(Circulation. 1995;91:2556-2565.)
© 1995 American Heart Association, Inc.
Articles |
Dobutamine Echocardiography Predicts Improvement of Hypoperfused Dysfunctional Myocardium After Revascularization in Patients With Coronary Artery Disease
Presented in part at the 43rd Annual Meeting of the American College of Cardiology, Atlanta, Ga, March 1994.
From the Divisions of Cardiology (P.P.-F., M.P., F.P., S.B., P.V., C.I., M.C.) and Nuclear Medicine (L.P., F.S., A.S., M.S.), "Federico II" University Medical School, Naples, Italy.
Correspondence to Pasquale Perrone-Filardi, MD, Cattedra di Cardiologia, Università degli Studi "Federico II," Via S Pansini 5, I-80131 Napoli, Italy.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background In patients with coronary artery disease, dysfunctional hypoperfused myocardium at rest may represent either necrotic or viable hibernating myocardium. The accuracy of inotropic stimulation in identifying hypoperfused, reversibly dysfunctional myocardium has not been extensively investigated.
Methods and Results Eighteen patients with stable chronic coronary artery disease underwent, while off drugs, quantitative 201Tl single-photon emission computed tomography after rest injection (2 to 3 mCi), two-dimensional echocardiography at rest and during dobutamine (5 to 10 µg/kg per minute IV), and radionuclide angiography. Single-photon emission computed tomography and echocardiography at rest were repeated 34±10 days after coronary revascularization, and radionuclide angiography was repeated 45±13 days after revascularization. Resting hypoperfusion was defined as 201Tl uptake <80% of maximal activity. Systolic function was scored from 1 (normal) to 4 (dyskinesia), and functional improvement was defined as a score change >1 grade. Of 79 dysfunctional hypoperfused segments, 48 (61%) improved function after revascularization. In 42 (88%) of these latter segments, function had improved during dobutamine. Conversely, systolic function after revascularization did not improve in 31 segments, and in 27 (87%), it had not improved during dobutamine. Functional improvement after revascularization was observed in 42 (91%) of 46 segments manifesting an improvement during dobutamine as opposed to 6 (18%) of 33 segments that did not improve during dobutamine. Resting 201Tl uptake (% of maximal activity) before revascularization (65±9%) significantly increased at follow-up in segments where function improved (70±12%, P<.005), whereas it did not change significantly in segments with unchanged systolic function after revascularization (from 57±13% to 60±17%, P=NS). In 10 patients with prerevascularization ejection fraction <45%, left ventricular ejection fraction significantly increased from 36±7% before revascularization to 42±7% at follow-up (P<.05).
Conclusions Inotropic stimulation using dobutamine echocardiography identifies hypoperfused reversibly dysfunctional myocardium. Functional improvement during dobutamine is highly predictive of improvement after revascularization.
Key Words: myocardium • perfusion • coronary artery disease • echocardiography • revascularization
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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In all patients with coronary artery disease, hypoperfused dysfunctional myocardium under resting conditions may represent either necrotic myocardium or viable hibernating myocardium.1 2 In the latter case, an improvement of regional systolic function can be achieved if coronary revascularization is performed.3 4 5 6 In selected patients, the improvement of regional function may translate into an improvement of global left ventricular function.5 6 7 Therefore, the distinction between necrotic and hypoperfused but viable myocardium is a clinically relevant task. Positron emission tomography8 and, more recently, quantitative 201Tl tomography, using the reinjection technique,9 10 have been reported to be quite accurate for identifying viable dysfunctional myocardium capable of functional recovery after revascularization. The rationale for the use of both techniques in the identification of viable myocardium relies on the demonstration of metabolic activity, and, hence, of myocardial cell integrity in myocardial territories showing impaired systolic function. In an alternative to this approach, experimental data have suggested that hypoperfused but viable myocardium showing impaired systolic function retains a residual contractile reserve, and it is, therefore, capable of improving systolic function upon inotropic stimulation.11 12 In the clinical setting, inotropic stimulation using low-dose dobutamine infusion has been reported to identify normoperfused dysfunctional viable (stunned) myocardium in patients after thrombolysis for acute myocardial infarction.13 14 15 However, the response to inotropic stimulation of hypoperfused and dysfunctional myocardium under resting conditions and its accuracy in predicting the functional outcome after revascularization have not been extensively investigated. Therefore, the goal of the present study was to assess the ability of inotropic stimulation, using dobutamine infusion, to identify hypoperfused, reversibly dysfunctional myocardium in patients with chronic coronary artery disease undergoing coronary revascularization.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patient Population
Nineteen consecutive patients with chronic coronary artery disease undergoing coronary revascularization were prospectively enrolled in the study. To enter the study, regional myocardial dysfunction at rest associated with resting hypoperfusion in the same myocardial territory, as described below, had to be demonstrated in each patient. One patient was subsequently excluded from the study because at the time of percutaneous transluminal angioplasty, no significant coronary stenosis was present. Therefore, the remaining 18 patients constitute the study cohort, and their characteristics are reported in Table 1
. There were 17 men and 1 woman
ranging in age from 45 to 70 years (mean, 59±8). All patients were in
stable hemodynamic condition, and no patient had had congestive heart
failure or unstable angina for at least 1 month before the study. No
patient was hypertensive, and 2 patients had type II diabetes mellitus.
