Positron emission tomography detects tissue metabolic activity in myocardial segments with persistent thallium perfusion defects

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lACC Vol. 10. NO.3 September 19X7:557-67

Positron Emission Tomography Detects Tissue Metabolic Activity in Myocardial Segments With Persistent Thallium Perfusion Defects RICHARD BRUNKEN, MD, FACC, MARKUS SCHWAIGER, MD, MALEAH GROYER-McKAY, MD, FACC, MICHAEL E. PHELPS, PHD, JAN TILLISCH, MD, HEINRICH R. SCHELBERT, MD, FACC Los Angeles, California

Positron emission tomography with uN-ammonia and (SF -2-deoxyglucose was used to assess myocardial perfusion and glucose utilization in 51 myocardial segments with a stress thallium defect in 12 patients. Myocardial infarction was defined by a concordant reduction in segmental perfusion and glucose utilization, and myocardial ischemia was identified by preservation of glucose utilization in segments with rest hypoperfusion. Of the 51 segments studied, 36 had a fixed thallium defect, 11 had a partially reversible defect and 4 had a completely reversible defect. Only 15 (42%) of the 36 segments with a fixed defect and 4 (36%) of the 11 segments with a partially reversible defect exhibited myocardial infarction on study with positron tomography.

Stress planar thallium-20l scintigraphy has been used extensively in clinical practice to assess myocardial perfusion in a variety of circumstances (l). Perfusion deficits that persist on serial images have usually been attributed to irreversible scar formation whereas deficits that improve or resolve on delayed images have been associated with viable tissue (2,3). For example, prior clinical studies (4,5) have From the Division of Nuclear Medicine and Biophysics, Department of Radiological Sciences, the Division of Adult Cardiology, Department of Medicine, UCLA School of Medicine, and the Laboratory of Nuclear Medicine, Laboratory of Biomedical and Environmental Sciences. * University of California, Los Angeles, California 90024. *Operated for the U.S. Department of Energy, Washington, D.C.. by the University of California under Contract DE-AC03-76-SFOOO12. This work was supported in part by the Director of the Office of Energy Research, Office of Health and Environmental Research, Washington D.C.. by Grants HL 29845 and HL 33177 from the National Institutes of Health, Bethesda, Maryland, and by an Investigative Group Award from the Greater Los Angeles Affiliate of the American Heart Association, Los Angeles. California. It was presented in part at the 58th Annual Scientific Sessions of the American Heart Association, November II to 14. 1985. Washington. D.C. Manuscript received September 29, 1986: revised manuscript received March 24, 1987, accepted April 10, 1987. Address for reprints: Richard Brunken, MD, Division of Nuclear Medicine and Biophysics, UCLA School of Medicine, Los Angeles. California 90024.
In contrast, residual myocardial glucose utilization was identified in the majority of segments with a fixed (58%) or a partially reversible (64%) thallium defect. All of the segments with a completely reversible defect appeared normal on positron tomography. Apparent improvement in the thallium defect on delayed images did not distinguish segments with ischemia from infarction. Thus, positron emission tomography reveals evidence of persistent tissue metabolism in the majority of segments with a fixed or partially resolving stress thallium defect, implying that markers of perfusion alone may underestimate the extent of viable tissue in hypoperfused myocardial segments. (J Am Coil CardioI1987;10:557-67)

suggested that myocardial segments with resting wall motion abnormalities and a fixed thallium-20l defect rarely exhibit functional improvement after revascularization, whereas segments with a reversible thallium-20l defect typically improve after revascularization. Other observations, however, suggest that viable but functionally impaired tissue may exist in some ventricular segments with a persistent thallium-20 I perfusion defect. Some myocardial segments with a fixed thallium-201 defect do exhibit improved function after revascularization (4,5). Liu et al. (6) noted that 75% of myocardial segments with a persistent thallium-20 I defect on stress scintigraphy exhibited a normal thallium pattern after angioplasty of the culprit lesion. In the series of patients undergoing coronary revascularization reported on by Gibson et al. (7), 45% of myocardial segments with a persistent defect on preoperative stress scintigraphy exhibited a normal thallium perfusion pattern and normal washout kinetics after coronary artery bypass surgery. The clinical problem is to distinguish hypoperfused but viable tissue from regions with extensive scar formation. Previous experimental studies (8-13) have demonstrated that hypoperfused, ischemic tissue may retain the ability to 0735-1097/X7/$3.50

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BRUNKEN ET AL. METABOLISM IN PERSISTENT THALLI UM DEFECTS

metabolize glucose . Residual tissue perfusion may allow aerobic or anaerobic glycolysis, and glucose utilization will be enhanced relative to blood flow. Because myocardial regions with extensive scar formation are metabolically inactive, the presence of metabolic activity distinguishes ischemic tissue from regions of extensive scar formation. With the advent of positron emission tomography and labeled tracers of blood flow and metabolism, it is now possible to noninvasively assess relative myocardial perfusion and glucose utilization in humans. Relative myocardial perfusion is assessed with 1JN-ammonia ( 14, 15), and relative glucose utilization is assessed with the glucose analog, 18F-2-deoxyglucose (16,17) . Criteria for myocardial ischemia and infarction have previously been reported (18). In ischemia , 18F-2-deoxyglucose tissue concentrations are augmented relative to those of UN-ammonia; in infarction, concentrations of both UN-ammonia and IXF-2-deoxyglucose are concordantly reduced. Persistence of metabolic activity in hypoperfused segments correlates well with the histologic presence of viable tissue ( 19) and is predictive of functional improvement after restoration of blood flow (20 ,2 1). Because thallium-20 I and UN-ammonia have previously been shown to correlate closely as markers of perfusion (15,22), we postulated that some myocardial segments that exhibited stress scintigraphic criteria for myocardial fibrosis (persistent or only partially resolving stress thallium defects) might exhibit residual glucose metabolism on study with positron tomography. The purpose of this study was to assess myocardial perfusion and glucose utilization with positron tomography in segments with a persistent or partially resolving stress thallium defect.

