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(Circulation. 1995;92:2863-2868.)
© 1995 American Heart Association, Inc.

Articles

Comparison of Myocardial Contrast Echocardiography and Low-Dose Dobutamine Stress Echocardiography in Predicting Recovery of Left Ventricular Function After Coronary Revascularization in Chronic Ischemic Heart Disease

Presented in part at the American College of Cardiology 43rd Annual Scientific Sessions, Atlanta, Ga, March 17, 1994.

Christopher R. deFilippi, MD; DuWayne L. Willett, MD; Waleed N. Irani, MD; Eric J. Eichhorn, MD; Carlos E. Velasco, MD; Paul A. Grayburn, MD

From the Department of Internal Medicine, Division of Cardiology, VA Medical Center, and the University of Texas Southwestern Medical Center, Dallas.

Correspondence to Paul A. Grayburn, MD, Division of Cardiology (111A), VA Medical Center, 4500 S Lancaster Rd, Dallas, TX 75216.

	Abstract

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Background Dobutamine stress echocardiography (DSE) and myocardial contrast echocardiography (MCE) can predict recovery of left ventricular function after myocardial infarction. DSE also has been shown to predict left ventricular functional recovery after revascularization in chronic ischemic heart disease, whereas MCE has not been evaluated in such patients. This study was performed to compare DSE and MCE in the prediction of left ventricular functional recovery after revascularization in patients with chronic ischemic heart disease.

Methods and Results MCE and DSE were performed in 35 patients with chronic coronary artery disease and significant wall motion abnormalities (mean ejection fraction, 0.36±0.09). Regional wall motion was scored by use of a 16-segment model wherein 1=normal or hyperkinetic, 2=hypokinetic, 3=akinetic, and 4=dyskinetic. Each segment was evaluated for contractile reserve by DSE and perfusion by MCE. Revascularization (coronary artery bypass graft [n=13] and percutaneous transluminal coronary angioplasty [n=10]) was successful in 23 patients. Follow-up echocardiograms were done to assess wall motion 30 to 60 days later. In 238 segments with resting wall motion abnormalities, perfusion was more likely to present than contractile reserve (97% versus 91%, P<.02). Revascularization resulted in functional recovery in 77 of 95 hypokinetic segments (81%) but only 18 of 57 akinetic segments (32%, P<.0001). DSE and MCE were not significantly different in predicting functional recovery of hypokinetic segments. In akinetic segments, DSE and MCE had similar sensitivities (89% versus 94%, respectively) and negative predictive values (93% and 97%, respectively) in predicting functional recovery. However, DSE had a higher specificity (92% versus 67%, P<.02) and positive predictive value (85% versus 55%, P<.02) than MCE in predicting functional recovery.

Conclusions Both contractile reserve by DSE and perfusion by MCE are predictive of functional recovery in hypokinetic segments after coronary revascularization in patients with chronic coronary artery disease. In akinetic segments, myocardial perfusion by MCE may exist in segments that do not recover contractile function after revascularization. Thus, contractile reserve during low-dose dobutamine infusion is a better predictor of functional recovery after revascularization in akinetic segments than perfusion.

Key Words: coronary disease • echocardiography • revascularization

	Introduction

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Clinical methods to predict left ventricular functional recovery after revascularization have focused on contractile reserve, myocardial perfusion, or metabolic activity.¹ Contractile reserve, ie, the ability of a dyssynergic segment to augment contractile function, was originally shown angiographically during inotropic stimulation or ventricular extrasystole.^{2 3} Recently, contractile reserve during dobutamine stress echocardiography (DSE) has been used to predict recovery of regional myocardial function in patients with chronic ischemic heart disease.^{4 5 6 7} Myocardial perfusion in dysfunctional segments by thallium-201 scintigraphy^{8 9 10 11} or positron emission tomography^{12 13} also has been used to predict left ventricular functional recovery in such patients. Evidence of myocardial perfusion by myocardial contrast echocardiography (MCE) has been shown to predict functional recovery after restoration of anterograde flow in patients with acute myocardial infarction.^{14 15 16} However, the ability of MCE to predict functional recovery after revascularization in chronic ischemic heart disease has not been studied.

Potentially, contractile reserve and myocardial perfusion may provide different information regarding functional recovery after revascularization. Myocardial perfusion may overestimate the extent of myocardial salvage early after reperfusion during experimental myocardial infarction.^{17 18} Moreover, islands of viable myocytes exist in human myocardial segments that are largely fibrotic and incapable of contraction.¹⁹ Thus, although perfusion is a sensitive marker of myocardial "viability," it may be less sensitive in predicting functional recovery than contractile reserve. On the other hand, the presence of a severe coronary stenosis may limit the ability to elicit contractile reserve in viable myocardial segments.²⁰ Therefore, the following study was performed to compare contractile reserve by DSE with myocardial perfusion by MCE in predicting functional recovery of regional wall motion abnormalities after revascularization in patients with chronic ischemic heart disease.