Sixteen (89%) of 18 patients had a history of previous myocardial
infarction, which occurred at least 3 months before the
echocardiographic study in 15 patients, whereas in 1 patient, it had
occurred 3 weeks before the protocol studies. Coronary angiography was
performed in all patients a mean of 32±58 days before the preoperative
201Tl scintigraphy, and it documented in all patients at
least one significant stenosis (>70% of maximal luminal diameter) of
a major epicardial coronary artery. Three patients had three-vessel, 6
patients two-vessel, and 9 patients one-vessel coronary artery disease.
No major clinical events occurred in any patient between coronary
angiography and 201Tl scintigraphy.
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Study Protocol
Baseline studies before revascularization
including resting
201Tl single-photon emission computed tomography (SPECT),
two-dimensional echocardiography at rest and during dobutamine
infusion, and radionuclide angiography at rest. The echocardiographic
dobutamine study was performed a mean of 26±28 days before
revascularization, and it was performed in the same day as the SPECT
study, immediately thereafter, in 16 of 18 patients, whereas in the
remaining 2 patients it was performed the following morning. SPECT and
two-dimensional echocardiography at rest were again repeated in the
same day 34±10 days after revascularization. Equilibrium radionuclide
angiography at rest was performed in all except 1 patient 12±16 days
before revascularization, and it was repeated 45±13 days after
revascularization.
In all patients, for both prerevascularization and postrevascularization studies, calcium antagonists and oral nitrates had been withdrawn for at least 48 hours, ß-blockers for at least 72 hours, and transdermal nitrates for at least 12 hours before the protocol studies.
Informed consent was obtained from each patient before the study protocol, which was approved by the Institutional Ethical Committee.
201Tl Imaging
After an overnight
fast, patients underwent quantitative SPECT
after the administration, under resting conditions, of 2 to 3 mCi of
intravenous 201Tl. Since the purpose of the SPECT study was
to assess resting regional myocardial perfusion, acquisition of SPECT
images was started 15 to 20 minutes after 201Tl
injection16 using a wide-field-of-view rotating gamma
camera (digitized ELSCINT, SP4HR) equipped with a low-energy,
medium-sensitivity, medium-resolution, parallel-hole collimator and
centered on the 68-kEv and the 160-kEv photo peaks, with a 15% window.
Thirty-two images (64x64 matrix) were acquired using a step-shoot
method over a 180° semicircular orbit around the patient's thorax,
from 30° right anterior oblique to 60° left posterior oblique view,
using 6° increments, for 30 seconds each. Three-pixel-thick slices
were reconstructed along the short, horizontal, and vertical long axes
of the heart. Flood, center of rotation, and decay correction were
applied during reconstruction. Filtered backprojection with a
Butterworth filter (order, 5; cutoff, 0.5 cm-1) was used.
No attenuation correction was applied.
In each patient, four consecutive midventricular slices from the short-axis series and two from the horizontal and vertical long-axis series were selected for subsequent quantitative 201Tl analysis.
Echocardiography
Two-dimensional
echocardiography was performed with a
2.5-MHz transducer and a commercially available scanner
(Hewlett-Packard, Sonos 1000) under resting conditions and in the last
3 minutes of each dobutamine infusion level. Echocardiographic images
were acquired in the left lateral decubitus position and recorded on
12.5-mm VHS videotape. Four standard views of the left ventricle were
obtained for each acquisition: parasternal long axis, short axis at
mitral and papillary muscle levels, and apical four- and two-chamber
views.
After baseline echocardiography had been performed, dobutamine infusion was started using a mechanical infusion pump. The initial dose was 5 µg/kg per minute for 5 minutes, and it was then increased to 10 µg/kg per minute for 5 additional minutes in all except 1 patient. Blood pressure was periodically measured, and a 12-lead ECG was continuously monitored throughout the study and during the recovery phase. The total study duration did not exceed 30 minutes. No patients reported angina or developed life-threatening arrhythmias or hypertension during dobutamine infusion. In 1 patient, dobutamine infusion had to be interrupted after 5 minutes for the development of ventricular bigeminy. Heart rate was 75±10 beats per minute (bpm) at baseline and increased to 92±18 bpm at the end of peak dose infusion (P<.005). Systolic blood pressure was 127±17 mm Hg at baseline and did not significantly change at the end of the study (135±22 mm Hg, P=NS).
