(Circulation. 1995;92:37-44.)
© 1995 American Heart Association, Inc.
Articles |
From the Divisions of Cardiology and Nuclear Medicine, University of Louvain Medical School, Brussels, Belgium.
Correspondence to Jean-Louis J. Vanoverschelde, MD, Division of Cardiology, Cliniques Universitaires St Luc, Avenue Hippocrate, 10-2881, B-1200, Brussels, Belgium. Email Vanoverschelde@card.ucl.ac.be.
| Abstract |
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Methods and Results Forty consecutive patients (age, 60±10
years) with coronary disease and an ejection fraction
35%
underwent dobutamine echocardiography
(10 µg/kg per minute) and exercise-redistribution-reinjection
thallium single photon emission computed tomography (SPECT) before
coronary revascularization by bypass
surgery (n=33) or angioplasty (n=7). Recovery of LV function was
evaluated by echocardiography 5.3±2.4 months after
revascularization. According to the changes in
end-systolic volume and ejection fraction after
revascularization, the patients were categorized
into groups with (n=19) and without (n=21) postoperative
functional
improvement, defined as a >5% increase in ejection fraction and >10
mL decrease in end-systolic volume. Before
revascularization, patients with improved
postoperative function had smaller end-diastolic volume
and less wall motion abnormalities than those with persistent
dysfunction. They also showed greater improvement of wall motion score
with dobutamine (6.1±2.4 versus 1.8±4.2 grades,
P<.001) and smaller thallium defect score after exercise
(38±12 versus 47±14 grades, P=.04). Discriminant
analysis selected the improvement in wall motion score with
dobutamine and baseline end-diastolic
volume as independent predictors of postoperative recovery.
Consideration of both parameters allowed prediction of
functional outcome in 84% of the patients with and 81% of those
without postoperative improvement.
Conclusions Among the parameters commonly available before surgery in coronary patients with depressed LV function, the maintenance of significant inotropic reserve, the severity of LV remodeling, and the magnitude of the perfusion defect after exercise can predict the reversal of LV dysfunction after revascularization.
Key Words: coronary disease echocardiography myocardial infarction revascularization
| Introduction |
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Several modalities, including thallium imaging9 10 11 12 13 and low-dose dobutamine echocardiography,14 15 16 17 18 19 20 recently have been proposed to predict the reversibility of left ventricular dysfunction in patients with ischemic heart disease. Accordingly, the present study was designed to evaluate whether the use of these new techniques during the preoperative assessment of patients with coronary artery disease and poor left ventricular function could improve our ability to identify those who are most likely to have improved global left ventricular function after revascularization.
| Methods |
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Cardiac Catheterization
Selective coronary arteriography and
contrast left
ventriculography were performed from the femoral approach before the
echocardiographic and scintigraphic studies.
Significant coronary disease was defined as a greater than 70%
luminal diameter stenosis in any major coronary branch.
Thirty patients had complete occlusion of one or more major epicardial
coronary segments, among whom 15 had occlusion of the left
anterior descending coronary artery, 10 of the proximal
circumflex artery, and 29 of the right coronary artery. The
remaining 10 patients had severe proximal stenoses on at least
one major epicardial segment. Four patients had single-vessel
disease, 9 patients had two-vessel disease, and 27 patients had
three-vessel disease. Two patients also had left main
stenosis.
Postoperative angiographic follow-up to assess the adequacy of revascularization was prospectively requested in every patient but could only be obtained in 20 of them. The interval between the revascularization procedure and the angiographic follow-up was 10±3 months. The reasons for why the other 20 patients did not have follow-up angiograms were always refusals by the patient or by the referring cardiologist. As judged from the results of this follow-up angiographic study, adequate revascularization of the initially dysfunctional segments was achieved in all 16 patients undergoing bypass surgery and in 3 of 4 patients undergoing PTCA (one patient had moderate restenosis [50% to 75% luminal diameter stenosis] at the site of an initially successful angioplasty).