	Methods

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Patient Population
We prospectively compared DSE and MCE in 35 patients with chronic ischemic heart disease referred for elective diagnostic cardiac catheterization. Patients were selected because they had 70% diameter stenosis in one or more coronary arteries and significant segmental wall motion abnormalities, defined as at least two contiguous dysfunctional segments by echocardiography. Patients were specifically excluded if they had recent myocardial infarction, history of sustained ventricular tachycardia, atrial fibrillation, left main coronary artery obstruction 50%, decompensated congestive heart failure, or protruding thrombus in the left ventricle.

All patients were men ranging in age from 42 to 75 years (median, 63 years). Cardiac catheterization was performed in 13 patients (37%) with stable angina and 22 patients (63%) with unstable angina. Ejection fraction ranged from 0.13 to 0.49 (mean, 0.36±0.09). Three-vessel disease was present in 25 patients (71%), two-vessel disease in 7 patients (20%), and single-vessel disease in 3 patients (9%). Remote myocardial infarction was present by history in 15 patients; 11 had pathological Q waves on ECG.

Protocol
The protocol was approved by the Human Studies Subcommittee of the Dallas Veterans Affairs Medical Center. Before enrollment in the study, all patients scheduled for diagnostic cardiac catheterization were screened by two-dimensional (2D) echocardiography. Patients with clear endocardial border definition in the parasternal or apical view and significant wall motion abnormalities as defined above were recruited. Written informed consent was obtained from all subjects. MCE was done after coronary angiography to assess myocardial perfusion. Low-dose DSE was performed within 24 hours after diagnostic cardiac catheterization and MCE. Coronary revascularization was recommended by the patient's attending physician independent of the results of DSE and MCE and was performed in 23 patients. A follow-up 2D echocardiogram was obtained 30 to 60 days after revascularization or after cardiac catheterization in patients who were not revascularized.

Myocardial Contrast Echocardiography
Renografin-76 was sonicated with a Heat Systems XL2020 by the technique of Feinstein et al.²¹ Separate injections of 2 to 3 mL sonicated contrast were made into both the left main and the right coronary arteries. Simultaneous 2D echocardiography was performed in standard parasternal and apical views with a Sonos 1500 (Hewlett Packard) or an Apogee CX (Interspec).

Images were subsequently analyzed by a reader blinded to the clinical data and cardiac catheterization results. The 16-segment model was used to grade systolic wall thickening of each segment visualized (see below). Perfusion in each segment was scored qualitatively: 0, not opacified; 0.5, patchy opacification or opacification of the epicardial layer only; and 1, homogeneous opacification.^{15 16} It was also noted whether the segment was perfused during left main or right coronary injections.

Dobutamine Stress Echocardiography
Patients underwent DSE after at least a 3-hour fast but while taking all prescribed medicine. All subjects underwent 2D echocardiography with a Vingmed CFM750 (Vingmed Sound). Parasternal long-axis, midventricular short-axis, apical four-chamber, and apical two-chamber images were acquired and recorded on 1/2-in videotape. For each view, one cardiac cycle was digitally transferred to a Macintosh IIci computer with commercially available software (ECHOPAC 4.2, Vingmed Sound). Next, dobutamine was infused in increments of 5, 10, 15, and 20 µg · kg^-1 · min^-1 IV at 3-minute intervals. Repeated (stress) images were obtained in all views before each incremental increase in infusion rate and were transferred digitally and recorded on videotape. Heart rate was observed continuously by a single-lead ECG monitor. Blood pressure was recorded at 3-minute intervals with an automated cuff.

