Thallium-201 redistribution after early reinjection in patients with severe stress perfusion defects and ventricular dysfunction

Volume 128, Number 1

American Heart Journal Gnlli and Marcassa

18. Biagini A, Maffei S, Baroni M, Levanto M, Comite C, Russo V, Salerno L, Borzoni G, Piacenti M, Salvatore L. Early assessment of coronary reserve after bypass surgery by dipyridamole transesophageal echocardiographic stress test. AM HEART J 1990;120:1097-101.

19. Cohen JL, Greene TO, Ottenweller J, Binenbaum SZ, Wilch- fort SD, Kim CS. Dobutamine digital echocardiography for detecting coronary artery disease. Am J Cardiol 1991;67: 1311-8.

20. Salustri A, Fioretti PM, Pozzoli MMA, McNeil1 AJ, Roelandt JRTC. Dobutsmine stress echocardiography: Its role in the diagnosis of coronary artery disease. Eur Heart J 1992;13:70.

21. Mazeika PK, Nadazdin A, Oakley CM. Dobutamine stress echocardiography for detection and assessment of coronary artery disease. J Am Co11 Cardiol 1992;19:1203-11.

22. Fung AY, Gallagher KP, Buda AJ. The physiologic basis of dobutamine as compared with dipyridamole stress interven- tions in the assessment of critical coronary stenosis. Circula- tion 1987;76:943-51.

23. Forster T, McNeil AJ, Salustri A, Reijs AE, El-Said EM, Roe-

landt JRTC, Fioretti PM. Simultaneous dobutamine stress echocardiography and technetium-99m isonitrile single-pho- ton emission computed tomography in patients with suspected coronary artery disease. J Am Co11 Cardiol 1993;21:1591-6.

24. Daniel WG, Erbel R, Kasper W, Visser CA, Engberding R, Sutherland GR, Grube E, Hanrath P, Maisch B, Dennig K, Schartl M, Kremer P, Angermann C, Iliceto S, Curtius JM, Miigge A. Safety of transesophageal echocardiography: a mul- ticenter survey of 10,419 examinations. Circulation 1991; 82817-21.

25. Stoddard MF, Longaker RA. The safety of transesophageal echocardiography in the elderly. AM HEART .J 1993;125:1358- 62.

26. Vandenberg BF, Fleagle SR, Skorton DJ. Exercise echocardiography and quantitative angiography: improved identification of physiologically significant coronary artery stenoses. J Am Co11 Cardiol 1990;15:1052-4.

27. Katritsis D, Webb-Peploe M. Limitations of coronary angiography: an underestimated problem? Clin Cardiol1991;14:20-4.

Thatiium-201 redistribution after early reinjection in patients with severe stress perfusion defects and ventricular dysfunction

Early poststress thallium-201 reinjection to obviate the need for two sets of redistribution images has been proposed as an alternative reinjection protocol although, in a preliminary study, it did not reduce the frequency of late redistribution. The efficacy of the early reinjection protocol was assessed in 102 patients with chronic ischemic heart disease and left ventricular dysfunction who showed severe thallium-201 defects on planar stress images. Thallium-201 was reinjected immediately after the poststress study, and redistribution images were acquired 4 and 24 hours later. By quaMtative anelysis, a further increase in thallium-201 uptake on 24-hour imaging was documented in only 49 (6%) of 740 segments still abnormal on Chour images, 26 (54%) of which were represented by partially reversible or not severe fixed defects. Overall, late thallium-201 uptake was less frequently observed in patients with depressed ejection fraction (p < 0.05). Clinicaly relevant late reversibilii was found in only 3 (3%) of 94 patients. 9cens were repeated after revascularization in 20 patients. Tracer uptake improved in 49 (34%) of 118 segments with 4-hour defect: the improvement mainly (85%) involved those segments already showing partial 4-hour reversbility or mild fixed defects on the preoperative study. Thus a n late tracer redistribution was found in patients with severe stress thallium-201 defects undergoing early reinjection and 4-hour imagtng; no significant 24-hour improvement was observed in those patients with depressed ventricular function and fixed 4-hour defects. This simpler imaging protocol could obviate the need for additional late imaging to detect residual viability. (AM HEART

J 1994;128:41-52.)

Michele Galli, MD, and Claudio Marcassa, MD Veruno, Italy

From the Division of Cardiology, “Clinics de1 Lavoro” Foundation IRCCS, Medical Center of Rehabilitation of Veruno. Received for publication May 25, 1993; accepted Nov. 3, 1993. Reprint requests: Micbele GaIli, MD, Fondazione Clinica de1 Lavoro, Cen- tro Medico, via Revislate 13, Veruno 28010 (No) Italy. Copyright @ 1994 by Mosby-Year Book, Inc. 0002.8703/94/$3.00 + 0 4/l/64516

There is still much debate surrounding the selection of patients with coronary disease and impaired ventricular function for revascularization procedures because of their uncertain outcome and higher oper- ative risk. Recent research has centered on develop- ing and defining the much needed reliable and acces-

41

July 1994

42 Galli and Marcassa American Heart Journal

Table I. Clinical, angiographic, and ergometric findings of study population

No. of patients Age (~4 History

Myocardial infarction Coronary revascularization Stable angina Chronic Heart Failure

Left ventricular ejection fraction (%) End-diastolic volume index (ml/m2) Coronary anatomy (86/102 patients)