Echocardiography at rest was repeated with the same modalities as under resting conditions at postrevascularization follow-up.
Radionuclide Angiography
Radionuclide angiography
was performed at rest with the patient
in the supine position after the administration of 25 mCi of
99mTc, as previously described.17 Imaging was
performed with a small-field-of-view Anger camera, equipped with a
low-energy, parallel-hole, general-purpose collimator, oriented in the
45° left anterior position with a 15° caudal tilt. Data were
acquired in frame mode by computer-based ECG gating. High temporal
resolution (20 milliseconds per frame) time-activity curves were
generated, from which the left ventricular ejection fraction was
calculated as usual. Radionuclide angiography was performed in 17 of 18
patients. One additional patient, who had undergone mitral valve
replacement for mitral insufficiency in addition to coronary artery
bypass, was also excluded from the ejection fraction analysis.
Therefore, the comparison between prerevascularization and
postrevascularization ejection fractions refers to the remaining 16
patients.
Data Analysis
Quantitative 201Tl Analysis
For each patient, regional 201Tl activity was
measured on the four midventricular short-axis tomograms and on the two
horizontal and vertical long-axis tomograms selected for analysis
using a semiautomatic, quantitative, circumferential profile
analysis. Briefly, an operator-defined region of interest was drawn
around the left ventricular activity of the short-axis and long-axis
tomograms. Short-axis tomograms were then divided into six sectors of
equal arc, starting at the 3 o'clock position and proceeding
clockwise, representing the posterolateral, inferior,
posteroseptal, anteroseptal, anterior, and anterolateral myocardium. To
measure apical 201Tl uptake, vertical and horizontal
long-axis tomograms were also divided into six sectors starting at the
12 o'clock and 3 o'clock positions, respectively, and proceeding
clockwise so that in each case, the fifth sector corresponded to the
apical segment. Regional 201Tl activity was measured in
each myocardial sector, and it was expressed in each patient as a
percent of the maximal 201Tl activity for each set of
images. To incorporate a meaningful amount of myocardium in each
myocardial segment analyzed, the corresponding sectors (sector 1 with
sector 1, and so forth) from two consecutive, 3-pixel-thick, short-axis
and long-axis tomograms were then grouped and averaged. Thus, in each
patient, 13 midventricular anatomic segments were evaluated. Of these
segments, 7 (2 anterior, 2 anteroseptal, 2 posteroseptal, and 1 apical)
were assigned to the territory of the left anterior descending coronary
artery, 4 segments (2 anterolateral and 2 posterolateral) were assigned
to the territory of the left circumflex coronary artery, and 2 inferior
segments were assigned to the territory of the right coronary artery.
In each of these segments, perfusion data were compared with the
functional data derived from the echocardiographic analysis as
described below. Regional resting hypoperfusion was defined when
201Tl activity measured <80% of maximal activity in two
consecutive sectors corresponding to the same myocardial territory.
This cutoff was chosen based on analysis of resting regional
201Tl uptake in a group of 10 age-comparable subjects with
normal coronary arteries undergoing planar 201Tl
scintigraphy at rest, which has been reported
previously.18 In these subjects, regional
201Tl uptake at rest averaged 94±7% of maximal activity,
and the 80% cutoff chosen in the present study represents
the mean-2 SD of this value.
Quantitative 201Tl analysis, using the same modalities, was applied to both prerevascularization and postrevascularization studies. Alignment and analysis of the two studies was visually made by two operators unaware of the echocardiographic results and of the time of the study (prerevascularization or postrevascularization).
Echocardiographic Analysis
Echocardiographic images were analyzed off-line from the
videotape playback by two operators unaware of the scintigraphic
results. To evaluate regional wall motion, the length of the left
ventricle was divided into a basal, middle, and apical third according
to the criteria of the American Society of
Echocardiography.19 To allow a more accurate matching of
the echocardiographic and scintigraphic data, only the apical and the
midventricular segments of the left ventricle were evaluated in each
patient. Two short-axis midventricular images at the chordal and
midpapillary muscle levels were acquired, and each of them was divided
into six myocardial segments as recommended by the American Society of
Echocardiography, representing the posteroseptal, anteroseptal,
anterior, anterolateral, posterolateral, and inferior myocardium and
corresponding to the same segments described for the 201Tl
analysis. As for the 201Tl analysis, the apex was
considered as a single myocardial region also in the echocardiographic
analysis. Thus, regional function was evaluated in 13 myocardial
segments corresponding to the 201Tl segments.