The DSEs were analyzed with a quad-screen format by a reader blinded to the clinical, angiographic, and MCE data. Rest and stress images were compared simultaneously in the same imaging planes. Regional wall thickening was assessed with the recommended American Society of Echocardiography 16-segment model.²² The stress image at the dobutamine dose showing maximal augmentation of wall motion was compared with baseline images. A subsequent worsening of wall motion at a higher dose was assumed to represent the onset of ischemia. For each segment, systolic wall thickening was graded visually with a semiquantitative scoring system wherein 1=normal or hyperkinetic, 2=hypokinetic, 3=akinetic, and 4=dyskinetic. A regional wall thickening score was quantified for each patient by summing the grades for each segment and dividing by the total number of segments analyzed. Contractile reserve was defined as the presence of improved wall thickening in at least two adjacent abnormal segments and a 20% reduction in wall motion score, the latter criterion representing the 95% confidence level for detecting a significant change in wall motion score in our laboratory.⁴ Left ventricular ejection fractions at rest and during dobutamine infusion were calculated by use of the biplane Simpson's rule.²²

Echocardiographic Follow-up
Follow-up echocardiograms were obtained in 30 patients, including all 23 revascularized patients. Five nonrevascularized patients did not have a follow-up echocardiogram: 1 died suddenly and 4 did not return for follow-up. Follow-up images were recorded digitally and were compared in a quad-screen continuous-loop format to the baseline images obtained at the time of the DSE. The reader was blinded to the results of the initial DSE and MCE and to whether the patient underwent coronary revascularization. Improved regional left ventricular function on follow-up was defined as both improvement in at least two adjacent abnormal segments and a 20% reduction in wall thickening score compared with baseline images. Revascularized segments were then classified as those segments that were supplied by a revascularized vessel.

Statistical Analysis
All data are reported as mean±SD. Contingency table analysis by use of ² with continuity correction was applied to determine whether wall thickening during low-dose DSE and myocardial perfusion by MCE predicted improved wall motion on follow-up. Concordance between low-dose DSE and MCE in identifying myocardial viability was assessed by use of a ² test calculated by McNemar's test. A value of P.05 was considered statistically significant.

	Results

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Factors Associated With Contractile Reserve
Contractile reserve by DSE was present in 24 patients and absent in 11 patients. There were no significant differences in heart rate, systolic pressure, or left ventricular end-diastolic dimension between patients with and without contractile reserve, suggesting that the presence or absence of contractile reserve was not due to differences in heart rate, afterload, or preload. Left ventricular ejection fraction and ß-blocker use were similar in patients with and without contractile reserve. The number of coronary arteries with 90% diameter stenosis was not different in patients with and without contractile reserve. In contrast, the perfusion score by MCE was 0.91±0.15 in patients with contractile reserve compared with 0.51±0.36 in those without contractile reserve (P<.0001).

Effect of Revascularization on Myocardial Functional Recovery
Revascularization was performed in 23 patients on the advice of their referring physicians. Coronary angioplasty was performed in 10 patients and was considered successful (residual stenosis <50%) when there was no clinical evidence of reocclusion between the time of angioplasty and the follow-up echocardiography. Coronary artery bypass surgery was performed in 13 patients, all of whom had multivessel disease. In these 23 patients, 155 segments were thought to have successful revascularization.

Resting wall motion score index and ejection fraction were similar in patients who were and were not revascularized (Table 1). However, revascularization led to significant improvement in regional wall motion score and ejection fraction. Revascularized segments were more likely to exhibit functional improvement at follow-up than nonrevascularized segments. Overall, 95 of 155 revascularized segments (61%) improved at follow-up compared with 3 of 46 nonrevascularized segments (7%; ²=40.4, P<.0001). Moreover, 77 of 95 revascularized hypokinetic segments (81%) showed improved systolic thickening on follow-up compared with only 2 of 27 hypokinetic segments in patients who were not revascularized (7%; ²=46.8, P<.0001). In contrast, only 18 of 57 revascularized akinetic segments (32%) exhibited improved systolic thickening on follow-up compared with only 1 of 11 akinetic segments in patients who were not revascularized (9%; ²=1.66, P=NS). Thus, although the majority of hypokinetic segments improved with revascularization, there was only an intermediate probability that akinetic segments would have functional recovery after revascularization (²=35.1, P<.0001). None of the 10 dyskinetic segments improved after revascularization.

View this table: [in this window] [in a new window]   Table 1. Comparison of DSE Parameters in Revascularized and Nonrevascularized Patients

Comparison of DSE and MCE
There were 238 dysfunctional myocardial segments in the 35 patients studied: 146 were hypokinetic, 82 were akinetic, and 10 were dyskinetic. Table 2 compares perfusion by MCE to contractile reserve by DSE. Dysfunctional segments were more likely to exhibit perfusion (79%) than contractile reserve (67%; ²=23.8, P<.0001). Nevertheless, the two techniques were concordant in 201 segments (84%), so perfusion and contractile reserve were either both present or both absent. Perfusion was almost always present in hypokinetic segments (97%) and was significantly more prevalent than contractile reserve (91%; ²=7.1, P<.01). DSE and MCE were concordant in 137 hypokinetic segments (94%). In contrast, perfusion was present in only 56% of akinetic segments, whereas contractile reserve was seen in only 33% (²=12.0, P<.001). MCE and DSE were concordant in 55 akinetic segments (67%). Of the 10 dyskinetic segments, 1 exhibited perfusion and 0 had contractile reserve. The concordance between DSE and MCE in dyskinetic segments was 90%.

