159-166. 2. C~tchley DJ, Ryan US, Ryan JW. Effect of aspirin and dipyridamole on the degradation of adenosinediphosphateby cultured cells derived from bovine pulmonary artery. J Clin Inwst 1980,66:29-35. 3. Albro PC, Gould KL, Weatcott RJ, Hamilton GW, Ritchie JL, Williams DL. Noninvasive assessmentof coronary artery stenosesby myocardial imaging during pharmacologic coronary vascdilation. III. Clinical trial. Am J Cardiol 1978;42:751-760. 4. LeppoJ, BoucherCA, Okada RD, Newell JB, StraussHW, PohostGM. Serial thallium-201 myocardial imaging after dipyridamole infusion: diagnosticutility in detectingcoronary stencuesand relationship to regional wall motion. Circulation 1982,66.649-457.

5. Pitxgerald GA. Dipyridamole. N Engl J Med 1987;316:1247-1257. 6. Kubler W, SpieckermannPG, BretscheniederHJ. Influence of dipyridamole (Persantin) on myocardii adenceinemetabolism.J MO/ Cell Cardiol1970;1:2338. 7. Afonso S. Inhibition of coronary vasodilating action of dipyridamole and adencaineby aminophylline in the dog. Circ Res 1970;26:743-752.

8. Beller GA, Holzgrefe HH, Watson DD. Intrinsic washout rates of thallium201in normal and ischemicmywardium after dipyridamoleinduced vasodilation. Circulation

1985:71:378-386.

9. Berger BC, Watson DD, Taylor GJ, Craddock GB, Martin RP, TeamsCD, Belier GA. Quantitative thallium-201 exercise scintigraphy for the detection of coronary artery disease.J Nucl Med 1981;22:585-593. 10. Watson DD, Campbell NP, Read EK, T&es CD, Beller GA. Spatial and temporal quantitation of planar thallium myocardial images. J Nucl Med 1981;22:577-584.

I I. Lcppo JA, O’Brien J, Rothendler JA, Getchell JD, Lee VW. Dipyridamolethallium-201 scintigraphy in the prediction of future cardiac events after acute myocardiil infarction. N Engl J Med 1984;310:1014-1018. 12. BoucherCA, Brewster DC, Darling C, Okada RD. StraussHW, PohcstGM. Determination of cardiac risk by dipyridamole-thallium imaging before peripheral vascular surgery. N Engl J Med 1985;312:389-394. 13. Leppo J, Plaza J, Gionet M, Tumolo J, ParaskosJA, Cutler BS. Noninvasive evaluation of cardiac risk before elective vascular surgery. JACC 1987,9:269277. 14. Gould KL, SorensonSG, Albro P, Caldwell JH, Chaudhuri T, Hamilton

GW. Thallium-201 myocardial imaging during coronary vasoclilationinducedby oral dipyridamole. J Nucl Med 1986;27:31-36. 15. Young DZ, Boucher CA. Unmasking potential myocardial ischemia with dipyridamole thallium imaging in patients with normal submaximal exercise thallium tests. Am J Nonirruasiw Cordial 1987:l:ll-14. 16. JosephsonMA, Brown BG, Hecht HS, Hopkins J, Pierce CD, PetersonRB. Noninvasive detection and localization of coronary stenosesin patients:comparisonof restingdipyridamole and exercisethallium-201 myccardial perfusionimaging. Am Heart J 1982:103:100&1018. 17. Gould KL. Noninvasive assessmentof coronary stencws by myocardial perfusion imaging during pharmacologic coronary vasodilation. I. Physiologic basis and experimental validation. Am J Cwdiol 1978;41:267-275. 16. Ruddy TD, Gill JB, Fiielstein DM, Strauss HW, McKusick KA, Okada RD, Boucher CA. Myocardial uptake and clearance of thallium-201 in normal subjects:comparison of dipyridamole induced hyperemia with exercise stress. JACC 1987;10:547-556. 19. Berger BC, Watson DD, Taylor GJ, Craddcck GB, Martin RP, TeateaCD,

Belier GA. Quantitative thallium-201 exercisescintigraphy for detectionof core nary artery disease.J Nucl Med 1981;22:585-593.

THE AMERICAN JOURNAL OF CARDIOLOGY OCTOBER 15,1989

877