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Clinical Investigation and Reports
Stress-Induced Reversible and Mild-to-Moderate
Irreversible Thallium Defects
Are They Equally Accurate for Predicting Recovery of Regional Left
Ventricular Function After Revascularization?
Anastasia N. Kitsiou, MD; Gopal Srinivasan, MD; Arshed A. Quyyumi, MD;
Ronald M. Summers, MD, PhD; Stephen L. Bacharach, PhD; Vasken Dilsizian, MD
Background—In patients with coronary artery disease, stress-redistribution-reinjection thallium scintigraphy provides
important information regarding myocardial ischemia and viability. Although both reversible and mild-to-moderate
irreversible thallium defects retain metabolically active, viable myocardium, we hypothesized that stress-induced
reversible thallium defects may better differentiate reversible from irreversible regional left ventricular dysfunction
after revascularization.
Methods and Results—Twenty-four patients with chronic coronary artery disease underwent prerevascularization and
postrevascularization exercise-redistribution-reinjection thallium single photon emission CT, gated MRI, and radionuclide angiography. After revascularization, mean left ventricular ejection fraction increased from 3069% to 37613%
at rest (P,0.001). Before revascularization, abnormal contraction at rest was observed in 56 of 110 reversible and 20
of 37 mild-to-moderate irreversible thallium defects (51% and 54%, respectively). After revascularization, regional
contraction improved in 44 of 56 reversible compared with 6 of 20 mild-to-moderate irreversible thallium defects (79%
and 30%, respectively; P,0.001). The final thallium content (maximum tracer uptake on redistribution-reinjection
images) was significantly higher in regions with reversible defects that improved than in those that did not improve after
revascularization (86616% versus 6669%, P,0.001). In contrast, final thallium content was similar in regions with
mild-to-moderate irreversible defects that improved and in those that did not improve after revascularization (6969%
versus 65610%, P5NS). Furthermore, when asynergic regions were grouped according to the final thallium content,
at 60% threshold value, functional recovery was observed in 83% of regions with reversible defects compared with 33%
of regions with mild-to-moderate irreversible defects (P,0.001).
Conclusions—These findings suggest that although both reversible and mild-to-moderate irreversible thallium defects after
stress retain viable myocardium, the identification of reversible thallium defect on stress in an asynergic region more
accurately predicts recovery of function after revascularization. Even at a similar mass of viable myocardial tissue (as
reflected by the final thallium content), the presence of inducible ischemia is associated with an increased likelihood of
functional recovery. (Circulation. 1998;98:501-508.)
Key Words: coronary disease n scintigraphy n myocardium n ischemia n revascularization
P
aradigms concerning the relationship between myocardial perfusion and contraction have changed over the past
2 decades. Substantial data now exist to indicate that impaired
left ventricular function at rest in patients with coronary
artery disease is not necessarily an irreversible process.1–10
Among patients with preoperative left ventricular dysfunction, it has been estimated that nearly one third may exhibit
improvement in global left ventricular function after revascularization.11–15 This is the same patient population, however,
that experiences high perioperative morbidity and mortality,
which explains the reluctance of cardiac surgeons to operate
on them. Because enhanced left ventricular function after
revascularization is associated with improved survival,16 –20
the clinically important task is to distinguish patients with
functionally recoverable myocardium from those who have
predominantly scarred, nonrecoverable myocardium.
Regional left ventricular dysfunction arising from a transient period of myocardial ischemia (repetitive stunning)
and/or a prolonged period of myocardial hypoperfusion at
rest (hibernation) may be reversible, whereas regional dysfunction arising from transmural myocardial infarction or
mixed scarred and viable myocardium may be irreversible
after revascularization. The distinction between reversible
and irreversible asynergic regions may be made by demon-
Received December 10, 1997; revision received March 23, 1998; accepted April 5, 1998.
From the Cardiology Branch, National Heart, Lung, and Blood Institute, and the Department of Nuclear Medicine, National Institutes of Health,
Bethesda, Md.
Correspondence to Vasken Dilsizian, MD, National Institutes of Health, 10 Center Dr, Clinical Center, Cardiology Branch, NHLBI, Building 10, Room
7B-15, Bethesda, MD 20892.
© 1998 American Heart Association, Inc.