For each myocardial segment analyzed, wall motion and systolic thickening were graded semiquantitatively using a scoring system where 1 indicated normal; 2, hypokinesia (severely reduced wall thickening and inward motion); 3, akinesia (absence of wall motion and of systolic thickening); and 4, dyskinesia. Improvement of contractile function in a segment was defined when systolic myocardial thickening became apparent in an akinetic or dyskinetic segment (score from 3 or 4 to 2 or 1) or when systolic thickening and wall motion comparable to those observed in the normal segments were observed in a previously hypokinetic segment (score from 2 to 1). Regional systolic dysfunction was defined when a score >2 was assigned to a myocardial segment in at least two different echocardiographic views. Discrepancies between observers were rare and were resolved by consensus.
To assess the reproducibility of the echocardiographic analysis, prerevascularization and postrevascularization echocardiograms were read in random order by the same observers at least 2 months after the initial reading. In this reading, the observers were unaware of the patient's identification and of the time of the study (prerevascularization or postrevascularization). The segmental exact score agreement was 82% (k value, 0.62; P<.01), and in 97.5% of all segments analyzed, the score difference between the two echocardiographic readings was within 1 point.
Coronary Revascularization
Eleven of 18 patients underwent
transluminal coronary
angioplasty of the left anterior descending coronary artery. Successful
dilatation was achieved in all cases, and it was defined when the
diameter of the residual stenosis of the target vessel did not exceed
30% of luminal diameter. The remaining 7 patients underwent coronary
artery bypass surgery. One surgical patient also had mitral valve
replacement for severe preoperative mitral insufficiency. No patients
had major complications associated with the revascularization
procedure. At the time of follow-up, only 1 patient had referred
atypical anginal pain. In this patient, repeat coronary angiography,
performed after the SPECT and echocardiographic follow-up studies,
revealed no significant lesion of the previously dilated left anterior
descending coronary artery. In the remaining 17 patients, repeat
coronary angiography was not performed because it was not clinically
indicated.
Statistical Analysis
All data are expressed as mean±1
SD. To account for the
potential statistical dependence between segments belonging to the same
vascular territory, differences among prerevascularization and
postrevascularization 201Tl data were first analyzed by
one-way ANOVA after grouping and averaging segments belonging to the
same vascular territory in each patient. Thereafter, a paired
Student's t test was used to compare prerevascularization
and postrevascularization 201Tl uptake in the same
myocardial segments, and an unpaired t test was used to
compare 201Tl uptake between different groups of myocardial
segments. A paired Student's t test also was used to
compare prerevascularization and postrevascularization ejection
fraction values.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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A total of 234 (13 per patient) myocardial segments were evaluated in 18 patients. Seventy-four showed normal 201Tl uptake at rest. Fifty (68%) of 74 segments with normal 201Tl uptake demonstrated normal function, 15 (20%) were hypokinetic, and 9 (12%) were akinetic at rest. Function after revascularization improved in 21 (88%) of 24 dysfunctional segments with normal 201Tl uptake, including 14 hypokinetic and 5 akinetic segments that became normokinetic and 2 akinetic segments that became hypokinetic. The remaining 160 segments showed reduced 201Tl uptake. Seventy-one (44%) of these hypoperfused segments manifested normal function at rest. Mean 201Tl uptake in these segments was 68±8% of maximal activity, and it significantly increased after revascularization to 74±10% (P<.01). Forty-three (61%) of these segments with mild hypoperfusion and normal function at rest belonged to myocardial territories supplied by stenosed vessels. The remaining 89 segments showed abnormal function at rest in association with reduced 201Tl uptake. Of these latter 89 segments, 79 were in territories subjected to revascularization. The present study focuses on the analysis of these 79 hypoperfused and dysfunctional segments. Forty (51%) of these segments were judged to be hypokinetic and the remaining 39 (49%) akinetic. The mean resting 201Tl uptake of these segments before revascularization was 62±11 (% of maximal activity; range, 21% to 78%), which was significantly lower than that of the 71 hypoperfused but normally contracting segments (P<.01). None of the 71 hypoperfused but normally contracting segments showed severely reduced (<50% of maximal activity) 201Tl uptake as opposed to 12 (15%) of 79 hypoperfused and dysfunctional segments. Eight (67%) of 12 severely hypoperfused segments were akinetic at rest.
All except 8 of the 79 hypoperfused dysfunctional segments were
supplied by coronary vessels with a 
80% stenosis. The remaining 8
myocardial territories, observed in 2 patients, were supplied by
descending anterior coronary arteries where 2 sequential >70%
stenoses were present.
Effects of Dobutamine on Regional Function
During dobutamine
infusion, none of 79 hypoperfused dysfunctional
segments manifested further deterioration of function, whereas 46
(58%) dysfunctional segments showed a functional improvement of at
least one score grade (Fig 1). In particular, functional
improvement was observed in 35 (88%) hypokinetic segments that became
normokinetic during dobutamine and in 11 (28%) akinetic segments (Fig
2). Of these latter segments, 4 became hypokinetic and 7
normokinetic during dobutamine infusion. The remaining 33 dysfunctional
hypoperfused segments did not show functional changes during
dobutamine; 28 (85%) of them were akinetic under resting conditions.
