Usefulness of dipyridamole-thallium-201 perfusion scanning for distinguishing ischemic from nonischemic cardiomyopathy

METHODS

Usefulness of Dipyridamole-Thallium-20 1 Perfusion Scanning for Distinguishing Ischemic from Nonischemic Cardiomyopathy Eric J. Eichhorn, MD, Edward J. Kosinski, MD, Stanley M. Lewis, MD, Thomas C. Hill, MD, Louis H. Emond, and 0. Stevens Leland, MD

To determine noninvasively the etiology of left ventricular (LV) dysfunction, 22 patients with a diagnosis of cardiomyopathy determined via cardiac catheterixatii and 5 normal control subjects underwent radionuclide ventriculography and intravenous dipyridamole-thallium-201 perfusion scanning. Roth ischemically and nonischemically induced LV dysfunction had comparable global LV ejection fractions (24 f 6 vs 23 f 8%, respectively) and extent of segmental wall motion abnormalities. Right ventricular ejection fraction was significantly better in the group with an ischemic etiology of LV dysfunction (41 f 26 vs 13 f lo%, p
he etiology of left ventricular (LV) dysfunction has important therapeutic and prognostic implications. Patients with impaired LV function due to coronary artery disease represent the major group of patients who demonstrate improved survival with coronary bypass surgery.lp2 Patients with nonischemic LV dysfunction are best treated with inotropic or afterload reduction therapy. Unfortunately, noninvasive methods to distinguish the etiology of LV dysfunction have been of limited value,3 which has necessitated cardiac catheterization and coronary angiography to establish a definitive diagnosis. This report demonstrates that intravenous dipyridamole thallium-201 (Tl-201) myocardial perfusion scanning can successfully distinguish ischemically from nonischemically induced LV dysfunction.

T

METHODS Patient population: The study group consisted of 22

consecutive patients with cardiomyopathy, defined by a ventriculographic ejection fraction of <0.35, and 5 volunteers with normal systolic performance. All underwent dipyridamole-Tl-201 scanning. Group A consisted of 10 patients who presented for evaluation of LV dysfunction and were found to have coronary artery disease, defined as >l coronary arteries with 270% diameter stenosis at cardiac catheterization and coronary angiography. Group B consisted of 12 patients with LV dysfunction, normal coronary arteries and no prior history of myocardial infarction. Group C consisted of the 5 control subjects with normal LV function. Two of the 5 patients in group C underwent cardiac catheterization for atypical chest pain and revealed normal coronary arteries and normal LV function. The other 3 patients in group C were young, healthy, asymptomatic volunteers who did not undergo catheterization but had no clinical evidence of coronary artery disease or congestive heart failure. All patients consented to a clinical investigation protocol approved by the Committee on Clinical Investigation of the New England Deaconess Hospital. Imaging technique: All group A and group B paFrom the Department of Medicine and Radiology, New England Dea- tients underwent gated radionuclide ventriculography, coness Hospital, Harvard Medical School, Boston, Massachusetts. which was performed using a previously defined techManuscript received June 17, 1987; revised manuscript received June nique.4*5 In vivo red blood cell labeling was performed 15, 1988, and accepted June 17. by injecting 15 to 25 mCi of technetium-99m (New EnAddress for reprints: Eric J. Eichhorn, MD, Veteran’s Administragland Nuclear) after intravenous stannous pyrophostion Medical Center and University of Texas, Southwestern Medical images School, Division of Cardiology (111 A), 4500 S. Lancaster, Dallas, phate. Gated radionuclide ventriculography Texas 75216. were obtained using a 30° slant hole, straight bore colliTHE AMERICAN