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Reversible vs Mild-to-Moderate Irreversible
201
strating stress-induced ischemia (reversible thallium defect)
in regions that are asynergic on the basis of repetitive
stunning and/or hibernation and scar or lack of ischemia
(irreversible thallium defect) in regions that are asynergic as
a result of transmural infarction or mixed scarred and viable
myocardium. Such a distinction prospectively has important
clinical implications, especially in patients who are being
considered for interventional therapy.
Thallium scintigraphy has occupied a unique place in
cardiac diagnostic imaging for both detecting coronary artery
narrowing and distinguishing viable from scarred myocardium.21,22 Although both reversible and mild-to-moderate irreversible thallium defects retain metabolically active, viable
myocardium by PET,23–25 the mere presence of viable myocardium may not necessarily translate into recovery of function in asynergic regions after revascularization. In this study,
we hypothesized that myocardial revascularization is more
likely to result in functional improvement of asynergic
regions with reversible stress-induced thallium defects rather
than mild-to-moderate irreversible thallium defects.
Methods
Patient Selection
Patients with coronary artery disease and left ventricular dysfunction
who were candidates for revascularization were prospectively enrolled in our protocol. Twenty-four patients (23 men, 1 woman) with
angiographically proven coronary artery disease, ranging in age from
42 to 76 years (mean, 57610 years) underwent prerevascularization
and postrevascularization stress-redistribution-reinjection thallium
single photon emission CT (SPECT), gated cardiac MRI, and
radionuclide angiography.
Before revascularization, all cardiac medications were discontinued in 16 of 24 patients for at least 48 hours before imaging. In the
remaining 8 patients, all imaging studies were performed while the
patients were receiving the same cardiac medications for each study.
After revascularization, 18 patients were studied after discontinuation of all cardiac medications, and 6 patients were studied while
receiving the same medical regimen for each study. Cardiac medications included either 1 or a combination of nitrates, calcium
channel blockers, ACE inhibitors, and digitalis. Prerevascularization
MRI, thallium, and radionuclide angiography were performed within
a mean of '1 month. An average of '8 months elapsed between the
revascularization procedure and the postrevascularization MRI and
radionuclide angiography. No patient had unstable angina, myocardial infarction, or congestive heart failure during the follow-up
period.
Fifteen patients underwent coronary artery bypass graft surgery
and 9 patients percutaneous transluminal coronary angioplasty. All 3
major coronary arteries were revascularized in 12 patients, 2 vessels
in 2 patients, and 1 vessel in 10 patients. The adequacy of
revascularization was based on review of the operative reports
documenting the successful placement of bypass grafts, and for
patients who underwent angioplasty, by immediate postangioplasty
angiographic documentation of successfully dilated vessels. Informed written consent for the study protocol was obtained from
each patient, and the Institutional Review Board on human research
approved the study protocol.
Thallium SPECT Imaging
All patients underwent exercise thallium SPECT as previously
described,26 except for 1 patient who underwent pharmacological
stress testing. Patients exercised on a treadmill according to a
symptom-limited, standardized, multistage exercise protocol with
continuous monitoring of heart rate and rhythm, blood pressure, and
symptoms. Nine of the 24 patients (38%) achieved .85% of
predicted maximal heart rate during exercise. In the remaining 14
Tl Defects
patients, the exercise was terminated because of cardiac symptoms.
At peak exercise, 2 to 3 mCi of thallium was injected intravenously,
and the patients continued to exercise for an additional 45 to 60
seconds. Approximately 10 to 15 minutes after termination of stress,
thallium imaging was begun. Seven patients were imaged with a
single-headed SPECT camera (Apex 415, Elscint), and the remaining
17 patients were imaged with a 3-headed camera (Triad, Trionix).
SPECT in plane and z-axis resolution was '15.5 mm, with a line
source used in an elliptical chest phantom (with lungs). Pixel size
was '4.7 mm for the single-headed and 3.56 mm for the 3-headed
camera. Redistribution images were obtained at rest '3 to 4 hours
after stress. Immediately thereafter, all patients received a second
injection of 1 mCi of 201Tl, and SPECT imaging was performed '10
to 15 minutes after the second administered dose (reinjection
imaging). Thallium images were reconstructed as a series of wholebody transaxial tomograms for direct comparison with the corresponding MRI images as described below. Transaxial images view
the heart at an oblique angle. To minimize the effects of slicing
through the myocardium tangentially, we studied midventricular
transaxial slices.