The echocardiographic score at rest was significantly lower in the
segments that improved during dobutamine compared with those that did
not (2.3±0.4 versus 2.9±0.4, P<.001). Mean resting
201Tl uptake was significantly higher in the segments
showing improved function during dobutamine (65±9%) compared with
those with unchanged function (58±13%, P<.008), and the
likelihood of a positive dobutamine response was correlated to the
level of resting 201Tl uptake (r=.91, P<.005;
Fig 3).
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Effects of Coronary Revascularization on Regional Function
Of
79 dysfunctional hypoperfused segments, 48 (61%) demonstrated
improved function at follow-up study after coronary revascularization
(Fig 1
). In particular, 32 (80%) of 40 hypokinetic segments and
14
(36%) of 39 akinetic segments before revascularization showed normal
function at follow-up, and 2 additional akinetic segments became
hypokinetic after revascularization. Thus, improved function after
revascularization was observed in 16 (41%) of 39 segments that were
preoperatively akinetic (Fig 2).
Overall statistical
difference in resting 201Tl uptake
before and after revascularization in segments with improved and
unchanged function was first analyzed by ANOVA test after
201Tl uptake values of segments belonging to the same
vascular territory had been averaged in each patient
(P=.013). In segments where function improved after
revascularization, resting 201Tl uptake significantly
increased from 65±9% before revascularization to 70±12%
(P<.005, Fig 4) at follow-up. As shown in
Fig 4, resting perfusion as evaluated by 201Tl
uptake was
enhanced in the majority of segments improving function after
revascularization.
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In contrast, the remaining 31 dysfunctional
hypoperfused segments did
not show functional changes after revascularization. In these segments,
mean resting 201Tl uptake before revascularization
(57±13%) did not significantly change at follow-up (60±17%,
P=NS; Fig 4), although enhanced
201Tl uptake was
observed in some individual segments. The mean change in resting
201Tl uptake from before to after revascularization did not
significantly differ between segments with improved function (4±10%)
and segments with unchanged function at follow-up (3±10%,
P=NS).
Mean resting 201Tl uptake was
significantly higher in
segments showing improved function after revascularization compared
with those that did not, both before (65±9% versus 57±13%,
P<.001) and after revascularization (70±12% versus
60±17%, P<.01; Fig 4), and the level of
resting
201Tl uptake strongly correlated with the frequency of
functional improvement after revascularization
(r=.97, P<.001; Fig 5).
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Accuracy of Dobutamine Response in Predicting the Functional
Outcome After Revascularization
Of 48 hypoperfused dysfunctional
segments showing improved
function after revascularization, 42 (88%) had also improved during
dobutamine infusion, whereas 27 (87%) of 31 segments with unchanged
function after revascularization had not improved during dobutamine.
The sensitivity and specificity of dobutamine infusion to identify
dysfunctional segments capable of recovering function after
revascularization were, therefore, 88% and 87%, respectively (Table
2).
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Of 46 dysfunctional segments showing improvement during dobutamine, 42 (91%) improved after revascularization as opposed to 6 (18%) of 33 dysfunctional segments showing no changes during dobutamine. Therefore, the positive accuracy and negative accuracy of dobutamine infusion for predicting functional improvement of dysfunctional hypoperfused segments after revascularization were 91% and 82%, respectively. The 4 myocardial segments demonstrating improved dobutamine during dobutamine but not at follow-up were observed in 2 (11%) of 18 patients. Similarly, the 5 myocardial segments that improved function at follow-up but not during dobutamine were observed in additional 2 patients. Therefore, dobutamine correctly predicted the functional outcome after revascularization of all dysfunctional segments identified in the same patient in 13 (72%) of 18 patients.
Exclusion of three dysfunctional segments belonging to the patient undergoing mitral valve replacement did not alter the results, as sensitivity and specificity were 91% and 87%, respectively, whereas positive and negative predictive accuracy were 91% and 81%, respectively.
The accuracy of dobutamine response in predicting the
functional
outcome after revascularization was further assessed in the group of 39
segments showing preoperative akinesia (Fig 2). Improved
function at
follow-up was observed in 16 (41%) of these segments. Eleven (69%) of
them improved during dobutamine administration. In contrast, no
preoperatively akinetic segments that remained akinetic after
revascularization showed improvement during dobutamine. Thus, the
response to dobutamine had a 69% sensitivity and a 100% specificity
for identifying akinetic but viable segments capable of improving after
revascularization.
Repeat analysis using blind echocardiographic readings did not significantly change the results, as sensitivity and specificity were 87% and 81%, respectively, and positive and negative predictive accuracies were 91% and 76%, respectively.