Single-vessel disease Multiple-vessel disease

Preliminary stress test (95/102 patients) Negative Angina ST depression ~1 mm

102 57 k 8

90 10

2 13

39 * 10 84 k 25

23 63

52 16 43

sible tools to assess residual myocardial viability in asynergic regions. Thallium-201 scintigraphy has proved useful in differentiating between ischemic and necrotic dysfunctioning myocardial segments.1-4 Recently, enhanced detection of viable myocardium has been documented in patients with persistent thallium-201 defects at standard stress-redistribution imaging by the use of a second thallium-201 injection (the reinjection technique): the greater tracer delivery to severely ischemic but still viable regions reduces the rate of false fixed defects.5-7 The direct comparison between 18F-deoxyglucose uptake and postreinjection thallium-201 redistribution showed concordant information regarding the presence of residual viability in most regions with impaired function.8T g In fact, the reinjection technique proved most efficient in the evaluation of segments with severe 4-hour irreversible defects, in up to 50% of which thallium-201 reinjection can induce late tracer uptake. Indeed, the amount of regional 18F-deoxyglucose uptake seems to correlate with the degree of thallium-201 defects and their severity.g

Thallium-201 reinjection after the 4-hour redistribution acquisitions requires an additional third set of images, which may inconvenience both patients and most busy nuclear medicine laboratories. In patients with an abnormal stress scan, the early reinjection of thallium-201 immediately after stress imaging has been proposed as an alternative method to obviate the need for two sets of 4-hour acquisitions. More- over, because thallium-201 redistribution is greatly influenced by the tracer serum concentration83 lo and the rate of its delivery in the redistribution period 11-i4 early tracer reinjection allows sustained serum thallium-201 levels during the poststress period

for the longest possible interval between the tracer reinjection and 4-hour imaging. The only published qualitative results with this approach in unselected patients evaluated for myocardial ischemia, however, showed that the frequency of late (18 to 72 hours) thallium-201 defect reversibility was not reduced after early poststress reinjectionr5 and that 3-hour redistribution images were not superior to images acquired 1 hour after postexercise reinjection.16

We prospectively tested the efficacy of the early reinjection protocol in a group of consecutive patients with resting left ventricular dysfunction and severe thallium-201 uptake defects on stress images. Redistribution acquisitions were performed at 4 hours, and 24-hour images were also acquired to assess the frequency of late reversibility by quantitative and qualitative analyses. Postrevascularization thallium-201 scans of some patients were also performed and compared with the preoperative results.

METHODS Patient population. The study population consisted of

102 consecutive men who met the following inclusion cri- teria: (1) history of chronic stable coronary artery disease; (2) evidence of regional left ventricular dysfunction (aki- nesia or dyskinesia) on resting two-dimensional echocardiography (2-D Echo); and (3) the presence of a severe thallium-201 defect on poststress planar images. The patients were referred to our nuclear laboratory for the functional evaluation of their coronary artery disease and the related risk stratification. Patients with recent (<l month) acute myocardial infarction or unstable angina were excluded from the study.

Global and regional ventricular function were assessed at rest by 2-D Echo performed on a separate day and within 1 week from the radionuclide study while the patients were stable; biplane measurement of left ventricular end-diastolic volumes and ejection fraction were obtained by oper- ators unaware of the scintigraphic findings as previously described.17 Cardiac catheterization was performed in 86 (84 %) of 102 patients: significant stenoses (275% coronary diameter reduction) involving 1,2, and 3 vessels were found in 23,27, and 36 patients, respectively. Of 23 patients with single-vessel disease, 19 had severe proximal left anterior descending artery stenosis. A preliminary exercise stress test was carried out in all but seven patients. The clinical, angiographic, and ergometric findings of the study population are reported in Table I.

Stress testing and thallium-201 imaging. In all patients cardiac medications were discontinued 212 hours before the test. Fifty-four patients underwent symptom-limited exercise testing; 48 patients who were unable to undergo the exercise test or to achieve at least 85 % of the maximal age-predicted heart rate (as documented by the preliminary exercise stress test) underwent a dipyridamole test (0.56 mg/kg in 4 minutes followed by 3 minutes of low-level


American Heart Journal Galli cd Marcassa 43

Stress test

i 0 1 2 3 4 5 18-24 m E5l Time (hours)

Thallium injection 4-4

Acquisitions

Fig. 1. Early poststress thallium-201 reinjection protocol. Stress, 4-hour redistribution, late 24-hour acquisitions sequence and timing of thallium-201 injection are shown.

isotonic exercise). At peak exercise or 2 minutes after the end of dipyridamole infusion, 2 mCi of thallium-201 was injected intravenously, and the patient continued exercise for 60 to 90 seconds. A first set of three planar images (left anterior oblique 45 degrees, anterior and left anterior oblique 70 degrees) started within 5 to 10 minutes. The venous line was maintained patent by infusion of saline so- lution. Immediately after the completion of the poststress images, on-line assessment of the early myocardial tracer distribution was performed by one of the two experienced readers (M. G., C. M.); in the presence of a severe thallium-201 defect, patients received an additional 1 mCi of thallium-201. A “redistribution” set of three images was acquired after 4 hours, and a third set of images was acquired 24 hours later. The scintigraphic protocol is sum- marized in Fig. 1.