View this table: [in this window] [in a new window]   Table 2. Comparison of Perfusion by MCE and Contractile Reserve DSE in Abnormal Myocardial Segments

Prediction of Functional Recovery by MCE and DSE
Of the 95 revascularized hypokinetic segments, 93 (98%) showed myocardial perfusion by MCE and 88 (93%) had contractile reserve by DSE (P=NS). Functional recovery occurred in 77 of 93 perfused segments (83%) and did not occur in the 2 segments that did not show perfusion by MCE (²=4.22, P=.04). Functional recovery took place in 77 of 88 hypokinetic segments with contractile reserve (88%) and in 2 of 7 segments that did not have contractile reserve (29%; ²=10.1, P=.0014).

In the 57 revascularized akinetic segments, 29 (51%) had evidence of perfusion and 20 (35%) had contractile reserve (7 patients). Functional recovery was present in 16 of 29 perfused akinetic segments (55%) and 2 of 28 nonperfused segments (7%; ²=13.1, P=.0003). Functional recovery occurred in 17 of 20 segments (85%) with contractile reserve by DSE and 1 of 37 segments (3%) without contractile reserve (²=37.0, P<.0001).

Table 3 gives the sensitivities, specificities, and positive and negative predictive values of MCE and low-dose DSE for predicting functional recovery after revascularization. There were no significant differences between the two methods in predicting functional recovery of hypokinetic segments. In akinetic segments, however, contractile reserve by DSE had a better specificity (92% versus 67%, P<.02) and positive predictive value (85% versus 55%, P<.02) than perfusion by MCE.

View this table: [in this window] [in a new window]   Table 3. Sensitivity, Specificity, and Predictive Values of Perfusion by MCE and Contractile Reserve by DSE in Predicting Functional Recovery After Revascularization

	Discussion

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It is well known that coronary revascularization may lead to left ventricular functional recovery in some patients with chronic ischemic heart disease and regional wall motion abnormalities (hibernating myocardium).^{23 24 25 26} Several studies have shown that contractile reserve by DSE predicts such functional recovery^{4 5 6 7} ; however, the value of MCE in chronic ischemic heart disease has not yet been established. In this study, hypokinetic segments generally manifested both contractile reserve by DSE and perfusion by MCE and were more likely to exhibit functional recovery after revascularization than akinetic segments (81% versus 32%, respectively). In contrast, akinetic segments often demonstrated perfusion but not contractile reserve. Such segments generally did not recover function after revascularization. Thus, the major new finding of this study is that contractile reserve by DSE is more specific and has a better positive predictive value than perfusion by MCE in predicting left ventricular functional recovery in akinetic segments after revascularization in patients with chronic ischemic heart disease.

It is not surprising that most hypokinetic segments manifested both contractile reserve and perfusion. A previous study showed that virtually all hypokinetic segments identified by magnetic resonance imaging had metabolic evidence of viability by positron emission tomography.²⁷ Moreover, hypokinetic segments with metabolic viability shown by positron emission tomography²⁸ or contractile reserve during nitroglycerin ventriculography¹⁹ have minimal fibrosis on transmural myocardial biopsies. Thus, the fact that most hypokinetic segments improved after revascularization in chronic ischemic heart disease is consistent with previous metabolic and histological data.

In contrast, akinetic segments have an intermediate probability of functional recovery with revascularization, as shown in this study and others.^{4 29 30} Thus, a clinical test to predict functional recovery is most relevant in akinetic segments. This study demonstrates that in akinetic segments myocardial perfusion is often present in the absence of contractile reserve. The presence of myocardial perfusion in regions that fail to show improved contractile function after revascularization is not unexpected. Using transmural myocardial biopsies obtained during bypass surgery, Vanoverschelde et al³¹ demonstrated severe ultrastructural changes with loss of contractile elements in myocardial regions with evidence of perfusion and metabolic activity by positron emission tomography. Bodenheimer et al¹⁹ showed that akinetic segments lacking contractile reserve in response to nitroglycerin contain islands of viable myocytes surrounded by extensive fibrosis. Thus, in chronic ischemic heart disease, extensive fibrosis may preclude contractile reserve despite preserved myocardial perfusion and metabolic activity by positron emission tomography.³²