An example of a myocardial
dysfunctional segment showing functional
improvement during dobutamine infusion and at follow-up study is
represented in Fig 6. Fig 7
shows the improvement of resting myocardial perfusion after
revascularization in the same myocardial territory.
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Effects of Coronary Revascularization on Global Left Ventricular
Function
In the group of 16 patients in whom the comparison was made,
left
ventricular ejection fraction did not significantly change (from
43±12% before revascularization to 47±10% at follow-up,
P=NS). However, in the subgroup of 10 patients with
preoperatively reduced (<45%) values, ejection fraction at rest
significantly increased from 36±7% before revascularization to
42±7% at follow-up (P<.05, Fig 8).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The findings of the present study demonstrate that, in patients with coronary artery disease, dobutamine echocardiography is a useful technique for identifying hibernating myocardium defined as hypoperfused and dysfunctional myocardium capable of recovering function after revascularization; in addition, the response to dobutamine highly predicts the effects of revascularization on regional systolic function.
Previous Studies
It is known that even severely impaired
regional myocardial
function under resting conditions does not necessarily indicate
irreversibly damaged myocardium, but, instead, it can be a partially or
completely reversible phenomenon when a substantial amount of residual
viable myocardium is present.6 20 21 In
fact, in
patients with chronic coronary artery disease and left ventricular
dysfunction, residual viable myocardium, as identified by persistence
of metabolic activity evaluated by positron emission
tomography22 23 or by 201Tl
uptake,21 can be demonstrated in up to 74% of myocardial
territories exhibiting severely depressed systolic function. The
findings of the present study, which enrolled a group of patients
without severe left ventricular dysfunction, are in agreement with
these previous observations, as only 7 (21%) of 39 akinetic segments
showed severely reduced 201Tl uptake.
Experimental24 25 and clinical13 15 studies have reported that impaired regional function due to myocardial stunning can be ameliorated or reverted by inotropic stimulation. Information on normoperfused stunned myocardium, however, cannot be extrapolated to myocardial hibernation, where impaired function arises from a presumably long-term functional adaptation to reduced perfusion.26 Experimental data suggest that dysfunctional, moderately hypoperfused but viable myocardium is capable of enhancing contractile function in response to inotropic stimulation.11 12 In the clinical setting, however, there are so far no studies reporting the response to inotropic stimulation of dysfunctional and hypoperfused myocardium under resting conditions and its accuracy in predicting the functional outcome of such myocardial territories after revascularization. Indirect data suggest that chronically asynergic but viable myocardium is capable of improving function upon inotropic stimulations such as postextrasystolic potentiation27 28 or epinephrine administration.29 In these previous studies, however, no regional assessment of perfusion was performed, and it is therefore impossible to retrospectively characterize the exact pathophysiological state leading to impaired function. More recently, Barilla et al14 and Cigarroa et al30 reported a high accuracy of the echocardiographic dobutamine test in predicting recovery of function after revascularization in dysfunctional myocardial segments. Regional resting perfusion, however, was not assessed in these studies, and dysfunctional myocardial segments showing improved function after revascularization were assumed to represent hibernating myocardium. However, apart from stunning and hibernation, regional dysfunction at rest may be observed in myocardial territories consisting of an admixture of normally perfused viable myocardium and necrotic myocardium31 or in normally perfused myocardial segments that are adjacent to ischemic dysfunctional territories.32 33 As a consequence, a distinction among these conditions and an accurate identification of hibernating myocardium can only be made when an assessment of both resting perfusion and function is performed in a given myocardial territory. Thus, the accuracy of inotropic stimulation using dobutamine in identifying hibernating myocardium cannot be determined exactly from previous studies.
Effects of Revascularization on Regional and Global Left
Ventricular Function
In the present study, only myocardial segments
exhibiting
impaired function under resting conditions in association with reduced
perfusion at rest were evaluated. These segments may, therefore,
represent necrotic myocardium, hibernating myocardium, or an
admixture of the two. Improved function at follow-up was observed in
61% of such hypoperfused dysfunctional segments, including 41% of
preoperatively akinetic segments, consistent with previous observations
on regional systolic function in patients with coronary artery disease
undergoing coronary revascularization.6 21
In agreement with previous observations,6 21 the improvement of regional systolic function was associated in some individual patients with an improvement of global left ventricular ejection fraction at rest. Such improvement, as expected, was more pronounced in the subgroup of patients showing reduced preoperative ejection fraction.
Accuracy of Dobutamine in Predicting Reversibility of Regional
Dysfunction
In hypoperfused and dysfunctional myocardial segments, the
functional response to dobutamine was quite accurate in predicting
their outcome after revascularization. A positive response to
dobutamine identified 88% of segments that eventually improved
function after revascularization; in addition, a positive response to
dobutamine was 91% accurate in predicting the improvement of function
after revascularization. In contrast, a negative response to dobutamine
identified 87% of dysfunctional segments that did not improve after
revascularization, and it was 82% accurate in predicting lack of
improvement after revascularization. Accurate information regarding the
outcome of all dysfunctional segments identified in the same patient
were obtained in 72% of patients.