Thallium Data Analysis
To objectively compare relative regional thallium uptake, 5 myocardial regions of interest representing the posterolateral, anterolateral,
anteroapical, anteroseptal, and posteroseptal myocardium were
drawn on each visually selected thallium stress tomogram and on
each corresponding thallium redistribution and reinjection tomogram
as previously described.23 Each region was then assigned to one of
the three vascular territories as follows: the anteroapical, anteroseptal, and posteroseptal regions, representing the left anterior descending territory; the anterolateral and posterolateral regions of the upper
tomograms, representing the left circumflex artery territory; and the
posterolateral region of the lower tomograms, representing the right
coronary artery territory. The SPECT and MRI slices had different
slice thicknesses and different interslice separations (slice separation,
6.88 mm for thallium SPECT and 10 mm for MRI). Therefore, we
performed a weighted resumming of the SPECT images to match the
MRI slice thickness. An average of '3 midventricular MRI slices
per patient were divided into 5 regions of interest that visually
matched the regions drawn on the thallium SPECT images. Because
each region encompassed a relatively large amount of myocardial
tissue, it is unlikely that minor differences in visual matching
between the 5 regions would alter the results appreciably.
Regional Myocardial Thallium Uptake
The myocardial region on the stress-redistribution-reinjection thallium images that corresponded to the region with the highest thallium
uptake on the thallium exercise image series was used as the
reference region for computing relative thallium uptake. Thallium
uptake in all other myocardial regions was expressed as a percentage
of the activity in this reference region. The presence of a thallium
defect on the stress images was defined as thallium activity ,85% of
the normal reference region. A defect was considered reversible if
thallium activity increased by $10% on the subsequent redistribution or reinjection images and the final defect activity was $50%.24
A defect was considered completely reversible if the increase in
thallium activity from stress to redistribution or reinjection images
resulted in final thallium uptake $85%. Irreversible thallium defects
were also subgrouped on the basis of severity of reduction in tracer
activity: mild-to-moderate (50% to 84% of peak activity) and severe
(,50% of peak) defects. On repeat stress thallium studies after
revascularization, myocardial perfusion was considered normal if
regional thallium activity was $85% on the stress images. Myocardial perfusion was considered improved after revascularization if the
thallium activity on stress images increased from before to after
revascularization by $10%.
Magnetic Resonance Imaging
ECG-gated MRI was performed with a 0.5-T magnet (Picker) in 9
patients and 1.5-T magnet (Signa, GE) in 15 patients as previously
described.23 Each MRI slice was 10 mm thick.
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Qualitative MRI Analysis
To assess regional systolic wall thickening, corresponding transaxial
end-diastolic and end-systolic MRI images were analyzed visually.
The stress-redistribution-reinjection thallium slice that best matched
the corresponding MRI slice was selected visually. Systolic wall
thickening was assessed qualitatively as normal or asynergic (hypokinetic or akinetic) by two observers, blinded to the thallium data,
with the movie display of superimposed MRI end-diastolic and
end-systolic images before and after revascularization. The MRI wall
thickening data on the first 8 patients were read as either normal or
abnormal. In the subsequent 16 patients, in addition to binary visual
readings, abnormal regions were further classified as hypokinetic,
severely hypokinetic, or akinetic. Differences were resolved by
consensus. To avoid the problem of postoperative paradoxical septal
motion, wall thickening was used for the classification of wall
motion. Myocardial regions with impaired systolic wall thickening
before revascularization were studied again after revascularization
and classified as regions with reversible or irreversible left ventricular dysfunction.