Methods Study patients. Twelve consecutive patients, II men and I woman, with a persistent defect on stress thallium scintigraphy were studied; their mean age was 56.3 ± 8.9 years. Ten patients had a clinical history of previous myocardial infarction; in these patients there was a total of 14 antecedent infarctions. Congestive heart failure was noted in seven. Angina was present in six patients and an additional patient had atypical chest discomfort. Four patients had a history of ventricular tachycardia, two had chronic atrial fibrillation, two had left bundle branch block and one had a permanent pacemaker for trifascicular block. Eleven of the 12 patients had coronary angiography: 7 had triple vessel disease, 2 had double vessel disease and 2 had single vessel disease. Nine patients had one or more vessels with :;:;::90% diameter narrowing. Two patients had had remote coronary bypass grafting; all grafts were closed on angiographic study in one patient and the other patient did not have graft angiography . Left ventricular ejection fraction, as determined by radionuclide ventriculography (n = 9), left ventricular angiography (n = 2) or echocardi-

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ography (n = I), averaged 32. 1 ± 13.7%. At our institution, an ejection fraction > 50% on left ventricular angiography or radionuclide ventriculography or > 55% on echocardiography is considered normal. At the time of study 10 patients were receiving nitrates (for angina or atypical chest discomfort in 7 and congestive heart failure in 3); 6 each were receiving digoxin and diuretics; 4 were receiving calcium channel blockers; 3 each were receiving beta-receptor blockers, type I antiarrhythmic drugs and other vasodilators; and I was receiving amiodarone. Stress thallium scintigraphy. All subjects underwent graded treadmill exercise with heart rate and blood pressure monitoring utilizing either the Bruce, Kattus or Naughton protocol. Exercise was terminated when 85% of the maximal predicted heart rate for age was achieved, when ST segment depression exceeded baseline by > 2 mm or when moderately severe symptoms or abnormal blood pressure response precluded further exercise. Leads II, V2 and Vs were continuously monitored during exercise and in the early recovery period; 12 lead electrocardiograms (ECGs) were obtained before and immediately after exercise. The mean achieved rate-pressure product was 17,377 ± 5,186; the mean percent of maximal predicted heart rate achieved was 78.8 ± 14.7%. Three patients achieved > 85% of their maximal predicted heart rate. Two patients had ST-T changes diagnostic of ischemia; the remainder had nonspecific ST-T changes. Thallium-201 chloride ( 1.5 to 2.0 mCi) was administered intravenously I minute before termination of exercise. Imaging was begun within 10 minutes of isotope administration and was performed for 600 seconds in the anterior, 45° left anterior oblique and left lateral projections using a Technicare series 100 camera equipped with a low energy, parallel-hole all-purpose collimator. Delayed images were obtained 4 hours after thallium administration in similar projections. Patients were allowed to ambulate and to drink clear liquids between the postexercise and delayed images. Count recovery was 600,000 to 800,OOO/image for the immediate postexercise and 400,000 to 600 ,000/ image for the redistribution views. Acquired images were stored on floppy disks as 128 x 128 matrices. Image processing was performed utilizing a Technicare 560 computer; each study was photographed at varying intensities directly from the computer CRT display. The mean interval between thallium scintigraphy and positron tomography was 10.6 ± 11 .6 days (range I to 33). Thallium image interpretation. Three experienced nuclear medicine physicians independently assessed thallium uptake in each of seven myocardial segments on both the postexercise and redistribution images (Fig. I) using the following scale: 0 = normal, I = mild but definite defect, 2 = moderately severe defect and 3 = complete defect (background level). Scores on multiple views were averaged to give a mean value for the following anatomic segments:

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September 1987:557-67

Ant

LAO

La t

Figure 1. Diagrammatic anterior (Ant), 45° left anterior oblique (LAO) and left lateral (Lat) planar thallium-20l images, illustrating assignment of anatomic ventricular segments. I and II = Anterobasilar segment; 2 and 12 = anterolateral segment; 3, 8 and 13 = apical segment; 4 and 14 = inferior segment; 5 and 15 = posterobasilar segment; 6 and 7 = anteroseptal segment; 9 and 10 = lateral segment. anterobasilar, anterolateral, apical, inferior, posterobasilar, anteroseptal and lateral. A thallium defect was defined by a mean segmental score 2:0.66 on the postexercise study; that is, at least two graders agreed that a defect was present. Defects were classified as fixed if the difference between the postexercise and redistribution scores was <0.5. Partial redistribution was defined by an improvement in the mean score of 2:0.5 but a failure to achieve a score of sO.33 on the redistribution study. A thallium defect was said to be completely reversible if the mean score on the redistribution study was sO.33 (that is, two observers agreed that the defect normalized). Simple analysis of variance did not reveal any significant difference between mean segmental scores for each observer (F = 2.64, P = NS) and scores differed by s I in 87% of the segments examined. Positron emission tomography. Tomographic imaging was performed with an ECAT II (CT!, Inc.) tomograph,

559

utilizing previously published methods (18). Six contiguous cross-sectional transmission images 1.0 to 1.5 ern apart were initially obtained to allow correction for photon attenuation. After the intravenous bolus administration of 15 to 20 mCi of the flow tracer 13N-ammonia, corresponding images of relative myocardial perfusion were obtained in the same cross-sectional planes. The specific activity of the 13N_ ammonia was 100 to 200 Ci/mmol. After acquisition of the perfusion images, 10 mCi of the metabolic tracer 18F_2_ deoxyglucose was administered as a single intravenous bolus. Acquisition of the metabolic images was begun 40 minutes after 18F-2-deoxyglucose administration to allow sufficient time for myocardial uptake and phosphorylationof the tracer (23). Identical positioning for each set of images was achieved by marking each subject's chest with washable ink and aligning the marks with a reference low power laser beam from the tomograph. The specificactivity of the 18F-2-deoxyglucose was 2 Ci/mmol (24). Subjects were studied I to 2 hours after a carbohydrate-containing meal and were given a 25 to 50 g oral glucose load I hour before the administration of the 18F-2-deoxyglucose. This served to enhance myocardial glucose utilization relative to that of free fatty acids (25). Total body radiation dose for a complete study was 0.08 rad (26,27). Each subject gave written consent on a form approved by the University of California at Los Angeles Human Subject Protection Committee. Analysis of tomographic images. An operator-interactive computer program was used to analyze the data (18). The normalizedcircumferentialcount profilesof both tracers for each tomographic plane were displayed as a function of the angle from a line from the mid-apex through the center of the ventricular cavity. The data were then referenced to

~ Anteroseptal

D Anterobasilar

o

Apex

Q Lateral ~ Posterobasilar

Figure 2. Diagrammatic representation of six crosssectional tomographic planes, illustrating the assignment of the seven anatomic ventricular regions.