Dobutamine and Follow-up
Echocardiography
All patients underwent low-dose dobutamine
echocardiography during the hospital stay for
cardiac catheterization. The patients were allowed to
take their prescribed medications with the exception of
ß-blockers, which were withdrawn for at least 24 hours before the
investigation. Before the test was started, a clinical history was
recorded, a rest ECG and echocardiogram were obtained, and a venous
line was secured. Dobutamine then was infused in 3-minute
dose increments of 5 and 10 µg/kg per minute under continuous ECG and
echocardiographic monitoring.22
Low-dose dobutamine infusion was always very well
tolerated. Clinical signs and the ECG and
echocardiographic images were recorded at the
beginning of the study and every 3 minutes thereafter until completion
of the stress. Follow-up echocardiograms were also obtained in
every patient 5.3±2.4 months after the
revascularization procedure. As for the initial
study, ß-blockers were withdrawn for at least 24 hours before
this investigation.
Exercise-Redistribution-Reinjection Thallium
Scintigraphy
All patients performed a symptom-limited, multistage
dynamic
bicycle exercise test during the same hospital admission for cardiac
catheterization. The initial workload was set at 20 W,
and the exercise intensity was increased by 20 W every minute until
subjective exhaustion or appearance of symptoms.21 Three
millicuries of thallium was injected intravenously during
the last minute of exercise. Approximately 10 minutes after completion
of the exercise test, single photon emission computed tomography
(SPECT) images were obtained with a wide-field-of-view
rotating camera equipped with a high-resolution, parallel-hole
collimator centered on the 73 keV and on the 164 keV photon peaks with
a 20% window. The camera was rotated over a 180° arc in a circular
orbit about the patient's thorax from a right anterior oblique angle
of 40° to a left posterior angle of 40° at 6° increments for 30
seconds each. Redistribution images were obtained 4 hours after stress,
while the patients were resting. Immediately thereafter, all patients
received an additional 1 mCi of thallium, and SPECT images were
acquired 20 to 30 minutes later. The exercise, redistribution, and
reinjection data were reconstructed in short-axis, vertical, and
longitudinal long-axis views with in-plane and
z-axis resolutions of 13 mm, a 6.2 mm per pixel sampling,
and a 6.2 mm separation between slices.
Data Analysis
Two-dimensional Echocardiography
Echocardiograms were obtained with commercially available
echocardiographic systems by use of a 2.5- or a 3.5-MHz
wide-angle, phased-array transducer with 64 or 96 channels.
Images from the parasternal long- and short-axis and apical four-
and two-chamber views were digitized on-line
(IMAGEVUE, NovaMicrosonics). Before
revascularization, the rest, 5-, and 10-µg/kg
per minute stages were recorded digitally in a
quad-screen, cineloop format and stored on 512 byte/sector
rewritable optical disks. All stages also were recorded on
videotape. Images were interpreted qualitatively in accordance with
previous guidelines by experienced observers who had no knowledge of
the angiographic and clinical data. Regional function was interpreted
in 16 myocardial segments (basal, midventricular, and
apical levels of the septum; lateral, anterior, and
inferior walls; and basal and
midventricular levels of the anteroseptal and posterior
walls) and defined as normal (1), hypokinetic (2), or akinetic
(3).23 Normal wall motion was defined as
5 mm of
endocardial excursion and obvious systolic wall thickening.
Hypokinesis was defined as <5 mm of endocardial excursion and reduced
wall thickening. Akinesis was defined as near absence of endocardial
excursion or thickening.
Dobutamine and Follow-up
Echocardiography
A normal segmental response to dobutamine was
defined as a progressive enhancement in contractility
during stress. Ischemia was identified by a stress-induced
wall motion abnormality. Akinetic myocardium at baseline
was considered as responsive to dobutamine if wall motion
improved by at least one full grade or as nonresponsive if regional
wall motion did not improve with low-dose (5 to 10 µg/kg per
minute) dobutamine. Similarly, dysfunctional
myocardium at baseline was considered to have improved
function after revascularization if wall motion
improved by at least one full grade at follow-up or to have
remained dysfunctional if regional wall motion did not improve at
follow-up.
In each patient, a global wall motion score was calculated at baseline, at all stages of the dobutamine stress, and at the follow-up two-dimensional echocardiographic study. Also, left ventricular volumes and ejection fraction were calculated in each patient before revascularization, at rest, at 10 µg/kg per minute of dobutamine, and again at follow-up. Left ventricular volumes both at end diastole and end systole were computed from the apical four- and two-chamber views by use of the standard Simpson method.
SPECT Thallium
201Tl scintigraphy was interpreted by
experienced observers who had no knowledge of the clinical,
echocardiographic, and angiographic characteristics of
the patients. A qualitative comparison between stress, redistribution,
and reinjection images was made by calculating a defect extent score.