A large-field-of-view gamma camera (Apex 409, Elscint, Israel), equipped with a low-energy, medium resolution, parallel hole collimator was used, with a dual energy pho- topeak (68% -t 15’F KeV and 162:; * 10% KeV); a 128 X 128 array with a 1.5 magnification factor was used. Poststress images were acquired for 500 seconds; both 4-hour and 24-hour images were acquired for 750 seconds to improve count density and avoid artifacts from the background subtraction processing, particularly in low count segments.ls

Quantitative analysis. The computer-stored images were processed by a semiautomatic technique. In each image, an operator-defined region of interest was drawn around the left ventricle. After standard nine-point spatial smoothing and interpolative background subtraction, the myocardial wall activity was displayed as a circumferential profilelg normalized for peak activity and then averaged into 15 regional values corresponding to the segments used for the qualitative analysis. A myocardial segment was considered abnormal if its thallium-201 uptake was <75 ‘% of peak myocardial activity20-z2; in particular, the defect was classified as severe, moderate, and mild in the presence of <50%, 50% to 59% and 60 % to 75% of peak tracer uptake, respectively.

In a randomly selected group of 10 patients, the quantitative analysis was repeated after 2 weeks and the operator variability was assessed by linear regression analysis (regression line: y = 0.93x + 3.60; r = 0.93; p < 0.001). The

mean absolute variability was -0.5 + 6. Thus only changes in segmental tracer uptake >llC;; units (mean + 2 SD) were considered significant. A segmental defect was considered reversible when its abnormal tracer uptake significantly increased on subsequent images. The defect was said to be irreversible if its abnormal tracer uptake did not change. Late reversibility in patients without 4-hour reversible defects that involved a substantial area of the myocardium (~2 segments with fixed defects) was said to be clinically relevant.2”

Qualitative analysis. The analysis of poststress, /i-hour and 24-hour images was performed offline independently by both investigators; all images were analyzed without background subtraction after normalization for peak cardiac activity. Each myocardial image in the three projec- tions were divided into five segments, as previously reported.3 The segmental distribution of thallium-201 uptake was qualitatively analyzed on a five-point grading system (4 = normal thallium-201 uptake; 3 = mild tracer uptake defect; 2 = moderate defect; 1 = severe defect; 0 = no thallium-201 uptake). The segmental tracer uptake was considered abnormal when a myocardial segment showed an initial poststress score of 52. A segmental defect was considered to be reversible when its abnormal score increased one or more on the delayed images. The defect was said to be irreversible if the assigned score was unchanged. The interobserver agreement in grading the stress, 4-hour, and 24-hour segmental tracer uptake was 95’; ; discrepancies were resolved by consensus.

Coronary revascularization. In 20 patients with stable symptoms who underwent coronary revascularization procedures, thallium-201 imaging was repeated 3 to 12 weeks later (32 t 20 days) and preoperative and postoperative thallium-201 scans were compared. All had an uncompli- cated clinical course after coronary angioplasty (three patients) or bypass surgery (17 patients). Perioperative infarction was excluded by serial electrocardiographic and isoenzyme monitoring in the days after surgery. At the op- eration an attempt was made to revascularize all major and branch vessels with >50% stenosis, yielding on average 2.3 grafts per patient. For the postoperative scintigraphic study, the same (exercise or dipyridamole) preoperative thallium-201 imaging protocol was repeated.

Statistical analysis. Data are presented as mean k SD.

44 Galli and Marcmsa July 1994

American Heart Journal

Fig. 2. Poststress, 4-hour, and 24-hour thallium-201 images in patient with left anterior descending coronary occlusion, previous anterior myocardial infarction, and severely depressed left ventricular function. Stress images show severe tracer uptake defect in anteroseptal wall and apex, largely resolving after thallium-201 reinjection. Mild-moderate perfusion defect is still present on 4-hour scan, without further improvement on 24- hour scan. LAO, Left anterior oblique; REDISTR, redistribution.

Differences in myocardial tracer uptake and score on poststress versus 4-hour acquisition and in 4-hour versus 24-hour acquisition were compared with analysis of vari- ance. The chi-square test was used to determine the signif- icance of differences in rates of occurrence.

RESULTS

For the purpose of this study, only patients showing a severe (score 51) stress thallium-201 defect in 13 myocardial segments were prospectively studied (Fig. 2). Of the 104 consecutive patients who underwent early poststress reinjection and completed the imaging protocol, two were excluded because the readers were unable to agree about the extent (1 case) and severity (1 case) of the stress defects. In five patients, the 24-hour images were unintelligible and were not considered for either quantitative or qualitative analysis. Comparison between 4-hour and 24- hour results was carried out in the remaining 97 patients; in 3 only analogic reports were available. Thus quantitative and qualitative results were available in

94 and 97 patients, respectively. At exercise or dipyridamole thallium-201 testing, 56 patients experienced angina or showed ischemic ST segment depression ~1 mm on electrocardiography.

Quantitative thallium-201 imaging analysis. Of the 1410 segments analyzed, 828 (59%) showed a reduced tracer uptake on poststress images; the defects were classified as mild, moderate, or severe in 286, 181, and 361 cases, respectively. The number of segments with severe stress-induced perfusion defects (<50 % normalized tracer uptake) averaged 4.9 * 1.4 per patient. On 4-hour images, a significant increase in thallium-201 uptake was observed in 172 (21%) segments (reversible defects), while 656 (79%) segments were unchanged or decreased their tracer uptake (fixed defects).