Quantitative MRI Analysis
Quantitative end-diastolic, end-systolic, and systolic wall thickening
measurements were also assessed before and after revascularization
from corresponding anatomically matched MRI slices. This quantitative method was then applied to the regions judged to be normal or
asynergic on the basis of qualitative analysis. At the center of each
region of interest, opposing points on the epicardial and endocardial
borders were identified manually, so that a line between the two
points was approximately perpendicular to the two surfaces. The
length of the line joining these two points was calculated and
considered to represent regional wall thickness. The intraobserver
variability was assessed by determining thickness values at each of
the 5 sectors on each of 8 MRI images (4 at end diastole and 4 at end
systole) and then repeating the sequence of thickness measurements
5 times (a total of 200 thickness measurements). We found that for
end diastole, the SD ranged from an average of 1.1 to 1.7 mm, and
averaged over all sectors and all subjects, it was 1.5 mm. At end
systole, it ranged from an average of 0.9 to 1.4 mm, and averaged
over all subjects and all sectors, it was 1.2 mm.
Gated Equilibrium Radionuclide Angiography
Gated equilibrium radionuclide angiography was performed at rest in
all 24 patients with a conventional Anger camera, with the patients
in the supine position. Red blood cells were labeled in vivo with 25
mCi of 99mTc pertechnetate. Time-activity curves were generated,
from which the left ventricular ejection fraction was computed as
previously described.27 The reproducibility limit of this technique is
4%28; therefore, we defined as change in ejection fraction any change
that was $4% ejection fraction units.
Statistical Analysis
Data are presented as mean6SD. In this analysis, each myocardial
region was considered an independent piece of information. For
comparison of differences, a 2-tailed Student’s t test for paired and
unpaired samples was applied. The x2 test was applied to determine
the significance in rate of occurrence. A value of P,0.05 was
accepted as the minimal level of significance.
Results
Clinical, Hemodynamic, and Left Ventricular
Ejection Fraction Changes Before to
After Revascularization
Before revascularization, 20 of the 24 patients (83%) studied had
angina. With regard to symptoms of heart failure, 19 patients
were in NYHA functional class I or II and 5 in functional class
III or IV. In all 24 subjects, left ventricular ejection fraction
ranged from 17% to 46% (mean, 3069%) at rest.
August 11, 1998
503
After revascularization, 22 of the 24 patients had no symptoms of angina, and there was a significant increase in the mean
left ventricular ejection fraction at rest from 3069% before to
37613% after revascularization (P,0.001), with 14 of 24
patients (58%) manifesting substantial improvement ($4%) in
resting ejection fraction after revascularization. Mean ratepressure product on treadmill exercise increased from
20.166.3 mm Hg z bpm2131023 before to 25.365.9 mm Hg z
bpm2131023 after revascularization (P,0.005). Similarly, mean
METs achieved during treadmill exercise increased from
6.362.9 before to 8.763.2 after revascularization (P,0.001).
Reversible and Mild-to-Moderate Irreversible
Thallium Defects
Two hundred twenty-one regions (a mean of '9 regions per
patient) were revascularized. During thallium stress studies,
perfusion defects developed in 164 regions, of which 110
were reversible on redistribution-reinjection studies and 37
were mild-to-moderate irreversible by quantitative analysis
(67% and 23%, respectively).
Relation to Regional Wall Thickness and Thickening in
Asynergic Regions
Before revascularization, abnormal systolic wall thickening at
rest was observed in 56 of 110 reversible and 20 of 37
mild-to-moderate irreversible thallium defects (51% and
54%, respectively). Quantitative analysis of regional wall
thickness and systolic wall thickening was feasible in 45 of
56 asynergic regions with reversible thallium defects and 19
of 20 asynergic regions with mild-to-moderate irreversible
thallium defects (80% and 95%). Twelve regions had to be
excluded from quantitative MRI analysis because of poor
endocardial border delineation and/or blood motion artifacts.
Prerevascularization end-diastolic thickness was similar in
asynergic regions with reversible and mild-to-moderate irreversible thallium defects (6.262.2 versus 6.062.0 mm,
P5NS). However, end-systolic wall thickness (7.862.5 mm)
and systolic wall thickening (1.661.9 mm) were significantly
higher in asynergic regions with reversible when compared
with end-systolic wall thickness (6.161.7 mm, P,0.01) and
systolic wall thickening (0.0861.3 mm, P,0.005) in asynergic regions with mild-to-moderate irreversible thallium
defects.