The score was derived from the number of abnormal segments among those
evaluated (36 from the short-axis views and 8 apical segments from
the long-axis views) and from the amplitude of the defect (mild
[1], moderate [2], and severe [3]). Visual
reversibility was
defined by a decrease in the defect score >3 between exercise and
either redistribution or reinjection. Short-axis tomograms from the
three sets of 201Tl images (stress, redistribution, and
reinjection) also were analyzed quantitatively by use of
circumferential profiles. An operator-defined region of interest
was drawn around the left ventricular activity on each
short-axis cross section. Myocardial activity then was subdivided
into 60 sectors emanating from the center of the tomograms. These
sectors were grouped and averaged into four myocardial regions:
anterior, septal, inferior, and lateral. Quantitative data
from two of three midventricular, 2-pixel-thick,
short-axis tomograms were analyzed, as previously
described.11 Only 201Tl activity data for the
dysfunctional region are reported. They are expressed as percent of
maximal activity in the corresponding short-axis slice. Absolute
changes in the amplitude of the perfusion defects from exercise to the
subsequent redistribution or reinjection studies also were calculated
to define potential reversibility.
Statistical Analysis
Results are expressed as mean±1
SD. A two-way ANOVA for
repeated measurements was used to assess differences in continuous
variables between patients with and without evidence of myocardial
viability. A
2 test was used to assess
differences in categorical variables. All tests were two sided, and
a probability value greater than .05 was considered indicative of a
statistically nonsignificant difference. All clinical, ECG,
angiographic, echocardiographic, and scintigraphic
variables then were proposed for inclusion into a stepwise linear
discriminant model for determination of the factors independently
associated with the return of global left ventricular
function. Variables were entered until no F-to-enter statistics
were significant at the 5% level and until the mean squared error
reached a minimum. The power of the discriminant function was assessed
by the canonical correlation.
| Results |
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At the time of the follow-up study, anginal symptoms were improved in all except one patient irrespective of the changes in global left ventricular function. In contrast, symptoms of heart failure (as reflected by New York Heart Association functional class) improved only in patients with reversible left ventricular dysfunction (from 1.6±1.0 to 1.2±0.4, P=.004) and not in those with persistent postoperative left ventricular dysfunction (from 1.7±0.9 to 1.8±0.9, P=NS).
Hemodynamic Response to Low-Dose
Dobutamine Infusion
The effects of dobutamine infusion on
hemodynamics and regional and global left
ventricular function in the two groups of patients are
shown in Table 3
. Infusion of a low dose (10 µg/kg per
minute) of dobutamine resulted in minor changes in heart
rate and mean blood pressure. Rate-pressure product increased
by an average of 15%. There was no difference in the evolution of
these parameters between the two groups of patients. During
low-dose dobutamine, regional wall motion score
improved in both groups, albeit significantly more in patients with
postoperative improvement (by 6.1±2.4 compared with 1.8±4.2 in
patients without, P<.001). Improvement in regional wall
motion in patients without postoperative improvement almost exclusively
involved previously hypokinetic segments, whereas it involved both
akinetic and hypokinetic segments in patients who showed improved
ejection fraction and end-systolic volume after surgery.
The cutoff value (from discriminant analysis) that best
differentiated between patients with and those without reversible left
ventricular dysfunction was an improved regional wall
motion score by at least 4 full grades during low-dose
dobutamine infusion. By use of this cutoff, 16 of 19 (84%)
patients with and 16 of 21 (76%) patients without postoperative
functional improvement were correctly identified. Overall accuracy was
80%.
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Exercise-Redistribution-Reinjection Thallium
Scintigraphy
All patients successfully completed a symptom-limited
bicycle
exercise protocol. Their exercise characteristics are shown in Table
4
. No difference was found in exercise capacity, maximal
heart rate, rate-pressure product, or exercise-induced ST
segment changes between the two groups.
Exercise-redistribution-reinjection thallium scintigraphic data
obtained in the area of dysfunction in the two groups of patients also
are shown in Table 4
. There was no significant difference
between
groups with regard to the amplitude of the defect at exercise,
redistribution, or reinjection, to the occurrence and magnitude of
thallium reversibility, or to the estimated defect extent score, at
redistribution and reinjection. There was, however, a significant
difference in the defect extent score at peak exercise between the two
groups.