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gions. The time activity curve was used to identify enddiastole and end-systole. Regional ejection fractions Regional Ejection Fractions were calculated by the formula: maximal counts (enddiastole) - minimum counts (end-systole)/maximal Group LVEF RVEF Anteroseptal Apical lnferoposterior counts (end-diastole) for each region. A 24f6 419~26 21 f 10 21f14 29fll Right ventricular ejection fractions were obtained 8 23f8 13ztlO* 16fll 35f12+ 26flO according to a previously published method.6T7 The right p <0.005 YSgroup A; + p <0.05 vs group A. ventricular end-diastolic region was initially drawn on LVEF = left ventricular ejection fraction; RVEF = right ventricular ejection fraction. the end-diastolic frame. A summation of stroke volume and paradox images,’ which aided in delineating the mator in a modified left anterior oblique projection (30° right atrioventricular plane, was used to redraw the caudal angulation). The camera was positioned to maxi- right ventricular region, if necessary. In drawing the mize interventricular and right atrioventricular separa- right ventricular end-systolic region, delineation of the tion. Data acquisition was gated to the patient’s electro- right atrioventricular separation was based on examinacardiogram with each cardiac cycle divided into 50-ms tion of the end-systolic image and an endless loop movframes. Six to 10 million counts were obtained over an ie-format display. Background was again subtracted &minute acquisition period. Images were processed on from end-diastolic and end-systolic regions using counts a dedicated nuclear medicine computer in a 64 X 64 per pixel in a paraventricular background region at the matrix. end-systolic frame. Right ventricular ejection fractions Radionuclide analysis: Global and regional LV ejec- were then obtained by analyzing maximal and minimal tion fractions were computer-derived by selecting a re- background corrected counts by the formula: maximal gion of interest and using a count-based method accord- counts (end-diastole) - minimal counts (end-systole)/ ing to the program of Maddox et a1.4v5To determine maximal counts (end-diastole). global LV ejection fraction, an LV region of interest Dipyridamole thallium-261 imaging technique: Diwas manually drawn at end-diastole using a computer pyridamole-Tl-201 imaging was accomplished in all pajoystick. Background activity was defined and subtract- tients by a previously described technique.*-lo With the ed using an automated assessment of 3 paraventricular patient supine, intravenous dipyridamole (Boehringerregions. After background corrections, LV ejection frac- Ingelheim) was infused at a rate of 0.14 mg/kg of body tion was then determined by the formula: maximal weight per minute for 4 minutes. All patients had eleccounts (end-diastole) - minimal counts (end-systole)/ trocardiographic and blood pressure monitoring during infusion and for 30 minutes after it. Intravenous amimaximal counts (end-diastole). Regional LV ejection fractions were determined by nophylline was available to treat adverse effects from computer division of the LV longitudinal axis into 8 dipyridamole. Patients then sat up or, if possible, stood subdivisions, using 3 quadrisecting transverse axes. The for 3 minutes. Upon resuming the supine position, 1.5 to 2 basilar subdivisions were excluded from analysis due 2.0 mCi of Tl-201 (New England Nuclear) was injected to their proximity to the left atrium and great vessels. intravenously. Initial imaging was performed in the anThe 6 remaining intraventricular subdivisions were terior, 45O and 75O left anterior oblique projections. grouped into 3 anatomic regions (anteroseptal, apical, Each image was collected for 8 minutes with a standard and inferoposterior) according to the scheme of Madgamma camera equipped with a high-resolution collidox et a1.5 Background correction for these 3 regions mator and interfaced with a dedicated computer system was estimated using a weighted average of the counts per cell in each of the 3 paraventricular background reTABLE

I Radionuclide

Ventriculographic

Results

I

l

0.9 0.6 -’

.

O.?-

LPICAL

0.4.. EF 0.3.

l l

0.6.. 0.5 -’

0 6

0.4 ., 0.3 ..

. .

PVEF

0.2 0.1

:

1

A

FIGURE 1. Group A patimts dmnonstratetl ejectkmfraction(EF)compardwithgroupBprtianb(~f ~~errorof~macm)(groupA?lfS%,grorpB35f 396, p
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B

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FIGURE 2. Right vembtab ebctlon sdmtantidlybetterinOroupApathts(meanf~~rorotthe~)(plwpA41fB%,groupB13f3%,~
low RVEF VOLUME

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TABLE II Dipyridamole-Thallium-201

Scan Quantitation

Percent Defect Group

450 IA0

750 LAO

Anterior

Mean Defect (3 views/patient)

Largest Defect (1 view/patient)

A

26f18

B C

6*8* l&1$

24f 13 6 f 6f o*ot

20fll 6 f 6’ 3 f 3*

25fll 6h6+ 1 f 1+

34f14 8*7+ 3*3+

p <0.05 vs group A; + p
l

vs group A.