Myocardial Viability
The term "myocardial viability" is widely used in current medical literature. Strictly speaking, it implies the absence of myocardial necrosis. Unfortunately, necrotic and viable cells may coexist within a given myocardial segment.^{19 31 32} Moreover, viable cells other than myocytes (ie, fibroblasts) may predominate in a given segment.¹⁹ Thus, as shown in this study, there is a fundamental difference between viability expressed as microvascular integrity by MCE and viability expressed as myocardial functional integrity by DSE. Myocardial segments that exhibit microvascular integrity may not show contractile reserve for several reasons. First, unrecognized myocardial infarction is common in patients with chronic ischemic heart disease.³³ Because the majority of wall thickening occurs in the subendocardial layer, subendocardial necrosis may result in resting akinesis and loss of contractile reserve despite normal perfusion of the noninfarcted subepicardium. Second, myocardial hypertrophy and fibrosis in patients with chronic coronary artery disease may be due to other causes (ie, hypertension, diabetes, or alcohol abuse) that result in contractile dysfunction that is disproportionate to perfusion abnormalities. Finally, as noted previously, transmural biopsies of patients with coronary artery disease and impaired left ventricular systolic function often show islands of viable myocardium surrounded by fibrotic or necrotic tissue.^{19 31 32} Thus, it seems likely that contractile reserve requires a critical mass of functional myocytes within a given segment, whereas perfusion can be detected in regions in which functional integrity is precluded by an insufficient number of myocytes, structural disorientation of myocytes, or dysfunctional myocytes. We chose to compare perfusion and contractile reserve in predicting recovery of contractile function after coronary revascularization because the latter is an important clinical goal.^{2 23 24 25 26} However, it should be recognized that microvascular integrity may be important in other ways such as protection against progressive ventricular dilation (remodeling) and arrhythmias.

MCE uses echogenic microbubbles that approximate the size of red blood cells and opacify the myocardium on 2D echocardiography after intracoronary injection. Myocardial opacification by MCE occurs at flow rates down to about 15% of normal.^{34 35 36} Thus, MCE is very sensitive in assessing myocardial perfusion. Assessment of myocardial perfusion by MCE currently requires intracoronary injection of microbubbles during heart catheterization. However, a recent study in a dog model of acute ischemia/reperfusion shows that myocardial risk area and infarct size can be assessed accurately by MCE using peripheral intravenous injection of a fluorocarbon emulsion that crosses the pulmonary circulation and opacifies the myocardium.³⁷ Such an agent would allow MCE and DSE to be done simultaneously, thereby taking advantage of the complementary nature of these techniques. In our study, when perfusion and contractile reserve were both absent, revascularization failed to result in functional recovery in 29 of 30 cases (97%). Conversely, when both perfusion and contractile reserve were present, revascularization led to functional recovery in 91 of 105 cases (87%). The ability to perform MCE and DSE simultaneously could allow visualization of endocardial borders in patients with technically marginal echocardiograms, thereby facilitating the identification of contractile reserve.

Study Limitations
The number of patients was relatively small, and revascularization was not performed in all patients in whom DSE and MCE were discordant. Moreover, we did not compare DSE or MCE with other accepted methods of assessing myocardial viability. However, DSE has been shown to compare favorably with both thallium-201 scintigraphy³⁰ and positron emission tomography³⁸ in chronic ischemic heart disease.

It has been proposed that in the setting of a severe coronary stenosis, dobutamine may provoke ischemia rather than contractile reserve.²⁰ In dogs with profoundly reduced coronary flow, however, low-dose dobutamine infusion improved dP/dt and left ventricular shortening in the absence of tachycardia.³⁹ The patients in this study did not develop tachycardia during low-dose DSE. Moreover, in this study and others,^{4 5 6 7} contractile reserve by DSE predicted functional recovery in patients with critical coronary stenoses undergoing revascularization. It is possible that in chronic ischemic heart disease the presence of collaterals or unknown myocellular adaptive responses may preserve the capability for contractile reserve even in the setting of a severe stenosis.

Conclusions
Contractile reserve by DSE and myocardial perfusion by MCE accurately predict recovery of regional left ventricular hypokinesis after revascularization. In akinetic segments, however, contractile reserve by DSE is superior to myocardial perfusion by MCE in predicting functional recovery. This is consistent with previous histological studies that show preservation of the microcirculation despite extensive myocardial fibrosis in chronic ischemic heart disease.

	Footnotes

 
Guest Editor for this article was Robert A. O'Rourke, MD, University of Texas Health Science Center, San Antonio.

Received August 31, 1994; revision received July 24, 1995; accepted August 15, 1995.

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