~ Anteroseptal

o

Apex

o

Anterolateral

~ Inferior

Q

Lateral

~ Posterobasilar

~

Anteroseptal

D Anterolateral Q

Lateral

fZi] Inferior

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BRUNKEN ET AL. METABOLISM IN PERSISTENT THALLIUM DEFECTS

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established normal laboratory values for each 30° sector of each tomographic plane (18). This dual isotopic technique eliminates concerns about the partial volume effect because any segmental anatomic differences in the myocardium will equally affect count recoveries for both tracers. Hypoperfused regions were identified on the 13N-ammonia study by 13N activity <2 SD below normal. Recovered F-18 activity in these regions discriminated between the absence or persistence of tissue metabolic activity. Myocardial infarction was defined by a concordant reduction in recovered 18F counts in three or more contiguous sectors (18). Myocardial ischemia was defined by an 18F, 13N count difference >2 SD above normal in two or more contiguous sectors (18). Anterobasilar, anterolateral, apical, inferior, posterobasilar, anteroseptal and lateral ventricular segments were defined (Fig. 2). Statistical analysis. Values reported are mean values ± I SD. Segmental thallium scores were analyzed using simple analysis of variance, followed by the F test for statistical significance. Comparisons between sets of clinical interest (for example, thallium scores for segments with tomographically defined ischemia versus infarction, or postexercise thallium scores versus delayed thallium scores) were performed with Student's t test for unpaired data. The characteristics of patients with and without tomographic ischemia were compared using the chi-square test (with Yates' correction when appropriate). Probability (p) values <0.05 were considered statistically significant.

Results Thallium scintigraphy. Fifty-five segmental thallium defects were identified on the postexercise images in the 12 patients. Two fixed septal defects were excluded from analysis because of associated left bundle branch block (28). Two anterobasilar segments with a thallium defect were not imaged with positron tomography and these segments were also excluded from analysis. Of the remaining 51 segmental Table 1. Classification and Location of 51 Segmental Thallium Defects*

Anterobasilar Anterolateral Apical Inferior Posterobasilar Anteroseptal Lateral Total

Fixed Defect

Partially Reversible Defect

Completely Reversible Defect

I

0

7 8 4

2

5 7 4

0

I 1 0 0 0 I I

36

II

4

4

2 I 2

*Excludes two anterobasilar defects (one fixed, one partially reversible) that were not imaged with positron tomography.

2.5

r p = NS 1

rpeO.Ol1

r P < 0.01 1

Partially Reversible n = 11

Completely Reversible n=4

2.0 G) ~

0 0

rn

1.5

E ::J

III

1.0

s:

I-

0.5

0.0

Post Exercise Delayed Fixed Defects n = 36

Figure 3. Immediate postexercise and 4 hour delayed segmental thallium scores for the fixed, partially reversible and completely reversible thallium defects. Thallium defects were assessed by three independent graders on a scale of 0 (normal) to 3 (complete defect, equivalent to background). The number of segments analyzed is given beneatheach classification. There was no significant difference between the postexercise and delayed studies in mean segmental thallium score for the fixed defects; in contrast, both partially reversible and completely reversible defects had significantly better delayed thallium scores.

thallium defects, 36 were fixed, 11 were partially reversible and 4 were completely reversible. The number of defects in each thallium category is listed by ventricular segment in Table 1. In the segments with a fixed thallium defect, there was no significant difference between the mean postexercise and delayed thallium scores. Mean delayed scores for both partially reversible and completely reversible defects were significantly better than the mean postexercise scores (Fig. 3). Mean segmental thallium scores are listed according to stress scintigraphic and tomographic classification in Table 2. On the postexercise studies, segments with a partially reversible defect had a significantly higher mean score than did segments with either a fixed or a completely reversible defect. On the delayed studies, however, the mean scores for segments with a fixed or partially reversible defect were equally poor; both were significantly worse than the score for segments with complete redistribution. Correlation with positron tomography. Of the 36 myocardial segments with a fixed thallium defect, only 15 (42%) fulfilled the criteria for tomographic infarction (Fig. 4). In contrast, criteria for tomographic ischemia were present in 9 segments (25%), and 12 segments (33%) appeared normal on tomographic study (Fig. 5). Similarly, of the 11 segments with a partially reversible thallium defect, only 4 (36%) exhibited tomographic criteria for myocardial infarction; criteria for tomographic ischemia were present in 4 segments (36%) (Fig. 6), and 3 segments (27%) were

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Table 2. Segmental Thallium Scores by Scintigraphic and Tomographic Classification Postexercise

Delayed

p Value'

1.23 ::: 0.60 1.1I ::: 0. 52 0. 16 :!: 0. 13

< 0.0 \ < 0.0 1

0.57 ::: 0.58 0.76 ::: 0.56 1.27 ::: 0.70"

NS NS NS

Stress Scintigra phy Fixed defects (n = 36) Part ially reversible defects (n II ) Completely reversible defects (n = 4 )

1.41 ::: 0.59 1.87 ::: 0.52t 1.04 ::: 0.35

NS

Positron Tomographyt

0.78 ::: 0.65 1.11 ::: 0.66 1.52 ::: 0.79\

PET norm al (n = 39) PET ischemia (n = 17) PET infarct (n = 22)

Summary of postexercise and 4 hour delayed mean thallium scores for myocardial segments when classified by stress thallium scintigraphic and positron emission tomograph ic (PET ) criteria. Thallium de fects were visually assessed and graded by three independent observers . PET class ifications are those of Marsh all et al. ( 18): PET normal = norm al perfu sion and glucose utilization ; PET infarct = concordant reduction in both perfusion and glucose utilizati on ; PET ischemia = preserved glucose utilization despite diminished perfu sion. See text for details. Analy sis of variance revealed a statistically significant difference in mean scores on both the postexercise and dela yed studies. when class ified either by stress sc intigraphic or by positron tomograph ic criteria . *Probability of delayed score as compared with postexe rcise score ; t p < 0.025 as compare d with fixed defe cts; p < 0.02 as co mpared with co mpletely re versible defec ts: t Exci udes the anterobasi lar segments in four patient s in which positron tomographi c imaging was inco mplete : \ p < 0.00 I as co mpared with PET normal: 0.05 < P < 0.10 as co mpared with PET ischemia: li p < O.()()) as compared with PET norma l; p < 0.02 as compared with PET ischemi a .

norm al. Thu s. residual tissue metabolic activity was identified in the majority of segments with a fixed (58%) or only a partially reversible (64%) thall ium defect. All segments with a completely reversible thallium defect were normal on positron tomography. The tomographi c finding s in the seg ments with fixed , partially reversible and completely rever sible thallium defects are summarized in Figure 7.