In the 94 patients with 24-hour quantitative data (Fig. 3), a further significant increase in thallium-201 uptake on 24-hour images was observed in 7 (6 % ) of 112 partially reversible defects and in 41 (6 % ) of 628 fixed defects. The frequency of the late 24-hour

Volume 128, Number 1 American Heart Journal Gnlli and Marcassa 45

Abnormal post-stress myocardial segments

$-hour images Unchanged:

-30% Uptake 250% Uptake

24-hour images: Normalized

or improved

Unchanged

Fig. 3. Flow diagram showing fate of poststress thallium-201 defects. Of 628 4-hour fixed defects, only 41 (6%) showed late 24-hour reversibility at quantitative analysis.

reversibility was comparable between mild-moderate (19 of 368, 5%) and severe (22 of 260, 8%) 4-hour fixed defects (Fig. 3). In reversible and fixed defects (Fig. 4), the mean normalized tracer uptake significantly decreased from 4-hour to 24-hour images.

Interestingly, of the 41 segments with 4-hour fixed defects showing late 24-hour redistribution, 27 (66 % ) were found in 18 patients who already showed 4-hour reversible perfusion defects. Of 35 patients without 4-hour reversible defects, 9 showed some late redistribution at 24-hour imaging; in 6 patients the redistribution was confined to 1 segment. Thus clinically relevant 24-hour reversibility was found in only 3 (3%) of 94 patients (Fig. 5).

Twenty-four (15 % ) of 165 reversible defects on the 4-hour images appeared fixed on the 24-hour images; such late “reverse redistribution” was found in 11 (12%) of 94 patients and affected both complete (6 of 53) and incomplete (18 of 112) 4-hour reversible defects. Clinically relevant late reverse redistribution was found in 9 (10 % ) patients.

Quslitative thallium-201 findings. The number of severe stress-induced perfusion defects (score 0 to 1) averaged 6.5 f 2 per patient. The patients’ average score showed an increase on 4-hour images (from 26.6 + 5.1 to 31.6 + 6.8; p < 0.01) and a decrease on 24-hour images (29.8 + 6.7, p < 0.01 vs poststress and 4-hour images). The relation between the seg-

‘O!L----- Stress 4-Hour 24-Hour

Fig. 4. Quantitative mean normalized tracer uptake in poststress, 4-hour, and 24-hour reversible and fixed defects.

mental thallium-201 uptake at quantitative analysis and the corresponding visual score is reported in Fig. 6.

Of the 1530 analyzed segments, 931 (61%) segments were graded as abnormal on poststress images; at 4-hour redistribution imaging, complete or partial reversibility was observed in 224 (24%) and 255 (27%) segments, respectively, and 452 segments

46 Galli and Marcassa July 1994


thallium reinjection -

24-HOUR IMAGES 9 PATIENTS WITH LATE REVERSIBLE DEFECTS

26 UNCHANGED

RELEVANT LATE REDISTRIBUTION

Fig. 5. Outcome of repeat imaging in 94 patients with quantitative analysis and frequency of clinically relevant late redistribution (24-hour reversibility in patients without 4-hour reversible defects and involving ~2 fixed defects).

n= 213 353 223 290 246

r*7r*7r*7rNs7

100 1 l-T

@ 80 Y

; 60

= F 40

:: 20

0 0 1 2 3 4 Visual Score

*= pto -01

Fig. 6. Correlation between visual segmental score and normalized thallium-201 (201 TZ) uptake on poststress images.

(49%) were unchanged. In the 97 patients with 24-hour images, only 15 (3%) of433 4-hour fixed defects showed some reversibility; a further improvement in the tracer uptake in segments showing incomplete reversibility at 4-hour imaging was observed in 37 (15%) of 240 segments. Of note, the 15 fixed defects showing late 24-hour reversibility were found in 13 patients already showing other 4-hour reversible defects; none of the 10 patients with fixed defects only on 4-hour redistribution imaging showed some late reversibility. Thus clinically relevant 24- hour reversibility was absent at qualitative analysis.

Left ventricular function and thallium901 late redistribution. According to their left ventricular ejection fraction (EF) values, 42 (41%) patients had severe (EF I 35%), 28 (27%) had moderate (EF 36% to 44%), and 32 (32%) had mild (EF L 45%) left ventricular dysfunction. The prevalence of stress-induced perfusion defects on 4-hour images in relation to the degree of left ventricular dysfunction is shown in Fig, 7. Late redistribution in 4-hour fixed defects was more frequently observed in patients with mild- moderate left ventricular dysfunction, both at quantitative (p < 0.05; Fig. 8) and qualitative (p < 0.05) analysis.

Postrevascularization results. The effects of coronary revascularization on the thallium-201 redistribution pattern were assessed in 20 patients by com- paring preintervention and postintervention scans (Figs. 9 and 10). Before revascularization, 17 patients experienced angina or showed ischemic ST-segment depression 11 mm on electrocardiography; at repeated stress testing after intervention, silent ST- segment depression ~1 mm was found in 1 patient (p < 0.001).