After revascularization, visual analysis of the MRI data
showed improvement in systolic wall thickening in 44 of the
56 regions with reversible thallium defects compared with
only 6 of the 20 regions with mild-to-moderate irreversible
thallium defects (79% and 30%, respectively; P,0.001,
Figure 1). Of the above-mentioned 44 regions with reversible
defects that were assessed visually by MRI, quantitative MRI
analysis was feasible in 36. Of the 14 regions with mild-tomoderate irreversible thallium defects that did not exhibit
visually improved wall thickening after revascularization,
quantitative MRI analysis was feasible in 13. These 13
regions had significantly lower postrevascularization end-diastolic and end-systolic wall thickness (6.462.2 and
6.662.3 mm, respectively) than the above-mentioned 36
regions with reversible defects whose function improved
(8.562.1 and 10.063.1 mm, respectively, P,0.005). Simi-
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Reversible vs Mild-to-Moderate Irreversible
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Figure 1. Recovery of asynergic regions after revascularization
regardless of final thallium content (top) and at same final thallium content of 60% threshold value (bottom). Pie charts comparing proportion of asynergic myocardial regions that improved
after revascularization in reversible (left) and mild-to-moderate
irreversible (right) thallium defects.
larly, postrevascularization systolic wall thickening was significantly lower in the 13 regions with mild-to-moderate
irreversible thallium defects (0.261.4 mm) than in the 36
regions with reversible thallium defects (1.563.2 mm,
P,0.001). Patient examples with reversible and mild-tomoderate irreversible thallium defects and their functional
outcome after revascularization are shown in Figures 2 and 3.
Relation to Severity of Systolic Wall
Thickening Abnormality
In addition to binary readings, visual assessment of the
severity of systolic wall thickening abnormality (hypokinetic,
severely hypokinetic, or akinetic) was made in 16 patients.
From a total of 76 abnormal regions (that were also classified
Tl Defects
Figure 3. Persistent postrevascularization regional asynergy is
shown in a patient with prerevascularization mild-to-moderate
irreversible thallium defect. Matched transaxial tomograms are
displayed for thallium stress, redistribution, and reinjection (left),
with corresponding end-diastolic and end-systolic MRI tomograms before and after revascularization (right). Mild-tomoderate septal thallium abnormality is seen during stress
(arrows) that persists on redistribution and reinjection images
(irreversible defect). Corresponding MRI tomograms demonstrate abnormal systolic wall thickening in septal region before
revascularization, which remains abnormal after
revascularization.
according to the degree of wall motion abnormality), 44
showed reversible defects, 15 mild-to-moderate irreversible,
7 severe irreversible thallium defects, and 10 normal stress
thallium uptake. Among the 44 regions with reversible
defects, 28 were hypokinetic, 4 severely hypokinetic, and 12
akinetic. Among the 15 regions with mild-to-moderate irreversible defects, 6 were hypokinetic, 3 severely hypokinetic,
and 6 akinetic (P5NS). Thus, there was no significant
difference in the severity of systolic wall thickening abnormality among regions with reversible and mild-to-moderate
irreversible thallium defects.
Prerevascularization and Postrevascularization
Thallium Patterns and Functional Outcome
After Revascularization
Figure 2. Improved postrevascularization systolic wall thickening is shown in a patient with prerevascularization stressinduced reversible thallium defects. Matched transaxial tomograms are displayed for thallium stress, redistribution, and
reinjection (left), with corresponding end-diastolic and end-systolic MRI tomograms before and after revascularization (right).
There are extensive thallium abnormalities in apical and posterolateral regions during stress (arrows) that improve on redistribution and reinjection images (reversible defects). Corresponding
MRI tomograms demonstrate abnormal systolic wall thickening
in apical and posterolateral regions before revascularization that
improve after revascularization.
Among the 24 patients studied, a total of 221 regions were
revascularized and 97 regions were not. Of the 221 revascularized regions, systolic wall thickening was normal in 121
regions (55%) before revascularization and abnormal in 100
(45%). After revascularization, systolic wall thickening improved in 60 asynergic regions (60%) and remained unchanged in 40 (40%). Mean regional thallium uptake on the
stress (69617%), redistribution (80616%), and reinjection
(83617%) images was significantly higher in asynergic
regions that improved than in those that did not improve after
revascularization (50619%, 55618%, and 55618%, respectively, P,0.001). Of the 100 asynergic regions, 11 had
normal thallium uptake, 56 reversible defects, and 33 irreversible defects; 20 mild-to-moderate and 13 severe. Of the
11 asynergic regions with normal stress thallium, 10 (91%)
demonstrated improved systolic wall thickening after revascularization. A flow diagram of prerevascularization systolic
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Kitsiou et al
Figure 4. Flow diagram of prerevascularization systolic wall
thickening and thallium pattern and postrevascularization functional outcome of the 221 revascularized regions.
wall thickening and thallium patterns and postrevascularization functional outcome is shown in Figure 4.