LAO

Positron emission tomo graph y detected seven myocardial segments with rest abnormalities of perfu sion that were not appreciated on thallium scintigraphy . Three segments (one

Figure 4. A, Postexercise and delayed thallium-20l images from a 66 year old woman who sustained a myocardial infarction 4 years before study. Fixed thallium-20l defects are noted in the anterolateral. apical and septal segments. 8, On study with positron tomography, concordant reductions in blood flow and glucose utilization are noted in the corresponding ventricular segments on the UN-ammonia and I~F-2-deoxyglucose studies, respectively, signifying tomographic infarction. Abbreviations as in Figure I .

Ant

Lat

A

Post Exercise

Delayed

B

Blood Flow

Glucose Metabolism

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BRUNKEN ET AL. METABOLISM IN PERSISTENT THALLIUM DEFECTS

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LAO

Ant

Lal

A

Post Exercise

Delayed

Figure 5. A, Postexercise and delayed thallium images from a 44 year old man who sustained a myocardial infarction 7 months before study, demonstrating fixed defects in the anterolateral, apical and septal segments of the ventricle. B, On positron tomography, perfusiondeficits are noted in the corresponding ventricular segments on the '3N-ammonia study (left). In addition, another perfusion defect is noted in the posterobasilar segment. On the '8F-2-deoxyglucose study (right), however, glucose utilization is well preserved in these ventricular segments, indicating tomographic ischemia. Abbreviations as in Figure I.

anterolateral, one inferior and one posterobasilar) exhibited tomographic criteria for myocardial infarction, and four segments (one inferior, one posterobasilar and two lateral) exhibited tomographic ischemia.

When mean thallium scores of all ventricular segments were compared according to positron tomographic classification, segments that were normal on tomographic study had significantly better scores than did segments with tomographic infarction on both the postexercise and delayed thallium studies (Table 2). On the postexercise studies, segments with tomographic ischemia had a mean score as poor as the score for segments with tomographic infarction. On the delayed study, however, the mean score for ischemic segments was significantly better than the score for segments with tomographic infarction. There was no significant difference between the scores for ischemic segments and normal segments on either the postexercise or delayed studies. None of the three tomographic classes exhibited a significant difference in mean score between the postexercise and delayed thallium study.

B

Blood Flow

Glucose Metabolism

Clinical correlation. Nine patients had one or more segments with tomographic ischemia. In two, ischemia was identified adjacent to segments with tomographic infarction. In the other seven patients, either ischemia was identified at sites remote from infarction or all of the hypoperfused segments in a vascular distribution exhibited tomographic ischemia. Patients with ischemia were as likely to experience chest pain (five of nine versus two of three), have triple vessel disease (six of nine versus one of two) or require treatment for congestive heart failure (six of nine versus one of three) or ventricular ectopic activity (three of five versus two of five) as were those without ischemia. Mean treadmill rate-pressure product (17,844 ± 4,801 versus 16,133 ± 7, lIS) and left ventricular ejection fraction (32.0 ± 14.8% versus 32.3 ± 12.5%) were similar in both groups. Two patients had ischemic ST-T changes while on the treadmill;

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563

LAO

Ant

Lat

A

B

Post Exercise

Delayed

both had rest tomographic ischemia in one or more corresponding myocardial segments, On stress thallium scintigraphy, improvement or normalization of the defect was not correlated statistically with uptake of '8F-2-deoxyglucose (II of 15 versus 21 of 36).

Discussion On study with positron tomography, only 15 (42%) of 36 fixed and 4 (36%) of II partially resolving segmental thallium defects exhibited tomographic infarction. In contrast, residual metabolic activity was detected in the majority of segments with a fixed (58%) or partially resolving (64%) thallium defect. All segments with a completely reversible thallium defect were normal on positron tomography. In this patient group, neither the clinical presentation nor improvement in the thallium defect 4 hours later was statistically associated with '8F-2-deoxyglucose uptake on study with positron tomography. Technical considerations. Fifteen (32%) of 47 segments with a persistent stress thallium defect had normal perfusion at rest when assessed with positron tomography. Relative 13N-ammonia tissue tracer concentrations were within the normal range, thereby failing to meet previously established definitions of ischemia or infarction. The mean value ± 2 SO had previously been chosen to define the normal range because it is the criterion used by many clinical laboratories to define normal values. The spatial resolution of the ECA T II tomograph is 1,8 em and count recovery reflects the sum of all activity in a relatively large anatomic region (each 30° sector could represent as much as 4.3 crrr'). Al-

Blood Flow

Glucose Metabolism

Figure 6. A, Postexercise and delayed thallium images from a 59 year old man who sustained a myocardial infarction I year before study. On the postexercise images, thallium-201 deficits are noted in the inferior, apical. anterolateral and septal segments. These improve but fail to normalize completely on the delayed study and were considered partially reversible defects. B, On study with positron tomography, diminished perfusion is noted in corresponding myocardial segments on the UN-ammonia images (left). On the 'RF-2-deoxyglucose study (right), however. glucose utilization is well preserved in these same segments, indicating tomographic ischemia. Abbreviations as in Figure 1.

though a rim of subendocardial fibrosis or multiple small foci of fibrosis might diminish count recovery, if the sum of all activity in a given sector fell within 2 SO of the mean, this would result in a normal tomographic classification and could explain why some segments with a persistent visual thallium defect were classified as normal on positron tomography. Tomographic ischemia and infarction were additionally defined by the extent of anatomic involvement; for example, ischemia was defined by the presence of the '8F-2~deoxy­ glucose/Plv-arnmonia mismatch in two or more contiguous 30° sectors. In this way, subtle differences in patient position or level of tomographic plane did not result in a false positive study. However, a segment with a relatively small thallium defect could have been classified as normal with positron tomography. Because of these factors, the current tomographic technique may have a higher specificity than sensitivity for the detection of myocardial ischemia and infarction. However, this same technique has proved useful in predicting improvement in segmental function after coro-

564

BRUNKEN ET AL. METABOLISM IN PERSISTENT THALLIUM DEFECTS

Fixed Defects

50

III

C CI>

E

58%

Partially Reversible

42%

40

Ol

'''I

Completely Revers ible

36%

100%

4

4

CI>

en

'0

30

C Q)

0

20

~

Q)

a.