Preoperative and postoperative quantitative data were available in 16 patients. Before revascularization there were 138 4-hour abnormal segments with either fixed (95 segments, 69%) or partially reversible (43 segments, 31%) thallium-201 defects: 12 (13 % ) of 95 and 6 (14 % ) of 43 segments, respectively, had enhanced thallium-201 uptake on late 24-hour acquisitions. On repeated images after revasculariza-


Amesican Heart Journal Galli and Marcassa 47

Wnents 379 (“=I

loo o “I

269 137

60

60

40

20

0 EF<35% 35%~ EF 245% EFAWo

q Fixed Defects

q Incomplete Reversibility

Complete Reversibility

Fig. 7. Different evolution of stress thallium-201 defects at 4-hour images according to baseline left ventricular function. Patients with severe reduction of ejection fraction (EF) showed more 4-hour fixed defects and fewer segments with complete reversibility. n, Number of stress-induced thallium-201 uptake defects.

26 30

Fig. 8. Comparative frequency of late 24-hour reversibility of 4-hour fixed thallium-201 defects according to degree of left ventricular dysfunction. Late reversibility mainly affected patients with preserved ejection fraction (EF).

tion, thallium-201 uptake significantly increased in (52 5% ) of 25 severe fixed defects. Of note, in all but 48 (35%) of 138 4-hour defects. The improvement one patient who had postoperative improved severe involved 17 (40%) of 43 segments already showing fixed defects, further 4-hour reversible thallium-201 partial 4-hour reversibility on the preoperative study, defects were documented at the preoperative scan. 18 (26%) of 70 mild-moderate fixed defects, and 13 At qualitative analysis (Fig. 11) all 20 patients had



Fig. 9. Poststress, 4-hour, 24-hour, and postbypass 4-hour thallium-201 images in patient with extensive coronary artery disease. Stress images show severe tracer uptake defects in multiple vascular territories, largely resolving after thallium-201 reinjection. Mild perfusion defect is still present on 4-hour scan, without further improvement on 24-hour and postintervention images (black arrows). ANT, Anterior; CABG, coronary artery bypass graft; LAO, Left anterior oblique.

4-hour reversible thallium-201 defects before revascularization. Of 118 4-hour abnormal segments, 53 (45%) were fixed and 65 (55%) were partially reversible thallium-201 defects. Two (4%) and 12 (18% ) segments, respectively, had enhanced thallium-201 uptake on late 24-hour acquisitions. On repeated images after revascularization, thallium- 201 uptake increased in 40 (34%) of 118 4-hour abnormal segments (13 segments improved and 27 normalized). The improvement, however, mainly (34 of 40, 85%) concerned segments already showing partial 4-hour reversibility or mild-moderate fixed defects on the preoperative study.

DISCUSSION Modifications of the thallium-201 imaging protocol.

Interest has recently been aroused by the growing realization that fixed stress thallium-201 defects de- tected by using conventional redistribution imaging are frequently associated with viable myocardium, as documented by their subsequent improvement on postrevascularization studiePv 24 or late 24-hour or thallium-201 reinjection images57 6~ 13, l4 and the evi-

dence of preserved metabolism at positron emission tomography. gl 25 At the time of writing, the redistribution-reinjection technique seems to be the thallium-201 protocol of choice whenever residual myocardial viability in dysfunctioning regions is ques- tioned because it provides more accurate diagnostic information than 24-hour late redistribution imag- ing7* s; its convenience seems to obviate the need for the more sophisticated positron emission technique in most instances. However, thallium-201 reinjection after 4-hour redistribution imaging requires immediate processing and expert interpretation of the stress-redistribution images to determine the patients for reinjection. Moreover, as a result of the repeated imaging after thallium-201 reinjection, this protocol is likely to inconvenience both patients and busy nuclear cardiology laboratories; furthermore, an additional venipuncture is usually required for the reinjection.

Early poststress thallium-201 reinjection. The early reinjection of thallium-201 immediately after stress imaging first proposed by Kiat et a1.i6 provides opti- mal time for myocardial uptake and redistribution of

VOIUIM 128, Number 1 Galli and Marcassa 49

Fig. 10. Poststress, I-hour, 24-hour, and postbypass redistribution thallium-201 images in patient with triple-vessel disease and severe left ventricular dysfunction after inferior myocardial infarction. Preintervention stress and 4-hour redistribution images show severe fixed defect in posterior, lateral, and apical segments. No further reversibility was observed 24 hours later or after revascularization. ANT, Anterior; CABG, coronary artery bypass graft; LAO, left anterior oblique.

Abnormal segmenls at pre-revascularizatio post-stress imaging

Pre-revaseularization 4-hour imaging

, Fixed ( Incomplete

Severe Mild/Moderate Redistribution Complete RcdistribUthNl

Post-revasculariastion 4-hr imaging: improved

unchanged

Fig. 11. Fate of 164 stress thallium-201 defects before surgery on postrevascularization images.

the reinjected dose and on a theoretic basis optimizes retie and practical advantages, a high frequency of the assessment of viability in hypoperfused regions. late (18 to 72 hours) reversibility. In an unselected However, in their study to assess the efficacy of this population of patients, Kiat et al. documented, by protocol Kiat et al. demonstrated, despite its theo- qualitative analysis, late reversibility in 58% of pa-



tients and 24% of segments with 4-hour nonreversible defects, a finding comparable to that observed in thallium-201 studies without reinjection.8

We assessed the efficacy of the early poststress reinjection followed by 4-hour redistribution images protocol in a larger, consecutive series of selected patients with ischemic left ventricular dysfunction and severe poststress perfusion defects. The detection of residual viable myocardium is of great importance in this subset of patients; however, their investigation is somewhat complicated by the consistent rate of false fixed thallium-201 defects on stress-redistribution imaging, which can lead to an overestimation of scarred tissue.