Systolic wall thickening analysis was feasible in 95 of 97
nonrevascularized regions. Of these 95 regions, systolic wall
thickening was normal in 65 regions (68%) before revascularization and abnormal in 30 (32%). After revascularization,
systolic wall thickening remained normal in all 65 regions
and abnormal in 15 of 30 asynergic regions. Of the 15 regions
that demonstrated improvement in regional function after
revascularization, 13 (87%) were perfused by collateral
vessels supplied by a stenosed artery that was amenable to
revascularization.29
Severity of Defects and Degree of Thallium Reversibility
in Relation to Functional Recovery
Of the 56 asynergic regions with reversible thallium defects,
39 had mild-to-moderate and 17 had severe reduction in
thallium activity on the stress images. Systolic wall thickening improved in 35 of 39 regions with mild-to-moderate
compared with 9 of 17 regions with severe reversible thallium
defects (90% and 53%, respectively; P,0.007). When regions with mild-to-moderate and severe reversible thallium
defects were further analyzed according to the degree of
reversibility (partial or complete), 24 of 39 regions with
mild-to-moderate defects had complete reversibility compared with only 2 of 17 regions with severe defects (62% and
12%; P,0.002). When the data were analyzed according to
the degree of reversibility alone, regardless of the severity of
reduction of thallium activity, 30 of 56 asynergic regions
(54%) showed partially and 26 regions (46%) showed completely reversible thallium defects. After revascularization,
systolic wall thickening improved in 19 of 30 regions with
partially reversible compared with 25 of 26 regions with
completely reversible thallium defects (63% and 96%;
P,0.008).
Final Thallium Content in Reversible and
Mild-to-Moderate Irreversible Defects
The final thallium content on delayed images (maximum
thallium uptake on either redistribution or reinjection images)
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505
Figure 5. Flow diagram displaying prerevascularization thallium
pattern in asynergic regions with improved perfusion and function (left) and those with persistent abnormal perfusion and
function (right) after revascularization. A larger proportion of
asynergic regions with improved perfusion and function after
revascularization demonstrated reversible thallium defects on
prerevascularization thallium study compared with those with
lack of improvement in regional perfusion and function.
in regions with reversible and mild-to-moderate irreversible
thallium defects was assessed. The thallium uptake on delayed images was significantly higher in abnormal regions
with reversible defects (82617%) than in regions with
mild-to-moderate irreversible defects (6669%, P,0.001).
Furthermore, the thallium uptake on delayed images was
significantly higher in regions with reversible defects that
improved than in those that did not improve after revascularization (86616% versus 6669%, P,0.001). In contrast, the
thallium uptake in delayed images was similar in regions with
mild-to-moderate irreversible defects that improved and in
those that did not improve after revascularization (6969%
versus 65610%, P5NS).
We then grouped the myocardial regions according to the
final thallium content on delayed images and compared the
proportion of regions that demonstrated functional recovery
among reversible and those with mild-to-moderate irreversible thallium defects. A total of 63 asynergic regions were
identified with a thallium uptake on delayed images of
$60%: 48 with reversible and 15 with mild-to-moderate
irreversible defects. Functional recovery was observed in 40
of 48 regions with reversible thallium defects compared with
5 of 15 regions with mild-to-moderate irreversible defects
(83% and 33%, respectively; P,0.001, Figure 1). Similar
results were obtained when the thallium uptake was set at
$70%. A total of 50 asynergic regions were identified with a
thallium uptake in delayed images of $70%: 43 with reversible and 7 with mild-to-moderate irreversible defects. Functional recovery was observed in 38 of 43 regions with
reversible thallium defects compared with 3 of 7 regions with
mild-to-moderate irreversible defects (88% and 43%;
P,0.02).