12

9

15

10

o PET

Figure 7. Summary of the positron emission tomographic (PET) findings in the myocardial segments with fixed, partially reversible and completely reversible thallium defects. The number of segments in each classification is indicated by the figure on the appropriate bar. Segments normal on positron tomography are indicated by vertical lines, ischemic segments by cross-hatched lines and infarcted segments by the open bars. The majority of segments with a fi xed or partially reversible thallium defect exhibited persistent tissue metabolic activity on study with 18F_2_ deoxyglucose. nary revascularization (2 1); thus the normal or ischemic tomographic classification of a myocardial segment with a persistent thallium perfusion defect is of practical clinical importance, despite the possibility that small amounts of fi brosis might exist in that segment and be visually detectable on the thallium study. Exercise versus rest studies for tissue viability. Comparing stress thallium scintigraphy, which assessed myocardial perfusion after exercise and at 4 hours delay, with positron tomography, which assessed rest myocardial perfusion and metabolism, also poses some difficulties. A previous report (29) has suggested that thallium redistribution may be delayed longer than 4 hours in vascular beds subserved by vessels with stenosis :::::90%. Given that most of the patients in the current study had one or more vessels with :::::90% stenosis, we cannot exclude the possibility that some of the persistent defects noted on the 4 hour thallium images may have exhibited some degree of redistribution had more delayed images been obtained. Several other reports have also compared rest and redistribution thallium images. In the series of patients with coronary artery disease reported on by Blood et al. (30),45 (73%) of 62 patients with signifi cant coronary artery disease had rest thallium images that were identical to the 4 hour redistribution images. In the report of Ritchie et al. (3 1), 25 of 27 patients with exercise-induced thallium defects had complete or at least partial redistribution on imaging at 4 to 5 hours. Thus,

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it is unlikely that more delayed imaging would have significantly altered the outcome of this study. Planar thallium versus positron tomographic imaging. Althoughthere are difficulties in comparing ventricular segments derived from planar and tomographic imaging techniques, we attempted to minimize these inherent differences by having experienced observers assess segmental thallium activity on multiple planar views and using the resultant average score for each anatomic segment. In an independent study (21), utilizing the same seven segment ventricular analysis technique, positron tomography successfully predicted functional improvement in asynergic myocardial segments after coronary revascuIarization . In that study, segmental wall motion was also assessed with planar techniques (for example, radionuclide ventriculography), and thus we believe that it is possible to achieve a good correlation between segments derived from planar imaging and those derived from positron tomography. More recent advances in thallium imaging, like single photon emission computed tomography or the analysis of thallium washout rates, or both (32-36), have been reported to enhance the sensitivity of thallium imaging for the detection of occult coronary artery disease and the identification and localization of antecedent myocardial infarction. Neither of these methods was available at our institution when this study was performed. Although the advantages of single photon emission computed tomography and thallium kinetic analysis for the detection of coronary artery disease and antecedent infarction are clear, it is less certain how useful the application of these techniques to this study would have been. The purpose of this study was to assess relative glucose metabolism in segments with persistent, readily identifiable thallium deficits. The aim was not to detect coronary disease, but to determine whether tissue metabolic activity was present in segments that exhibited persistent thallium defects. Abnormal thallium washout rates would have been anticipated in most of the segments with a persistent thallium defect. Also, others (22) have previously shown a good correlation between tomographic thallium defects and 13N-ammonia defects noted on positron tomography. Thus, it is unlikely that the use of a tomographic thalliumtechnique or analysis of segmental thallium washout rates, or both, would have signifi cantly contributed to this study. Effect of dietary state. Positron tomography was performed in the postprandial state, increasing myocardial glucose utilization relative to that of free fatty acids (25) . Although the factors regulating glucose utilization in ischemic myocardium are poorly understood. glucose uptake may persist despite a systemic metabolic milieu favoring fatty acid utilization (37). In the current study, tracer concentrations were normalized to maximal activity in the myocardium. In the fastingstate, normal myocardium preferentially utilizes free fatty acids and glucose uptake is low (25) . As

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a result, 1KF-2-deoxyglucose uptake in ischemic myocardium is increased relative to that in normal myocardium. In the postprandial state, augmented utilization of glucose by normal myocardium would tend to result in a relative decrease in I ~F-2-deoxyglucose uptake in ischemic regions that could result in a classification of infarction and underestimate the extent of tissue viability. Although the quality of the ' ~F-2-deoxyglucose study is enhanced by imaging in the postprandial state, this may have resulted in an underestimation of the extent of viable tissue. Correlation with thallium scintigraphy. Preservation of tissue metabolic activity and, thus, evidence of tissue viability, was noted in the majority of myocardial segments with a fixed or partially reversible thallium defect. The data in this study are consistent with the study of Gibson et al. (7), in which 45% of persistent thallium defects on preoperative stress scintigraphy exhibited a normal thallium perfusion pattern and normal washout kinetics after coronary artery bypass surgery; improvement in segmental function provided additional evidenceof tissue viability in these myocardial segments. Four (36%) of 11 of the segments with partial redistribution exhibited criteria for myocardial infarction on study with positron tomography, indicatingthat apparent improvement in a thallium defect docs not exclude the possibility that extensive scar formation may exist in that myocardial segment. Although this may reflect observer error or the possibility that exercise-induced ischemia may have occurred in tissue adjacent to scar tissue, other investigators (38) have argued that thallium redistribution is a complex process that must be interpreted with caution. The findings of our study would similarly suggest that partial thallium redistribution on 4 hour delayed images must be interpreted with caution if taken to be an indicator of the presence of substantial amounts of viable tissue. Becauseof the entry criteria employed in this study, there were only four myocardial segments with a thallium perfusiondefect that exhibited complete redistribution. Because a good correlation has previously been demonstrated between thallium-201 and N-13 ammonia as markers of myocardial perfusion (15,22), it was expected that positron tomography (performed in the rest state) would demonstrate a normal perfusion pattern. Although there were relatively few segments for analysis. all were normal on positron tomography. Additional perfusion defects noted with positron tomography. Positron tomography detected a perfusion defect that was not detected on thallium imaging in seven segments. Six of the seven defects were in inferior, posterobasilar or lateral segments. that is. in the distribution of the left circumflex or the right coronary artery, for which the sensitivity of planar thallium imaging is relatively low (39), and in segments for which interobserver agreement is poorest (40). Although positron tomography does have the