The present study. In fact, in this population of well-selected patients we were unable, both at qualitative and quantitative analysis, to confirm the preliminary qualitative data of Kiat et all5 At odds with their results, in the present study late 24-hour reversibility was negligible: at qualitative analysis, 24-hour reversibility was observed in only 8% of the segments with still reduced thallium-201 uptake on 4-hour images and mainly (79 % ) involved segments showing partial reversibility-and already judged as a site of jeopardized viable myocardium-or mild 4-hour false fixed defects. In such defects, the amount of 4-hour thallium-201 activity may be already taken as evidence of viability.g On the contrary, only 11 (3 %) of 309 segments with severe (score 0 to 1) 4-hour defects (thus indicating the absence of a substantial amount of viable tissue) improved their tracer uptake at 24-hour imaging. Moreover, none of the 10 patients without 4-hour reversible perfusion defects showed late reversibility.

Visual analysis results were confirmed by quantitative analysis. Despite the low (>ll%) threshold used to identify thallium-201 uptake changes, an improvement in the tracer uptake on 24-hour scans was observed in 6 % of the partially reversible and in 6 % of the fixed defects on 4-hour acquisitions.

It is worth noting that the rate of false fixed defects (i.e., showing some 24-hour reversibility) was particularly negligible in those patients with severely depressed ventricular function and who were sched- uled for thallium-201 study to predict the potential benefit of revascularization (Fig. 10).

Recently, van Eck-Smit et a1.16 proposed an even shorter reinjection imaging protocol. In 120 unselected patients evaluated for suspected ischemia, they reinjected thallium-201 immediately after postexercise imaging and acquired images at 45 to 60 min and 3 hours later. They found that immediate postexercise reinjection followed by 3-hour image acqui-

sition was not superior to l-hour redistribution images in identifying viable myocardium. This con- clusion, however, was drawn on the basis of qualitative data only and was related to a study population that differed from ours because of their lower (41% vs 88%) prevalence of myocardial infarction and re- markably lower number of abnormal segments on poststress images (33 % vs 61% ).

Postrevascularization findings. Our preliminary results on the effects of coronary revascularization on thallium-201 uptake pattern obtained in the small group of patients studied before and after intervention seem to confirm that 4-hour imaging after early poststress reinjection provides most of the relevant information regarding residual viable myocardium. Some underestimation of cellular integrity still seems to affect the preoperative study as suggested by the rate of postoperative thallium-201 uptake improvement in severe fixed defects documented at qualitative (6 of 35, 17%) and quantitative (13 of 25, 52%) analysis. In the interpretation of these preliminary results (in particular regarding the reduced accuracy of preoperative quantitative data), however, the small number of patients must be emphasized and the potential selection bias resulting from the high rate of ischemic findings at the preoperative stress testing (angina or ischemic electrocardiographic changes in 85% and reversible thallium-201 defects in 100% of patients).

Study limitations. In our study there was no comparison with either the standard 4-hour or the standard reinjection technique; furthermore, we failed to provide any functional correlation of the thallium- 201 content to myocardial viability. However, the aim of our study was to verify in a selected population of patients the true rate of late 24-hour thallium- 201 reversibility after early reinjection. At the time this article was written, only one other report? has addressed this issue. Nonetheless, it must be emphasized that, although late reversibility improves the accuracy of stress-redistribution thallium-201 scintigraphy for the assessment of myocardial viability, it has been shown to be an inadequate gold standard for reversibility because more than one third of thallium-201 defects that remain irreversible 24 hours after the stress injection improve after reinjection7 or revascularization.13

Possible study limitations include our decision to consider the value of <75% of peak myocardial activity to be abnormal at quantitative analysis. This arbitrary cut-off value has been used by several investigators in similar study cohorts.gl 2op 21p 26 More- over, this empiric value does not seem to represent a



potential bias affecting our results: in fact, late reversibility was negligible both in mild-moderate and severe 4-hour defects.

One further limitation of our study could stem from the so-called thallium-201 differential uptake phenomenon. The traditional thallium-201 reinjection protocol requires two sets of delayed acquisitions (4-hour redistribution followed by postreinjection images); to avoid this logistically difficult imaging protocol, several laboratories have adopted the prac- tice of performing only immediate postreinjection images. However, an apparent washout of thallium- 201 early after reinjection has been recently documented in some 4-hour reversible defects as a result of the low diffe’rential uptake26, 27; this finding has therefore highlighted the risk of misinterpreting irreversible perfusion defects on images acquired just a few minutes after tracer reinjection if conventional redistribution imaging is not performed as well. On the whole, the differential uptake phenomenon in reversible defects is uncommon (8 % of abnormal poststress segments in the report by Dilsizian and Bonow27); moreover, this issue does not represent a limitation of our 4-hour postreinjection imaging protocol, in agreement with the documented further thallium-201 redistribution late after reinjection.