Analysis on the Basis of Success of Reperfusion
The data were also analyzed on the basis of success of
myocardial reperfusion, defined as normal or improved thallium activity on repeat stress thallium studies after revascularization. Successful reperfusion on repeat stress thallium
studies was observed in 42 of 60 asynergic regions that
demonstrated improved wall thickening compared with only
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Reversible vs Mild-to-Moderate Irreversible
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9 of 40 asynergic regions that did not demonstrate improved
wall thickening after revascularization (70% and 23%, respectively; P,0.001). Of the 42 asynergic regions with both
improved stress thallium perfusion and regional function after
revascularization, 31 exhibited reversible and only 2 had
mild-to-moderate irreversible thallium defects on their prerevascularization thallium studies (74% and 5%). In contrast, of
the 31 asynergic regions with persistent thallium perfusion
and regional contractile abnormalities after revascularization,
12 exhibited mild-to-moderate irreversible and 7 reversible
thallium defects on their prerevascularization thallium studies
(39% and 23%; P,0.001, Figure 5).
Discussion
In patients with chronic coronary artery disease and left
ventricular dysfunction, the distinction between viable and
nonviable myocardium can be difficult when based on regional contraction alone. Assessment of regional perfusion
and cell membrane integrity with thallium scintigraphy can
shed light on the distinction of reversibility or irreversibility
of asynergic regions. In the present study, we demonstrate
that a more accurate noninvasive determination of myocardial
viability requires the demonstration of myocardial ischemia,
because asynergic regions with reversible thallium defects on
the prerevascularization thallium studies were more likely to
improve after revascularization than asynergic regions with
mild-to-moderate irreversible defects (79% versus 30%, respectively; P,0.001).
Presence of Myocardial Viability Versus
Inducibility of Ischemia
In most cases, the identification of the presence and extent of
myocardial ischemia is much more important clinically in
terms of patient management and risk stratification than
knowledge of myocardial viability. However, in a subset of
patients who have already undergone coronary angiography,
the relevant clinical question may be whether there is sufficient evidence for myocardial viability in a noncontractile
region perfused by a critically stenosed coronary artery. In
these patients, it is reasonable to perform rest-redistribution
thallium imaging. By planar quantitative analysis, when
myocardial viability was defined in a binary manner (.50%
or ,50%), 57% of severely asynergic regions that were
viable by thallium showed improved wall motion after
surgery, compared with only 23% of severely asynergic
regions that were considered to be nonviable by thallium.30
The relatively low positive predictive value of this and most
other studies using rest-redistribution thallium protocol is that
in these studies, myocardial viability is defined in a binary
manner.30 –34 Such classification of asynergic regions as viable
or nonviable may be an oversimplification of the rather
continuous nature of structural damage in coronary artery
disease. In a clinicopathological study by Zimmerman and
colleagues35 in which two transmural biopsy specimens were
taken from myocardial regions subtended by $75% coronary
artery stenosis during revascularization, the regional volume
fraction of interstitial fibrosis varied in a continuous manner
ranging from 14.5 to 59.6 vol%. Although an inverse correlation was observed between regional thallium activity and
Tl Defects
regional volume fraction of interstitial fibrosis, such good
correlation does not necessarily translate to recovery of
regional function after revascularization.
An asynergic region with a mild-to-moderate reduction of
thallium activity on rest-redistribution imaging may result
from viable tissue (transient ischemia or chronic hypoperfusion) or nontransmural infarction with mixed scarred and
viable tissue. If regional asynergy is a consequence of
transient ischemia or chronic hypoperfusion, such regions
might be expected to exhibit improvement in function after
revascularization. Conversely, regions with nontransmural
infarction are composed of mixed scarred (often confined to
the endocardial layers) and normal (often confined to the
epicardial layer) myocardium. Such regions may regain
adequate perfusion after revascularization to sustain cellular
viability but not contractility. Several experimental studies
have examined the influence of subendocardial ischemia on
transmural myocardial function.36 –38 In an open-chest canine
model of partial coronary artery occlusion, the relationship
between myocardial contraction and blood flow was examined in the subepicardial and subendocardial walls of the left
ventricle.38 During nontransmural ischemia, although there
was a close coupling between regional perfusion and function
in the subendocardium, there was a striking dissociation
between perfusion and function in the subepicardium. Despite
the demonstration of preserved subepicardial blood flow,
subepicardial function was markedly diminished, similar to
that observed in the subendocardial region. These data in
animals suggest that the contractile function of the outer left
ventricular wall appears to be dependent on the blood flow or
function of the inner wall, such that severe hypoperfusion or
dysfunction confined to the endocardial layers of the myocardium can result in transmural akinesis despite normal
epicardial blood flow. Assessment of the magnitude of
thallium uptake in this situation may show only a mild-tomoderate defect, because the proportion of scarred myocardium may extend only from one third to one fourth of the
transmural thickness of the asynergic region. Unfortunately,
current noninvasive imaging techniques lack the resolution to
assess differences between endocardial, midwall, and epicardial blood flows. Hence, conditions that affect predominantly
subendocardial perfusion, and consequently transmural regional function, cannot be estimated clinically.