(Med-X) which collected the images in a 64 X 64 matrix. Delayed images were collected in a similar fashion 3 hours after injection. Analysis of thallium-201 images: All Tl-201 scans were analyzed both qualitatively and quantitatively. For qualitative analysis of analog images, 2 independent blinded observers with no knowledge of the patients or results of cardiac catheterization interpreted the scans. Quantitative analysis of all Tl-201 images was performed using the methods of Wackers et al.” After 9 point image smoothing, a region of interest was determined by 1 observer. This reference boundary was used for weighted bilinear interpolative background correction. The geometric center of the LV region of interest was determined and a radial map dividing the region into 36 equal segments of 10” arcs was made. The segment with the maximal number of background-corrected counts was determined and the uptake in all the other segments was expressed as a percentage of this uptake. Circumferential profiles for mean relative radioisotope uptake in each segment were thus determined and a distribution profile was plotted by computer. The lower limits of normal perfusion-previously determined by Wackers et al”--consist of 2 standard deviations below the mean value for normal patients. The computer quantitated all defects by expressing the percentage of area under the lower limits of normal perfusion curve compared with the total area under the lower limit of normal curve. Statistical analysis comparing groups was carried out using the Student t test, with a p value <0.05 considered significant. RESULTS Adverse effects of dipyridamole: Dipyridamole was well tolerated by most of the patients in our study. There were no episodes of myocardial infarction, severe angina pectoris or hypotension induced by drug administration. Six of the patients complained of mild symptoms including headache, lightheadedness or nausea. No patient required intravenous aminophylline for severe symptomatology. Radionuclide angiographic results: The radionuelide ventriculographic results in both group A and B patients are listed in Table I. All patients had a global LV ejection fraction <35%, with no difference in mean LV ejection fraction (group A 24 f 6%, group B 23 f 8%, difference not significant). Regional LV ejection fractions were determined in both group A and B patients. Of 30 regional ejection fractions in the 10 pa-

tients from group A, only 1 of 30 regions demonstrated normal performance (i.e., regional defect >2 standard deviations below normal value as reported by Maddox et aP). In addition, out of 36 regional segments in the 12 patients from group B, only 1 segment demonstrated a normal regional ejection fraction. Extent of diffuse involvement as assessed by analysis of regional ejection fractions was comparable in both groups. No significant differences were found in mean regional ejection fractions from the anteroseptal (group A 21 f lo%, group B 16 f 1l%, difference not significant) or inferoposterior segments (group A 29 f 1 l%, group B 26 f lo%, difference not significant). However, group A patients did demonstrate a lower apical ejection fraction compared with group B patients (21 f 14 vs 35 f 12%, p <0.05). Despite the statistical difference in apical segment function, there was marked overlap which failed to distinguish either group A or group B patients (Figure 1). The right ventricular ejection fraction was substantially better in group A patients (41 f 26%) as compared to the group B patients (13 f 10% p
Qualitative analysis of the dipyridamok-thalliimscans: All dipyridamole-Tl-201 analog images

were reviewed by 2 independent and blinded observers. There was no significant interobserver variation in the interpretation of all 27 scans. Segmental defects were present in 10 of the 10 group A patients and 4 of the 12 group B patients. Three of the 4 defects seen in group B patients were interpreted as being too small to account for LV dysfunction on the basis of significant coronary artery disease. In general, group A patients exhibited grossly larger defects than group B patients. All group C subjects were interpreted as having normal analog images. An example of a group A dipyridamole-Tl-201 scan is shown in Figure 3A (major perfusion defects are present in all 3 projections). An example of a group B scan is the dilated ventricle with homogeneous perfusion in all projections shown in Figure 3B. An example of a normal group C subject is the scan shown in Figure 3C, which demonstrates a normal-size ventricle with homogeneous uptake. Quantitative analysis of the dipyridamole-thallium201 scans: A typical circumferential profile for a group