Conclusions. Thallium-201 reinjection early after poststress imaging followed by 4-hour redistribution scans seems to provide reliable information regarding both residual ischemia and myocardial viability in patients with ventricular dysfunction and severe poststress perfusion defects. Although some further thallium-201 redistribution was documented on 24- hour or postrevascularization imaging with respect to 4-hour postreinjection acquisitions, it was clinically insignificant for the functional assessment and decision-making in these patients.

We thank George A. Beller, MD, for reviewing this article; Orazio Zoccarato, PhD, and Giacomina Romolo for technical ad- vice; and Gillian Jarvis for editorial assistance.

REFERENCES

Pohost GM, Zir LM, Moore RH, McKusic KA, Guyney TE, Beller GA. Differentiation of transiently ischemic from in- farcted myocardium by serial imaging after a single dose of thallium-201. Circulation 1977;55:2941302. Grunwald AM, Watson DD, Holzgrefe HH, Irving JF, Beller GA. Myocardial thallium-201 kinetics in normal and ischemic myocardium. Circulation 1981;64:610-8. Rozanski A, Berman D, Gray R, Levy R, Raymond M, Mad- dahi J. Pantelo N, Waxman AD. Swan HJC. Matloff J. Use of thallium-201 redistribution scintigraphy in the preoperative differentiation of reversible and nonreversible myocardial asynergy. Circulation 1981;64:936-44. Iskandrian A, Hakki AH, Kane SA, Goel IP, Mundth ED, Hakki A, Segal BL, Amenta A. Rest and redistribution thallium-201 myocardial scintigraphy to predict improvement in

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

(ialli and Marcassa 51

Left ventricular function after coronary arterial bypass graft- ing. Am J Cardiol 1983;51:312-6. Rocco TP, Dilsizian V, McKusick KA, Fischman AJ, Boucher CA, Strauss HW. Comparison of thallium redistribution wit.h rest reinjection imaging for detection of viable myocardium. Am J Cardiol 1990;66:158-63. Dilsizian V, Rocco T, Freedman NMT, Leon M, Bonow R. Enhanced detection of ischemic but viable myocardium by the reinjection of thallium after stress-redist,ribution imaging. N Engl J Med 1990;323:141-6. Kayden DS, Sigal S, Soufer R, Mattera J, Zaret BL, Wackers FJ. Thallium-201 for assessment of myocardial viability: quantitative comparison of 24-hour redistribution imaging with imaging after reinjection at rest. .I Am Co11 Cardiol 1991;18:1480-6. Bonow RO, Dilsizian V. Thallium-201 for assessment of myocardial viability. Semin Nucl Med 1991;21:230-41. Bonow RO, Dilzisian V, Cuocolo A, Bacharach SL. Identifica- tion of viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction. Comparison of thallium-201 scintigraphy with reinjection and PET imaging with 18F-fluorodeoxyglucose. Circulation 1991;83:26-37. Budinger TF, Pohost GM, Bischoff P. Thallium-201 integral blood concentration over 2 hours explains persistent defects in patients with no evidence of MI by ECG [.4bstract]. Circula- tion 1987;76(suppl IV):64. Gutman J. Berman DS. Freeman M. Rozanski A. Maddahi J. Waxman k, Swan HJC: Time to completed rediitribution or thallium-201 in exercise myocardial scintigraphy: relationship to the degree of coronary artery stenosis. Am Heart ,J 1983; 106:989-95. Cloninger KG, DePuey G, Garcia EV, Roubin GS, Robbins WL, Nody A, DePasquale EE, Berger NJ. Incomplete redistribution in delayed thallium-201 SPECT images: an overestimation of myocardialscarring. J Am Co11 Cardiol1988;12:955- 63. Kiat H, Berman DS, Maddahi J, Yang I,D, Van Train K, Rozanski A, Friedman J. Late reversibility of tomographic myocardial thallium defects: an accurate marker of myocardial viabilitv. J Am Co11 Cardiol 1988:12:1456-63. Botvinick i. Late reversibility: a viability issue. d Am Co11 Cardiol 1990;15:341-4. Kiat H, Friedman JD, Wang FP, Van Train KF, Maddahi J, Takemoto K, Berman DS. Frequency of late reversibility in stress-redistribution thallium-201 SPECT usinn an earlv reinjection protocol. AM HEART J 1991;122:613-9.- ” van Eck-Smit BLF, van Der Wall EE, Kuijper AF, Zwinder- man AH, Pauwels EK. Immediate Thallium-201 reinjection following stress imaging: a time saving approach for detection of myocardial viability. J Nucl Med 1993$4:737-74X Giannuzzi P, De Vito F, Imparato A, Tavazzi 1,. Influence of left ventricular cavity dimension on electrocardiographic esti- mation of the extent of wall motion abnormalities. Clin Car- diol 1987;10:521-27. Wackers FJ, Fetterman RC, Mattera J, Clements JP. Quan- titative planar thallium-201 stress scintigraphy: a critical evaluation of the method. Semin Nucl Med 1986;15:46-66. Garcia E, Maddahi J, Berman D, Waxman A. Space/time quantitation of thallium-201 myocardial scintigraphy. .I Nucl Med 1981;22:309-17. Gibson R, Taylor G, Watson D, Stebbins PG, Martin R, Crampton D, Beller G. Predicting the extent and location of coronary artery disease during the early postinfarction period by quantitative Thallium-201 scintigraphy. Am J Cardiol 1981;47:1010-9. Gibson RS, Watson DD, Taylor GJ, Crosby IK, Wellons HL, Holt ND, Beller GA. Prospective assessment of regional myocardial perfusion before and after coronary revascularization surgery by quantitative thallium-201 scintigraphy. J Am Co11 Cardiol 1983;1:804-15. Picano E, Marzullo P, Gigli G. Reisenhofer H. Parodi 0, Dis-

Miiller et al. July 1994


23.