These data indicate that hibernating myocardium retains a residual contractile reserve and is capable of facing the increased oxygen demand due to inotropic stimulation. In this respect, our data are in agreement with previous experimental observations demonstrating both contractile11 12 and vasodilator34 35 reserve in moderately hypoperfused and dysfunctional myocardium and with a recent clinical report36 that demonstrated blunted but preserved vasodilator reserve in moderately hypoperfused and dysfunctional human myocardium under resting conditions.
Lower sensitivity in identifying reversibly dysfunctional myocardium was observed in segments showing preoperative akinesia. In such segments, therefore, dobutamine may underestimate viability. This might be explained by the possibility that some severely dysfunctional but viable segment might have exhausted its coronary reserve, or alternatively, it might retain only subepicardial but not subendocardial coronary reserve.37 In such segments, therefore, any additional increase of oxygen demand (as during inotropic stimulation) might not translate into an appreciable change of wall motion despite the presence of viable myocardium. Thus, in these territories, resting systolic function could only improve upon amelioration of the resting perfusion status.
The accuracy of dobutamine in identifying dysfunctional hypoperfused but viable myocardium in the present study was comparable to that previously reported using positron emission tomography. In particular, Tillisch et al6 and Tamaki et al38 reported that enhanced 18fluorodeoxyglucose uptake in hypoperfused dysfunctional myocardium (the so-called mismatch pattern) was 85% to 78% accurate in predicting the reversibility of systolic dysfunction after revascularization, whereas the absence of such a pattern was 92% to 78% accurate in predicting the lack of functional improvement.
Effects of Revascularization on Regional Resting 201Tl
Uptake
In this study, regional 201Tl uptake was
specifically
used as an indirect marker of regional perfusion to identify
hypoperfused myocardial segments. Therefore, acquisition of
201Tl images was purposely started early after injection to
reflect predominantly regional myocardial perfusion at
rest16 and to minimize the occurrence of redistribution
that might have caused underestimation of hypoperfusion. As the
redistribution process importantly contributes to the identification of
viability by 201Tl, the accuracy of 201Tl in
predicting the functional outcome of dysfunctional segments cannot be
determined exactly from the present study. Nevertheless, regional
201Tl uptake before revascularization was significantly
higher in those dysfunctional segments due to improve at follow-up
compared with those that did not, and the level of resting
201Tl uptake was strongly correlated with the likelihood of
functional improvement (r=.97, Fig 5).
Similarly, regional
201Tl uptake was significantly higher in dysfunctional
regions showing improvement during dobutamine compared with those that
did not (Fig 3). These findings are in agreement with previous
observations reporting that the magnitude of regional 201Tl
uptake reflects the mass of viable tissue and correlates with metabolic
activity and systolic function.39 40 In addition, it
has
been reported recently by Ragosta et al21 that
dysfunctional myocardial segments demonstrating only a mild to moderate
reduction of 201Tl uptake at rest are more likely to
improve function after revascularization compared with those in which
201Tl uptake is more severely reduced. Our findings,
although without the incorporation of the redistribution information,
are indeed very consistent with Ragosta's observations: 67% (45 of
67) of segments with resting 201Tl uptake >50% of maximal
activity improved after revascularization compared with 57% in
Ragosta's study. In contrast, only 3 (25%) of 12 segments with
severely reduced 201Tl uptake improved after
revascularization, which is similar to the 23% reported by Ragosta et
al.21
In the present study, 201Tl uptake
significantly
increased at follow-up in regions with improved function, indicating
enhanced resting perfusion, although the mean change from before to
after revascularization did not significantly differ between segments
with improved or unchanged function. In fact, increased
201Tl uptake at follow-up was also observed in some
dysfunctional myocardial segments with unchanged function (Fig
4).
Improved regional perfusion without improved function has been observed
previously. Gropler et al,41 using positron emission
tomography to measure regional blood flow in patients with coronary
artery disease undergoing revascularization, reported a 35% increase
in resting blood flow in territories where function did not improve
after revascularization. In addition, Ragosta et al21
recently demonstrated enhanced 201Tl uptake after
revascularization in the majority (58%) of segments showing
persistently and severely reduced 201Tl uptake before
revascularization. Improved function, however, occurred in only 19% of
such segments. From a pathophysiological standpoint, it is conceivable
that revascularization of myocardial segments containing a limited
amount of viable cells19 or of subepicardial viable
myocardium, which minimally contributes to systolic
thickening,42 43 although resulting in improved
perfusion,
may not determine any detectable effect of function.