The demonstration of stress-induced ischemia could be
helpful in differentiating reversible from irreversible regional
asynergy. Although mild-to-moderate irreversible thallium
defects provide evidence of structural integrity of some
myocytes, reversible thallium defects imply the presence of
abnormal flow reserve in areas of viable myocardium. The
final thallium content (maximum on redistribution-reinjection
images) was significantly higher in regions with reversible
defects that improved than in those that did not improve after
revascularization (86616% versus 6669%, P,0.001). In
contrast, final thallium content was similar in regions with
mild-to-moderate irreversible defects that improved and in
those that did not improve after revascularization (6969%
versus 65610%, P5NS). Furthermore, when asynergic regions were grouped according to the final thallium content, at
60% threshold value, functional recovery was observed in
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Kitsiou et al
83% of regions with reversible defects compared with 33% of
regions with mild-to-moderate irreversible defects
(P,0.001). These findings suggest that the regions most
likely to improve function after revascularization are those
with asynergy arising from repetitive stunning and/or hibernation, which can become transiently ischemic (reversible
thallium defects), rather than those regions without ischemia
(irreversible mild-to-moderate thallium defects). Although
the findings in these patients support our conclusion, we
acknowledge that the number of patients and myocardial
segments submitted to revascularization is not large.
Adequacy of Revascularization and
Functional Outcome
Because of the lack of postrevascularization coronary angiography, the success of revascularization cannot be assessed
with certainty. However, an important feature of our study is
that we examined regional perfusion and function both before
and after revascularization. For an asynergic region to improve function after revascularization, it must not only retain
viable myocardium but also be adequately revascularized.
Thus, the adequacy of myocardial reperfusion may play an
important role in the functional outcome of asynergic regions.
Although an improvement in thallium uptake from before to
after revascularization suggests that a region has been adequately revascularized, the converse may not be true. Lack of
improvement in thallium uptake after revascularization may
be attributed to either inadequate revascularization or successful revascularization in a region with normal midwall and
epicardial blood flow and scarred endocardium. The majority
of regions that demonstrated improvement in thallium uptake
on postoperative scans had reversible thallium defects, and
97% demonstrated improvement in postoperative function. In
contrast, among regions classified before revascularization as
having mild-to-moderate irreversible thallium defects, 90%
had persistent thallium defects on postoperative scans, and
only 22% of regions demonstrated improvement in postoperative function.
Conclusions
These findings suggest that most mild-to-moderate irreversible thallium defects after stress represent an admixture of
viable and scarred myocardium that may not improve after
revascularization. Conversely, the identification of reversible
thallium defect on stress in an asynergic region more accurately predicts recovery of function after revascularization.
Even at a similar mass of viable myocardial tissue (as
reflected by the final thallium content and supported by
histomorphological studies), the presence of inducible ischemia (a reversible defect) is associated with an increased
likelihood of functional recovery.
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Stress-Induced Reversible and Mild-to-Moderate Irreversible Thallium Defects: Are They
Equally Accurate for Predicting Recovery of Regional Left Ventricular Function After
Revascularization?
Anastasia N. Kitsiou, Gopal Srinivasan, Arshed A. Quyyumi, Ronald M. Summers, Stephen L.
Bacharach and Vasken Dilsizian
Circulation. 1998;98:501-508
doi: 10.1161/01.CIR.98.6.501
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