24.

25.

tante A, L’Abbate A. Identification of viable myocardium by dipyridamole-induced improvement in regional left ventricular function assessed by echocardiography in myocardial infarction and comparison with thallium scintigraphy at rest. Am J Cardiol 1992;70:703-10.

26.

Lemlek J, Heo J, Iskandrian A. The clinical relevance of myocardial viability in patient management. AM HEART J 1992; 124:1327-31. Liu P, Kiess MC, Okada RD, Block PC, Strauss HW, Pohost GM, Boucher CA. The persistent defect in exercise thallium imaging: does it represent scar or ischemia? AM HEART J 1985;110:996-1001.

27.

Brunken R, Schweiger M, Grover-McKay M, Phelps ME, Tillish J, Schelbert HR. Positron emission tomography de-

tects tissue metabolic activity in myocardial segments with persistent thallium perfusion defects. J Am Co11 Cardiol 1987; 10~557-67. Dilsizian V, Freedman NMT, Bacharach SL, Perrone-Filardi P, Bonow RO. Regional thallium uptake in irreversible defects. Magnitude of changes in thallium activity after reinjection distinguishes viable from nonviable myocardium. Circu- lation 1992;85:627-34. Dilsizian V, Bonow RO. Differential uptake and apparent thallium-201 wash-out after thallium reinjection. Options regarding early redistribution imaging before reinjection or late redistribution imaging after reinjection. Circulation 1992; 85:1032-8.

Effect of exercise supplementation during adenosine infusion on hyperemic blood flow and flow reserve

Physical stress might modulate myocardial blood flow in near-maximally dilated coronary arteries by increasing coronary perfusion pressure, myocardial contractility, and heart rate. The net effect of these changes on hyperemic blood flows has not yet been defined in humans. To quantify the effect of physical exercise on pharmacologically induced hyperemia, myocardial blood flow was measured in 11 healthy volunteers. Measurements were performed with positron emission tomographic imaging with nitrogen-13 ammonia at rest, during intravenous (IV) adenosine administration (140 Ag . kg-’ . min-’ over 6 minutes), and during IV adenosine administration plus supine bicycle exercise with a maximal workload of 125 W. Myocardial blood flow was quantified by using a previously validated graphic analysis. Heart rate, systolic blood pressure, rate-pressure product, and mean aortic blood pressures were significantly higher during combined physical and pharmacologic stress than during pharmacologic stress alone. However, myocardial blood flow decreased from 2.6 + 0.4 to 2.2 f 0.4 ml . min-’ . gm-’ with the addition of physical stress (p < 0.05). This decline was associated with a significant increase in coronary vascular resistance (35 k 6 vs 52 -t 13 mm Hg . ml-’ . gm . min; p < 0.05). Accordingly, myocardial flow reserve declined, from 5.0 ? 0.9 to 4.3 + 1.0, with exercise supplementation (p < 0.05). Exercise in addition to pharmacologic stress increases coronary vascular resistance and thus significantly decreases hyperemic myocardial blood flow and flow reserve. This decrease results most likely from an increase in extravascular restrictive forces caused by higher ventricular pressures and contractility during physical stress. (AM HEART J 1994;128:52-60.)

Peter Miiller, MD, Johannes Czernin, MD, Yong Choi, PhD, Francitie Aguilar, CNMT, Egbert U. Nitzsche, MD, Denis B. Buxton, PhD, Karl Sun, MD, Michael E. Phelps, PhD, Sung-Cheng Huang, DSc, and Heinrich R. Schelbert, MD Los Angeles, Calif.

From the Division of Nuclear Medicine and Biophysics, Department of Ra- diological Sciences, School of Medicine, and the Laboratory of Nuclear Medicine, Laboratory of Biomedical and Environmental Sciences, Univer- sity of California, Los Angeles.

Received for publication Oct. 12, 1993; accepted Nov. 30, 1993.

The Laboratory of Biomedical and Environmental Sciences is operated for the United States Department of Energy by the University of California under contract DE-FC03-87ER60615.

Supported in part by the Director of the Office of Energy Research, Office

of Health and Environmental Research, Washington, D.C.; by Research Grants HL 29645 and HL 33177, National Institutes of Health, Bethesda,

Md.; and by an Investigative Group Award from the Greater Los Angeles A5liate of the American Heart Association, Los Angeles, Calif. Peter Mtiler is the recipient of a Conrad Gessner Fellowship.

Reprint requests: Heinrich R. Schelbert, MD, Department of Pharmacol- ogy, Division of Nuclear Medicine and Biophysics, UCLA School of Med- icine, 10633 Le Conte Ave., Los Angeles, CA 90024-1721.

Copyright @ 1994 by Mosby-Year Book, Inc. 0002~8703/94/$3.00 + 0 4/l/54548

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Thallium-201 redistribution after early reinjection in patients with severe stress perfusion defects and ventricular dysfunction