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advantage of being a tomographic imaging technique, adequate assessment of the anterobasilar segment was not achieved in four patients. Future developments in tomographic instrumentation, including the ability to image or format the cross-sectional images of the ventricle along the long or short axis in multiple, interdigitating planes, will more reliably enable complete visualization of the myocardium. Thallium scores of segments classified by positron tomographic criteria. When the thallium scores of myocardial segments were analyzed according to positron tomograph ic classification, neither normal, ischemic, nor infarcted segments exhibited statistically significant differences between the postexercise and delayed scores (Table 2). Normal segments remained normal, and infarcted segments had scores that remained equally poor with time. Ischemic segments did exhibit the largest change in mean thallium score (0.35 or 32%), but this was not statistically significant. Although statistical significance might have been achieved had more segments been analyzed. it is also possible that some of these segments may have had such a severe perfusion defi cit at rest that exercise failed to enhance the relative magnitude of the deficit suffi ciently for visual detection. On the delayed thallium images, ischemic segments had a mean thallium score that was significantly better than the score for infarcted segments (p < 0.0 I). Although a similar trend was observed on the postexercise images, this was not statistically significant. These data suggest that ischemic segments have a less severe reduction in perfusion than do infarcted segments and these findings are consistent with previous observations (4 1). ln patients with chronic ischemic heart disease, mean relative tissue concentrations of l3N-ammonia are significantly less in regions with tomographic infarction than in regions with ischemia (41). However, in both the current and the previous study (4 \), relatively large standard deviations were present in the measured segmental values, denoting considerable overlap between values for ischemic and infarcted segments. Thus, assessment of relative perfusion in any given myocardial segment, panicularly one with a moderately severe reduction in flow (41), would be unlikely to be successful in predicting the presence or absence of glucose utilization. Clinical significance of findings. As a readily available, noninvasive method of assessing myocardial perfusion, thallium-20 I scintigraphy has proved invaluable for detecting coronary artery disease ( I), for assessing the severity of coronary stenoses (42.43) and the response to therapeutic procedures (44-48 ) and for stratifying risk in patients with ischemic heart disease (49-52). As such, it will likely remain in the clinician's armamentarium for many years to come. However, the results of the current study, in conjunction with previous reports (6,7), would indicate that the reliance on perfusion markers alone for assessment of tissue

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viability in segments with persistent abnormalities of myocardial blood flow might lead to underestimation of the extent of salvageable tissue. Myocardial regions associated with a large thallium-201 defect may contain only small amounts of fibrosis (53) and, conversely, some investigators have argued that the accumulation of thallium-20l is a passive process, depending on blood flow rather than on tissue viability (54). Thus, use of an independent marker of tissue viability like 18F-2-deoxyglucose would appear to be clinically helpful in these situations. Myocardial infarction is a heterogeneous process and the degree of myocardial fibrosis occurring as a result of an ischemic injury varies considerably (55-57). Because the spatial resolution of the ECAT II tomograph utilized in this investigation was 18 mm, it is possible that the observed uptake of '8F-deoxyglucose in the myocardial segments appearing hypoperfused on thallium scintigraphy might, in some instances, have represented accelerated glucose utilization in a rim of viable epicardial myocardium adjacent to a dense subendocardial infarct. In such a situation the extent of functional recovery of segmental wall motion after coronary revascularization would depend on the amount of viable myocardium remaining in the epicardium. Although a previous report from this laboratory (21) noted that segments that demonstrated preserved myocardial uptake of 18F-deoxyglucose had an 85% probabilitiy of improved wall motion after coronary revascularization, future studies with positron tomography should be able to provide even more information about the extent of tissue viability in hypoperfused myocardial segments. With the advent of the next generation of tomographs offering better spatial resolution and higher efficiency, noninvasive quantitative measurements of myocardial blood flow and glucose utilization should be feasible, allowing more accurate determination of the amount of viable but jeopardized tissue in hypoperfused myocardial segments. Conclusions. In this study, positron emission tomography with 13N-ammonia and 18F-2-deoxyglucose revealed persistent tissue metabolic activity in the majority of myocardial segments with a fixed or partially reversible thallium defect, implying the presence of viable tissue in these segments. Neither the severity of the thallium defect nor apparent improvement in the defect 4 hours after exercise reliably distinguished tomographically identified segments with ischemia from those with infarction. Thus, reliance on markers of perfusion alone for the assessment of tissue viability in segments with persistent abnormalities of blood flow may underestimate the extent of salvageable myocardium. We thank N. S. MacDonald, PhD and the Cyclotron Staffforthe production of the isotopes. The tomographic studies were performed by the following dedicated nuclear medicine technologists: Francine Aguilar, Cynthia Whitt, Lawrence Pang and Ron Sumida. M. Lee Griswold, Cynthia Whitt and Ron Sumida assisted with the illustrations and Kerry Engber prepared the manuscript.