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Stepwise Linear Discriminant Analysis
To define further the
variables associated with the return of
global left ventricular function after coronary
revascularization, all clinical (age, angina, New
York Heart Association functional class, history of previous
infarction, type of revascularization,
prerevascularization medical treatment),
angiographic (number of diseased vessels, presence or absence of left
main disease), ECG (Q waves), echocardiographic, and
scintigraphic data available were proposed for inclusion into a
multivariate discriminant model. As shown in Table 5
, with
univariate analysis, the
improvement in wall motion score at follow-up, the improvement in
wall motion score during low-dose dobutamine, baseline
left ventricular end-diastolic volume, the
occurrence of dyspnea during exercise, and the perfusion defect score
at peak exercise and reinjection were significantly associated with the
return of left ventricular function after
revascularization. Stepwise linear discriminant
analysis selected the improvement in wall motion score during
low-dose dobutamine and baseline left
ventricular end-diastolic volume as
independent predictors of an improved left ventricular
function after revascularization. Of these two
parameters, the improvement in wall motion score during
low-dose dobutamine was the most significant. The
discriminant function slightly but nonsignificantly improved our
ability to categorize patients into groups with and without functional
improvement. Consideration of end-diastolic volume in
addition to the segmental response to dobutamine allowed
correct classification in 16 of 19 (84%) patients with and in 17 of 21
(81%) patients without postoperative functional improvement. Overall
accuracy improved to 83%.
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| Discussion |
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The concept of reversible left ventricular ischemic dysfunction, which is often referred to as "chronic myocardial hibernation," has been introduced in the mid 1980s by Rahimtoola8 24 to describe the improvement of left ventricular function seen after CABG in patients with coronary artery disease and severe preoperative left ventricular dysfunction. Since its original description, this concept has gained increasing recognition25 26 and in recent years has stimulated the development of new diagnostic methods aimed at identifying reversible dysfunction before operation. Although the exact pathophysiology of myocardial hibernation remains controversial,24 27 28 several features may allow it to be distinguished from irreversible injury. These include an increased glucose uptake, detectable with positron emission tomography,29 30 31 the presence of partially or completely reversible exercise-induced thallium defect at delayed imaging or reinjection,9 10 11 12 13 a preserved wall thickness at magnetic resonance imaging,32 and the maintenance of significant inotropic reserve during the infusion of a low dose of dobutamine.19 20 Most of these features have been used successfully to predict which segment is likely to resume function after coronary revascularization. In only a few instances, however, they were used to predict the functional outcome of patients with severely depressed left ventricular function.
Low-Dose Dobutamine
Echocardiography for Delineation of
Reversible Dysfunction
Earlier studies have shown that reversal of
regional asynergy
during inotropic stimulation could predict functional recovery after
revascularization.6 7 More recently,
conventional dobutamine echocardiographic
protocols have been used for identification of residual myocardial
viability early (<2 weeks) after myocardial
infarction.14 15 16 17 18
While there is little doubt that
augmentation of regional function in response to low-dose
dobutamine infusion accurately identifies reversible
dysfunction early after infarction, fewer data are available to support
the efficacy of this method in patients with chronic myocardial
hibernation.19 20 In 25 patients undergoing
coronary revascularization, Cigarroa et
al19 showed that a >20% improvement of the
systolic wall thickening score during dobutamine
had a sensitivity of 82% and a specificity of 86% for recovery at
follow-up. Similar results (87% sensitivity and 82% specificity)
were recently reported by La Canna et al20 in 33 selected
patients undergoing coronary artery bypass surgery. The
present findings confirm that the hibernating
myocardium conserves significant inotropic reserve when
challenged with a low dose of dobutamine. In our study,
regional wall motion score improved by an average of 6.1±2.4 grades
during low-dose dobutamine in patients with reversible
dysfunction compared with an improvement of only 1.8±4.2 grades in
patients with persistent postoperative dysfunction. A decrease in
global wall motion score by 4 grades or more during low-dose
dobutamine infusion best differentiated between patients
with and without postoperative improvement. With the use of this
cutoff, 84% of the patients with and 76% of those without
postoperative functional improvement were correctly identified.
Overall, 80% of the patients were correctly categorized.