It is also noteworthy that improved function at follow-up was observed in some myocardial segments with no change in perfusion. Although a certain degree of misalignment between echocardiographic and scintigraphic segments is conceivable, the tethering phenomenon also may help to explain functional improvement in some myocardial segments with no improvement of 201Tl uptake as a consequence of improvement of adjacent dysfunctional segments.32 33 As the sensitivity of the test in identifying reversible dysfunction was very high, occurrence of such a potential mechanism of functional improvement, however, it is not likely to affect the accuracy of the test.
In the present study, 44% of segments with reduced 201Tl uptake showed normal function at rest. Such a finding also has been observed in previous studies.21 40 44 45 Although misalignment of scintigraphic and echocardiographic segments as well as underestimation of functional abnormalities by visual echocardiographic analysis may partly account for this observation, other pathophysiological explanations are also likely to occur. The level of 201Tl uptake in such segments indicates only a mild hypoperfusion, and it has been reported in animal studies that a considerable decrease in regional blood flow is necessary before an effect on regional function can be detected.46 Experimental studies also demonstrated that transmural blood flow (as indirectly reflected by 201Tl uptake) is only poorly correlated to regional systolic function, which predominantly depends on subendocardial perfusion.26 47 Thus, a mild reduction of regional transmural perfusion can be associated with no detectable effects on resting systolic function.
Limitations of the Study
In the present study, regional
perfusion data derived from
201Tl tomography were correlated to functional data derived
from echocardiographic analysis. Although particular care was taken
to optimize the matching of myocardial segments, some anatomic
misalignment is expected in the comparison of two different imaging
modalities.
The study population consisted of a group of patients referred for coronary revascularization on the basis of symptoms and/or instrumental evidence of myocardial ischemia. Therefore, it is uncertain whether the same incidence of dysfunctional segments showing improvement after revascularization would have been observed in a more general population of patients with chronic coronary artery disease. Similarly, the observed impact of revascularization on left ventricular global function could be less pronounced in a less selected population of patients with moderately depressed global left ventricular function. The mean preoperative resting 201Tl uptake observed in the dysfunctional segments indicates a mild to moderate severity of hypoperfusion in the majority of them. Therefore, whether the observed accuracy of dobutamine in identifying viable segments also applies to more severely hypoperfused yet viable segments cannot be anticipated from the present study. Finally, although none of the 17 patients not undergoing coronary angiography after revascularization was symptomatic, asymptomatic restenosis in some patients cannot be excluded with certainty. However, the observation that the majority of segments with unchanged function after revascularization were observed in the same vascular territories of segments that demonstrated improved function further minimizes this possibility.
Conclusions
The present study demonstrates that the majority
of
hypoperfused and dysfunctional viable myocardial segments are capable
of improving function upon inotropic stimulation using dobutamine.
Hypoperfusion in association with reversibly impaired systolic function
at rest indicates the presence of hibernating myocardium in these
territories. The response to dobutamine yields a very high accuracy in
predicting the functional outcome of hypoperfused myocardium after
revascularization, comparable to that reported using positron emission
tomography.
Received November 2, 1994; accepted December 13, 1994.
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P. G. Camici, W. Wijns, M. Borgers, R. De Silva, R. Ferrari, J. Knuuti, A. A. Lammertsma, A. J. Liedtke, G. Paternostro, and S. F. Vatner Pathophysiological Mechanisms of Chronic Reversible Left Ventricular Dysfunction due to Coronary Artery Disease (Hibernating Myocardium) Circulation, November 4, 1997; 96(9): 3205 - 3214. [Full Text]
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A. Cohen, C. Chauvel, B. Benhalima, P. Guyon, I. Desert, J. Valty, and A. Cohen Is Dobutamine Stress Echocardiography Useful for Noninvasive Differentiation of Ischemic from Idiopathic Dilated Cardiomyopathy? Angiology, September 1, 1997; 48(9): 783 - 793. [Abstract] [PDF]
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M. D. Cheitlin, J. S. Alpert, W. F. Armstrong, G. P. Aurigemma, G. A. Beller, F. Z. Bierman, T. W. Davidson, J. L. Davis, P. S. Douglas, L. D. Gillam, et al. ACC/AHA Guidelines for the Clinical Application of Echocardiography : A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Clinical Application of Echocardiography) Developed in Collaboration With the American Society of Echocardiography Circulation, March 18, 1997; 95(6): 1686 - 1744. [Full Text]
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COMMITTEE MEMBERS, J. F. WILLIAMS Jr, M. R. BRISTOW, M. B. FOWLER, G. S. FRANCIS, A. GARSON Jr, B. J. GERSH, D. F. HAMMER, M. A. HLATKY, C. V. LEIER, et al. Guidelines for the Evaluation and Management of Heart Failure : Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure) Circulation, November 1, 1995; 92(9): 2764 - 2784. [Full Text]
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