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References I. Iskandrian AS, Hakki AH. Thallium-201 myocardial scintigraphy. Am Heart 1 1985;109:113-29. 2. Pohost GM, Zir LM, Moore RH, McKusick KA, Guiney TE, Beller GA. Differentiation of transiently ischemic from infarcted myocardium by serial imaging after a single dose of thallium-20 I. Circulation 1977;55:294-302. 3. Berman DS, Garcia EV, Maddahi J, Rozanski A. Thallium-201 myocardial perfusion scintigraphy: redistribution. In: Freeman LM, ed. Freeman and Johnson's Clinical Radionuclide Imaging. 3rd ed. Orlando, FL: Grune & Stratton, 1984:481-2. 4. Rozanski A, Berman DS, Gray R, et al. Use of thallium-201 redistribution scintigraphy in the preoperative differentiation of reversible and nonreversible myocardial asynergy. Circulation 198 I;64:936-44. 5. Iskandrian AS, Hakki AH, Kane SA, et al. Rest and redistribution thallium-201 myocardial scintigraphy to predict improvement in left ventricular function after coronary arterial bypass grafting. Am 1 CardioI1983;51:1312-6. 6. Liu P, Kiess MC, Okada RD, et al. The persistent defect on exercise thallium imaging and its fate after myocardial revascularization: does it represent scar or ischemia') Am Heart J 1985;110:996-1001. 7. Gibson RS, Watson DD, Taylor GJ, et al. Prospective assessment of regional myocardial perfusion before and after coronary revascularization surgery by quantitative thallium-201 scintigraphy. J Am Coli CardioI1983;1:804-15, 8. Brachfeld N, Scheuer J. Metabolism of glucose by the ischemic dog heart. Am J Physiol 1967;2 I2:603-6. 9. Opie LH, Owen P, Riemersma RA. Relative rates of oxidation of glucose and free fatty acids by ischaemic and nonischaemic myocardium after coronary artery ligation in the dog. Eur 1 Clin Invest 1973;3: 419-35. 10. Neely JR, Whitmer JT, Rovetto MJ. Effect of coronary blood flow on glycolytic flux and intracellular pH in isolated rat hearts. Circ Res 1975;37:733-41. I I. Opie LH. Effects of regional ischemia on metabolism of glucose and fatty acids. Circ Res 1976;38(suppl 1):1-52-74. 12. Marshall RC, Nash WW, Shine KI, Phelps ME, Ricchiuti N.Glucose metabolism during ischemia due to excessive oxygen demand or altered coronary flow in the isolated arterially perfused rabbit septum. Circ Res 1981;49:640-8. 13. Liedtke Al. Alterations of carbohydrate and lipid metabolism in the acutely ischemic heart. Prog Cardiovasc Dis 1981;23:321-36. 14. Schelbert HR, Phelps ME, Hoffman El , Huang SC, Selin CE, Kuhl DE. Regional myocardial perfusion assessed with N-13 labeled ammonia and positron emission computerized axial tomography. Am 1 Cardiol 1979:43:209-18. 15. Schelbert HR, Wisenberg G, Phelps ME, et al. Noninvasive assessment of coronary stenoses by myocardial imaging during pharmacologic coronary vasodilation. VI. Detection of coronary artery disease in human beings with intravenous N-13 ammonia and positron computed tomography. Am 1 Cardiol 1982;49: 1197-207. 16. Gallagher BM, Fowler 15, Gutterson NI, MacGregor RR, Wan CN, Wolf AP. Metabolic trapping as a principle of radiopharmaceutical design: some factors responsihle for the biodistribution of rIRF j-2deoxy-2-fluoro-D-glucose. J Nucl Med 1978;19:1154-61. 17. Ratib 0, Phelps ME, Huang SC, Henze E, Selin CE, Schelbert HR. Positron tomography with deoxyglucose for estimating local myocardial glucose metabolism. 1 Nucl Med 1982;23:577-86. 18. Marshall RC, Tillisch lH, Phelps ME, et al. Identification and differentiation of resting myocardial ischemia and infarction in man with positron computed tomography, 18F-Iabeled fluorodeoxyglucose and N-13 ammonia. Circulation 1983;67:766-78. 19. Sochor H, Schwaiger M, Schelbert HR, et al. Assessment of tissue viability in reperfused canine myocardium by a multiple radiotracer techinque (abstr). 1 Am Coli Cardiol 1985;5:451. 20. Schwaiger M, Schelbert HR, Ellison D, et al. Sustained regional

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abnormalities in cardiac metabolism after transient ischemia in the chronic dog model. J Am Coli Cardiol 1985;6:336-4 7. 21. Tillisch J, Brunken R, Marshall R, et al. Reversibility of cardiac wall motion abnormalities predicted by positron tomography. N Engl J Med 1986;314:884-8. 22. Tamaki N, Senda M, Yonekura Y, er al. N-13 ammonia myocardial positron computed tomography: ( I ) Comparative study with thallium201 SPECT. Kaku Igaku 1985;22:185- 91. 23. Krivokapich J, Huang SC, Phelps EM, et al. Estimation of rabbit myocardial metabolic rate for glucose using fluorodeoxyglucosc. Am J Physiol I982;243:H884-95. 24. Bida GT , Satyamurthy N, Barrio JR. The synthesis of 2-lF- 111 I fluoro2-deoxy-D-glucose usingglycals: a reexamination. J Nuel Med 19S4:25: 1327-34 . 25. Drake-Holland AJ. Substrate utilization. In: Drake-Holland AJ, Noble MIM, eds. Cardiac Metabolism. Chicester: John Wiley, 1983:195-213 26. Lockwood AH. Absorbed doses of radiation after an intravenous injection of N-13 ammonia in man: concise communication. J Nucl Med 1980:21:276- 78. 27. Jones Sc. Alavi A, Christman D, Montanez I, Wolf AP, Reivich M. The radiation dosimetry of 2-lF-1SI fluoro-2-denxy-D-glucose in man. J Nuel Med 1982;23:6 13- 7. 28. Hirzel HO, Senn M. Nuesch K, et al. Thallium-201 scintigraphy in complete left bundle branch block. Am J Cardiol 1984;53:764- 9. 29. Gutman J, Berman DS, Freeman M, et al. Time to completed redistribution of thallium-201 in exercise myocardial scintigraphy: relationship to the degree of coronary artery stenosis. Am Heart J 1983:106: 989-95 . 30. Blood OK, McCarthy OM, Sciacca BR, Cannan PJ. Comparison of single-dose and double-dose thallium-20 I myocardial perfusion scintigraphy for the detection of coronary artery disease and prior myocardial infarction. Circulation 1978;58:777- S8. 31. Ritchie JL, Albro PC, Caldwell JH, Trobaugh GB, Hamilton GW. Thallium-201 myocardial imaging: a comparison of the redistribution and rest images. J Nuel Med 1979;20:477- 83. 32. Ritchie JL, Williams OL, Harp G, Stratton JL, Caldwell JH. Transaxial tomography with thallium-201 for detecting remote myocardial infarction: comparison with planar imaging. Am J Cardiol 19S2:50: 1236-41. 33. Kirsch CM, Doliwa R, Buell U, Roedler D. Detection of severe coronary heart disease with TI -20I: comparison of resting single photon emission tomography with invasive arteriography. J Nucl Med 1983:24:761- 7. 34. Tamaki N, Yonekura Y, Mukai T, et al. Stress thallium-201 transaxial emission computed tomography: quantitative versus qualitative analysis for evaluation of coronary artery disease. J Am Coll Cardiel 1984;4:1213- 21. 35. Garcia EV, Van Train K, Maddahi J, et al. Quantification of rotational thallium-201 myocardial tomography. J Nuel Med 1985:26:17- 26. 36. Abdulla A, Maddahi 1. Garcia E, Rozanski A. Swan HJe. Berman OS. Slow regional clearance of myocardial thallium-20 I in the absence of perfusion defect: contribution to detection of individual coronary artery stenoses and mechanism for occurrence. Circulation 19S5:71: 72-9 . 37. Brunken RC, Schwaiger M, Schelbert HR. PET detection of residual. viable tissue in acute MI. J Appl Radiol 1985:14:82- 6. 38. Bergmann SR, Hack SN, Sobel BE. "Redistribution" of myocardial thallium-20 I without reperfusion: implications regarding absolute quantification of perfusion. Am J Cardiol 1982;49:1691- S. 39. Rigo P, Bailey IK, Griffith LSC, Pill B. Wagner HN. Becker i.c . Stress thallium-2ot myocardial scintigraphy for the detection of individual coronary arterial lesions in patients with and without previous myocardial infarction. Am J Cardiol 1981;48:209-16.