Extent of Left Ventricular Remodeling as a Determinant
of Reversible Dysfunction
The present findings indicate that the
severity of left
ventricular remodeling, evaluated by left
ventricular end-diastolic volume, is
another important determinant of the reversibility of left
ventricular dysfunction after
revascularization, the likelihood of postoperative
recovery being less in the presence of more extensive preoperative left
ventricular dilation and remodeling. Extensive left
ventricular remodeling is known to be associated with
markedly elevated myocardial wall stresses and functional mitral
regurgitation, both of which play important roles in
the pathophysiology of left ventricular dysfunction and may
not be entirely reversible upon coronary
revascularization. Extensive remodeling is also
known to be associated with more severe tissue damage and infarct
expansion in the area of dysfunction and hence with a greater
likelihood of irreversibility.
Exercise-Redistribution-Reinjection 201Tl
Scintigraphy for Identification of Reversible
Dysfunction
Several previous studies have reported on the predictive
accuracy
of 201Tl imaging for prediction of the reversibility of
wall motion abnormalities after
revascularization.9 10 11 12 13
While most
studies have found that thallium imaging accurately delineated the
potential for recovery after revascularization,
sensitivity and specificity figures have been quite variable,
depending on the imaging protocol and criteria used to define
positivity. In the present study, the criterion that best
differentiated between patients with and without postoperative
improvement in global function was the defect extent score at peak
exercise: the larger the defect score, the smaller the likelihood of
functional recovery after revascularization. This
index mainly reflects the extent and severity of the underlying
coronary artery disease and thus the total amount of
jeopardized myocardium.33 Thus, our results
indicate that the likelihood of functional recovery after
revascularization is the largest in patients with
the least extensive disease. One possible explanation for these
findings could be that in patients with small exercise-induced
defects, the collateral vessels supplying the dysfunctional segments
are less likely to be dependent on stenotic arteries than in
patients with larger defects. In these patients, collateral flow and
viability therefore could be better preserved than in those with more
extensive defects and jeopardized
myocardium.34
Study Limitations
This study has several limitations that
should be acknowledged.
First, because the adequacy of coronary
revascularization was not assessed in every
patient, we cannot dismiss the possibility that early graft closure or
restenosis prevented the recovery of otherwise viable
segments and thereby influenced our results. However, in those patients
who were followed up angiographically after
revascularization, these events were rare and thus
can be expected to be rare in the whole group as well. Second, because
ejection fraction and end-systolic volume are important
prognostic indicators in patients with left ventricular
dysfunction undergoing
revascularization,35 the effects of
revascularization on these parameters
were used to define myocardial viability. While
end-systolic volume and ejection fraction may reflect
global ejection performance and contractility,
they also depend on the loading conditions. It is therefore possible
that some of the changes noted after
revascularization were not related to the
revascularization procedure itself but resulted
from changes in the loading conditions. This possibility seems
unlikely, however, because the changes in global left
ventricular function observed in our study did not parallel
those in either mean arterial pressure or left
ventricular end-diastolic volume (used as
rough measures of afterload and preload) and were always attended by
similar directional changes in regional wall motion. Finally, we used
the postoperative improvement in ventricular function as
the outcome measurement for patient selection, while relief of anginal
symptoms or actuarial survival are usually the preferred end points.
Obviously, the present study did not have the statistical power to
address the effects of revascularization either on
symptoms or survival in any meaningful way. We therefore relied on the
evaluation of the response of left ventricular function to
revascularization, which was recently shown to be
intimately related to long-term prognosis.36 While the
results of the present study suggest that evaluation of residual
inotropic reserve is useful in predicting the return of left
ventricular function after
revascularization, further studies will be
warranted to address its impact on the long-term prognosis of
patients with advanced coronary artery disease and left
ventricular dysfunction.
Conclusions
This study attempted to determine which
preoperative
parameters were associated with the return of global left
ventricular function after coronary
revascularization in patients with poor left
ventricular ejection fraction. The results indicate that
among the parameters commonly available in the preoperative
assessment of these patients, maintenance of a significant
degree of inotropic reserve in the area of dysfunction, the severity of
left ventricular dilatation and remodeling, and the
severity and extent of the perfusion defect at peak exercise are
associated with the reversibility of dysfunction. These observations
may be useful in determining which patients are most likely to have
improved global left ventricular function after
revascularization.
| Acknowledgments |
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| References |
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