A patient can be seen in Figure 4A. A large (12%) an-

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teroseptal defect can be seen in the left anterior oblique 45’ projection. This defect was 20 and 39% in the left anterior oblique 75” and anterior projections, respectively (not shown). An example of a group B patient is seen in Figure 4B. A large dilated ventricle is seen with a 0% uptake defect. A group C subject is presented in Figure 4C, which shows a normal size ventricle with no uptake defect. The results of the quantitative analysis of the dipyridamole-Tl-201 scans can be seen in Table II. In all 3 views, the mean percent defect determined by our analysis was significantly greater in group A patients than in group B and C patients. There was no significant difference in mean uptake defects between groups B and C. The mean perfusion defect for group A (30 views in 10 patients) was significantly greater than that for group B (36 views in 12 patients) (25 f 11 vs 6 f 6%, p 15% as representing ischemic or infarcted tissue, the quantitative

analysis of the dipyridamole-Tl-20 1 images correctly predicted the etiology of LV dysfunction in 20 of 22 patients (91%) (Figure 5). The mean of the largest perfusion defect seen on any 1 view was considerably greater for group A (10 views in 10 patients) than group B (12 views in 12 patients) (34 f 14 vs 8 f 7%, p
FIGURE 3. Exmpks *e-hknaS-fargroup& BandCpaBents.Asisevident, ~groupApatiant(fop)~a brge=t-=Wdaplcd defectseeninaU3view8,whii -&mwBpaknt(-l~ adilatedleftvsntrklewith homoseneouruptdce.mgroup Crubjed(beffem)hasanemud sizedleftlfentaewRhd aem

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cardiomyopathy (compared with segmental LV dysfunction, which favors an ischemic basis). Greenberg et alI6 analyzed 59 patients using radionuclide ventriculography and found that LV dysfunction induced by coronary artery disease did demonstrate greater asymmetry of LV dysfunction, although the overlap between the 2 groups prevented clear delineation of underlying etiology. As in the present study, Greenberg et all6 noted

B

i

c

c

worse apical wall motion in patients with coronary artery disease. In our study comparison of computer-generated assessment of LV segmental wall motion, including apical analysis, did not consistently distinguish ischemic from nonischemic dysfunction. However, in both the Greenberg study and the present study, right ventricular ejection fraction was lower in the nonischemit cardiomyopathy group compared with patients

*

FlGURE4.E~afclua~ecircumfwentiel~o~forgroy,A,BandC~~.ThegroupApatiant(top)hssa 12%defactin~anteroreptalandapicalregionintheLAO45”view.Thispatientobohaddefectrof20%intheLAO75” view and 39% in ths anterior view (not shown). The group B patient (mkfdk) fects, as determined by quantitative analysis. The group C subject (bottom) Wake defect.

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with coronary artery disease. Unfortunately, the overlap was again substantial and prevented clear delineation of the 2 groups. Therefore, when radionuclide ventriculography demonstrates marked asymmetry of segmental wall motion or preservation of right ventricular ejection fraction, there is a higher likelihood that coronary artery disease is the underlying basis for the LV dysfunction. There remains, however, substantial overlap when using this criterion and it is not sufficient to establish a definitive diagnosis. Thallium-201 uptake is predominantly determined by coronary perfusion and, to a lesser extent, by cellular extractions and myocardial mass.17-19 Therefore, relative perfusion differences are present in patients with obstructed coronary arteries. Bulkley et a120performed resting Tl-201 scanning and calculated the percent of image circumference that failed to accumulate Tl-201. Patients with coronary artery disease uniformly had defects >40% of image circumference whereas patients with nonischemic LV dysfunction had defects <20%. Using a combination of resting Tl-201 scanning and radionuclide ventriculography, Bulkley et al were able to distinguish idiopathic from ischemic cardiomyopathy. Saltissi et al*l used exercise Tl-201 imaging and demonstrated that reversible defects were equally common in the 2 patient subgroups. They also found that extensive fixed defects involving >40% of the outer perimeter of the LV image were more frequent in coronary artery disease patients than in nonischemic LV dysfunction patients. In distinction to the above studies, Dunn et a122 performed exercise Tl-201 scanning in 25 patients with severe LV dysfunction. Patients with coronary artery disease demonstrated more complete segmental perfusion defects than patients with idiopathic dilated cardiomyopathy. However, extensive defects involving >40% of the LV circumference, number of myocardial seg-