BRUNK EN ET AL. METABOLI SM IN PERSISTENT THALLIUM DEFECTS

567

40. Atwood JE. Jensen O. Froelicher V, et al. Agreement in human interpretation of analog thallium myocardial perfusion images. Circulation 1981:64:60 1-9. 41. Brunken RC. Schwaiger M. Tillisch JH , Marshall RC, Phelps ME, Schelbert HR. Relation between blood flow and glucose metabolism in hypoperfused ventricular segments in chronic ischemic heart disease (abstr). J Am Coli Cardiol 19S6;7:202A. 42. Reisman S. Berman O. Maddahi 1, Swan HJe. The severe stress thallium defect: an indicator of critical coronary stenosis. Am Heart J 1985:110:12S- 34. 43. Kalil V. Kelly MJ. Soward A, et al. Assessment of hemodynamic significance of isolated stenoses of the left anterior descending coronary artery using thallium-20 I myocardial scintigraphy. Am J Cardiol 1985:55:342-6 . 44. Iskandrian AS. Haaz W, Segal BL, Kane SA. Exercise thallium-201 scintigraphy in evaluating aortocoronary bypass surgery. Chest 1981 ;80: 11-5. 45. Greenberg BH. Hart R. Botvinick EH, et al. Thallium-201 myocardial perfusion scintigraphy to evaluate patients after coronary bypass surgery. Am J Cardiol 1975:42:167- 76. 46. Scholl JM. Chaitman BR. David PRoet a!' Exercise electrocardiography and myocardial scintigraphy in the serial evaluation of the results of percutaneous transluminal coronary angioplasty. Circulation 1982:66: 380-90. 47. Okada RO. Lim YL. Boucher CA, Pohost GM, Chesler OA. Block Pc. Clinical. angiographic. hemodynamic. perfusional and functional changes after one-vessel left anterior descending coronary angioplasty. Am J Cardiol 19S5;55:347- 56. 48. Wijns W. Serruys W. Reiber JHC. et al. Early detection of restenosis after successful percutaneous transluminal coronary angioplasty by exercise-redistribution thallium scintigraphy. Am J Cardiol 1985;55: 357-6 1. 49. Becker LC. Silverman K1. Bulkley BH, Kallman CH, Mellits ED, Weisfeldt M. Comparison of early thallium-201scintigraphy and gated blood pool imaging for predicting mortality in patients with acute myocardial infarction. Circulation 1983;67: 1272- 82. 50. Gibson RS, Watson 00. Craddock GB, et a!' Prediction of cardiac events after uncomplicated myocardial infarction: a prospective study comparing predischarge exercise thallium-201 scintigraphy and coronary angiography. Circulation 1983;611 :321-36. 51. Iskandrian AS, Hakki AH. Kane-Marsch S. Prognostic implications of exercise thallium-20 I scintigraphy in patients with suspected or known coronary artery disease. Am Heart J 1985;110:135-43 . 52. Ladenheim ML. Pollock BH. Rozanski A, et al. Extent and severity of myocardial hypopcrfusion as predictors of prognosis in patients with suspected coronary artery disease. J Am Coli Cardiol 1986;7: 464- 71. 53. Bulkley BH. Silverman K. Weisfeldt ML. Burow R, Pond M, Becker LC. Pathologic basis of thallium-20 I scintigraphic defects in patients with fatal myocardial injury. Circulation 1979:60:7115- 92. 54. Forman R, Kirk ES. Thallium-20J accumulation during reperfusion of ischemic myocardium: dependence on regional blood flow rather than viability. Am J Cardiel 19S4:54:65Y-63. 55. Stinson EB. Billingham ME. Correlative study of regional left ventricular histology and contractile function. Am J Cardiol 1977:39: 37S- R.1. 56. Hameng W, Suy R. Schwarz F, et al. Ultrastructural correlates of left ventricular contraction abnormalities in patients with chronic ischemic heart disease: determinants of reversible segmental asynergy post-rcvascularization surgery. Am Heart J 1981;102:S46-57. 57. Freifeld AG, Schuster EH. Bulkley BH. Nontransmural versus transmural myocardial infarction . A morphologic study. Am J Med 1983:75: 423- 32.