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(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.

Pasquale Perrone-Filardi, MD, PhD; Leonardo Pace, MD; Mariella Prastaro, MD; Federico Piscione, MD; Sandro Betocchi, MD; Fiorenzo Squame, MD; Pasquale Vezzuto, MD; Andrea Soricelli, MD; Ciro Indolfi, MD; Marco Salvatore, MD; Massimo Chiariello, MD

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.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
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

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
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.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
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.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the Study Group

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.

	Results

Top Abstract Introduction Methods Results Discussion References

 
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).

View larger version (45K): [in this window] [in a new window]   Figure 1. Pie charts showing the effects of dobutamine infusion and of coronary revascularization on regional systolic function in the whole group of hypoperfused dysfunctional myocardial segments.

View larger version (44K): [in this window] [in a new window]   Figure 2. Pie charts showing the effects of dobutamine infusion and of coronary revascularization on regional systolic function in the subgroup of myocardial segments demonstrating akinesia before revascularization.

View larger version (22K): [in this window] [in a new window]   Figure 3. Bar graph shows relation between the level of resting 201Tl uptake and the response to dobutamine in dysfunctional myocardial segments. Each bar indicates the frequency of a positive response to dobutamine in the group of dysfunctional myocardial segments with the corresponding resting 201Tl uptake. The mean level of 201Tl uptake within each group of 201Tl segments strongly correlated with the frequency of improvement during dobutamine (r=.91, P<.005).

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.

View larger version (26K): [in this window] [in a new window]   Figure 4. Plots show regional 201Tl uptake at rest before (Pre) and after (Post) coronary revascularization in myocardial segments demonstrating improved or unchanged systolic function after revascularization.

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).

View larger version (22K): [in this window] [in a new window]   Figure 5. Bar graph shows relation between the level of resting 201Tl uptake and the effects of revascularization on dysfunctional myocardial segments. Each bar indicates the frequency of functional improvement after revascularization in the group of dysfunctional myocardial segments with the corresponding resting 201Tl uptake. The mean level of 201Tl uptake within each group of 201Tl segments strongly correlated with the frequency of improvement after revascularization (r=.97, P<.001).

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).

View this table: [in this window] [in a new window]   Table 2. Accuracy of Dobutamine Echocardiography in Identifying Viable Hypoperfused Dysfunctional Myocardium

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.

View larger version (119K): [in this window] [in a new window]   Figure 6. End-diastolic and end-systolic apical echocardiographic two-chamber view images under basal conditions (upper row), during dobutamine infusion (middle row), and at follow-up after bypass grafting of the left anterior descending coronary artery (lower row). Preoperative images demonstrate akinesia of the anteroapical segment that improved by dobutamine infusion and remained improved at follow-up study.

View larger version (94K): [in this window] [in a new window]   Figure 7. Corresponding contiguous horizontal long-axis 201Tl tomograms from the same patient in Fig 6 before (upper row) and after (lower row) coronary artery bypass grafting. Preoperative tomograms, obtained the same day of the dobutamine echocardiographic study, demonstrated a large 201Tl defect in the antero-apical territory (arrows) corresponding to the akinetic region, which was reduced at follow-up study.

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).

View larger version (16K): [in this window] [in a new window]   Figure 8. Resting left ventricular ejection fraction before (Pre) and after (Post) coronary revascularization in the subgroup of 10 patients showing preoperative ejection fraction <45% (left) and in the remaining 6 patients with preoperative ejection fraction >45% (right).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
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 tomography^{22 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.

Experimental^{24 25} and clinical^{13 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 potentiation^{27 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 contractile^{11 12} and vasodilator^{34 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.

	References

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