ments involved and reversibility of Tl-201 perfusion defects did not predict the presence of LV dysfunction induced by coronary artery disease. They concluded that Tl-201 perfusion scanning failed to reliably distinguish the etiology of LV dysfunction. To take advantage of possible differences in Tl-201 uptake in ischemic and nonischemic LV dysfunction, dipyridamole was infused intravenously to produce a maximal coronary hyperemic response. The difficulty in obtaining a good background to target the ratio of Tl201 with resting myocardial scans as well as the difficulty of subjectively assessing the extent of myocardial perfusion may well explain the discrepancies found in previous studies. In our study, 20 of 22 patients (91%) were correctly identified using dipyridamole-Tl-201 scanning when a perfusion defect of 515% was used as an indication of nonischemically induced LV dysfunction. The basis for the difference in Tl-201 perfusion appears to reflect both differences in potential homogeneous increase of coronary blood flow and myocardial cellular metabolic activity. Coronary artery disease patients with substantial LV dysfunction frequently have occluded coronary arteries supplying the infarcted zone. Therefore, Tl-201 is unable to reach the myocardial cell for subsequent uptake. In addition, the myocardium is frequently replaced with extensive fibrous tissue metabolically unable to accumulate Tl-201. In contrast, idiopathic cardiomyopathy, although it exhibits a lower than normal myocardial blood flow per unit mass, is still capable of increasing flow to all areas after a metabolic stress such as atria1 pacing.23 The lower myocardial perfusion found in dilated cardiomyopathy reflects the decreased myocardial metabolic demands resulting from the depressed functional characteristics of the cardiomyopathic ventricle. Although both ischemic and idiopathic cardiomyopathy patients exhibit decreased total coronary blood flow, the coronary artery disease patients have greater heterogeneity of regional myocardial perfusion. This is accentuated by dipyridamole and therefore results in successful delineation of these 2 entities.

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A

B Group

C

FIGURE 5, Using a perfusion defect of >I§% as e kchemk or Infarcted tissue, the wdtative analysis of the dipydamobll-201 images correctly pfdcted the ethlof# of venMdardyshmctknin2Oof22patients(91%).Therewas 1patkmtfmmgreqtAwheselargestddedmmyviewwas S%,uwll~ingroupB~lsrgertdefect:was27%. AngroupCsubjectshaddefectsof~7%.Themaanotthe laaestdefsctmsentwassltMcantlyIgsakKforgroupA (meanfstandadwrorefthemean)(34f5%)thangroy,B (8*2%,p10.ooo1)orgroupC(3*1%,p<0.0005).

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16. Greenberg JM, Murphy JH, Okada RD. Pohost GM, Strauss HW, Boucher CA. Value and limitations of radionuclide angiography in determining the cause of reduced left ventricular ejection fraction: comparison of idiopathic dilated cardiomyopathy and coronary artery disease. Am J Cardiol 1985;55:541-544. 17. Strauss HW, Harrision K, Langan JK, Lebowitz E, Pitt B. Thallium-201 for myocardial imaging. Relation of thallium-201 to regional myacardial perfusion. Circulation 1975;51:641-645. 18. Weich HF. Strauss HW, Pitt B. The extraction of thallium-201 by the mywardium. Circulation 1977;56:188-191. 19. Straw BE, Bull U, and Burger S. Clinical studies concerning the determinants of myocardial 20’thallium uptake. Basic Res Cardiol 1978:73:365-379. 20. Bulkley BH, Hutchins GM, Bailey I, Strauss HW, Pitt B. Thallium-201 imaging and gated cardiac blood pool scans in patients with ischemic and idiopathic congestive cardiomyopathy: a clinical and pathologic study. Circulafion 1977;55:753-760. Pl.Saltissi S, Hockings B, Croft DN, Webb-Peplw MM. Thallium-201 myocardial imaging in patients with dilated and ischemic cardiomyopathy. Br Heart J 1981;46:290-295, 22. Dunn RF, Uren RF, Sadick N, Bautovich G, McLaughlin A, Hiroe M, Kelly DT. Comparison of thallium-201 scanning in idiopathic dilated cardiomyopathy and severe coronary artery disease. Circulation 1982,66:804-810. 23. Weiss MB, Ellis K, Sciacca RR, Johnson LL, Schmidt DH, Cannon PJ. Myocardial blood flow in congestive and hypertrophic cardiomyopathy. Circulation 197654:484-494.

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