Nobuaki Hirata, MD, Yasuhisa Shimazaki, MD, Susumu Nakano, MD, Kei Sakai, MD, Shigehiko Sakaki, MD, and Hikaru Matsuda, MD, Osaka, Japan

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1 Evaluation of regional myocardial perfusion in areas of old myocardial infarction after revascularization by means of intraoperative myocardial contrast echocardiography Because myocardial revascularization to areas of old myocardial infarction brings about functional recovery to some extent to myocytes in those areas, the assessment of regional myocardial perfusion on those areas after myocardial revascularization may allow myocardial viability to be estimated. Using intraoperative myocardial contrast echocardiography by direct injection of 2 ml sonicated 5 % hmnan albumin into saphenous vein grafts, we assessed regional myocardial perfusion in 16 revascularized areas of old myocardial infarction. We estimated the myocardial viability of those areas with respect to myocardial perfusion, and we compared these results to both the improvement of regional wall motion after myocardial revascularization (increase in segmental wall thickening during systole) and relative thallium 201 activity obtained by quantitative analysis of preoperative exercise myocardial thallium 201 distribution on delayed images. The background-subtracted peak intensity of myocardial enhancement and the ratio of endocardial to epicardial intensity were determined in each revascularized area. An inverse correlation existed between peak intensity (18 ± 7) and the endocardial/ epicardial ratio (0.88 ± 0.17) (r = -0.63, p < 0.01). A good correlation was found between peak intensity and both the percent increase in segmental wall thickening (r = 0.73, p < 0.005) and the relative thallium 201 activity (r = 0.81, p < 0.005). These results suggested that regional myocardial perfusion after myocardial revascularization in areas of old myocardial infarction distributed better to the epicardial halves than to the endocardial halves, and that the peak intensity could be related to myocardial viability. (J THORAC CARDIOVASC SURG 1994;108: ) Nobuaki Hirata, MD, Yasuhisa Shimazaki, MD, Susumu Nakano, MD, Kei Sakai, MD, Shigehiko Sakaki, MD, and Hikaru Matsuda, MD, Osaka, Japan Indication for myocardial revascularization to areas of old myocardial infarction (OMI) remains controversial. To decide whether OMI areas should be revascularized, the surgeon must estimate myocardial viability in those areas. Myocardial revascularization to OMI areas revives From the First Department of Surgery, Osaka University Medical School, Division of Cardiac Surgery, Sakurabashi Watanabe Hospital, Osaka, Japan. Received for publication Dec. 17, Accepted for publication May 31,1994. Address for reprints: Nobuaki Hirata, MD, Division of Cardiac Surgery, Sakurabashi Watanabe Hospital, , Umeda, Kitaku, Osaka 530, Japan. Copyright 1994 by Mosby-Year Book, Inc /94 $ /1/58204 the myocytes. Accordingly, assessment of regional myocardial perfusion to those areas after revascularization may allow myocardial viability to be estimated. Recently, myocardial contrast echocardiography has allowed regional myocardial perfusion to be assessed. 1-3 We have used intraoperative myocardial contrast echocardiography to assess the effectiveness of grafting in non-om I areas as well as OMI areas. 4, 5 Regional myocardial perfusion in OMI areas was poorer than that in non-omi areas, which suggested that myocardial viability in the OMI areas might be estimated. This study, in which intraoperative myocardial contrast echocardiography was used, was designed to assess regional myocardial perfusion in OMI areas after myocardial revascularization. Retrospectively, the possibility of assessing the myocardial viability of those areas by

2 Hirata et al. The Journal of Thoracic and December 1994 ~ Area obtained myocardial enhancement o Region of interest Fig. 1. A diagram of the analysis of myocardial contrast echocardiography. Region of interest was defined as an area where myocardial enhancement was obtained. Each area was divided into two layers of epicardial and endocardial halves. myocardial contrast enhancement was evaluated in comparison with both the improvement of regional wall motion after revascularization and preoperative relative thallium 201 activity on the revascularized areas. Patients and methods Patients. We studied 16 0 MI areas revascularized with saphenous vein graft in 16 patients. The subjects included two women and 14 men, and the average age was 63 ± 7 years (mean ± standard deviation) (range 49 to 72 years). Informed consent for the procedure was obtained from all patients. The subjects comprised nine patients with anterosepta1 OMI and seven patients with inferior OMI. The preexisting OMI was defined by the existence of both abnormal Q waves on the electrocardiograms and chest pain indicating myocardial infarction. All OMI areas had wall motion abnormalities (hypokinesis or akinesis) as observed by left ventriculography and two-dimensional echocardiography. We did not treat dyskinetic areas. Preoperative coronary arteriography was carried out on all patients. The infarct-related vessels in the nine patients with anteroseptal infarctions were the left anterior descending coronary arteries, which were totally occluded with good collaterals in six and were partially occluded in three. The affected vessels in the seven patients with inferior infarctions were the right coronary arteries, which were totally occluded with good collaterals in five and partially occluded in two. These infarct-related vessels were bypassed with saphenous vein grafts (SVGs). Thirteen of the 16 patients had another vessel lesion (two-vessel diseases) and the remaining three patients had triple vessel diseases. These areas were noninfarcted and were perfused with 75% stenosed coronary arteries, but they did not have wall motion abnormalities as observed by left ventriculography and two-dimensional echocardiography and were bypassed by individual SVGs. The indication for bypass grafting in all patients was postinfarction effort angina caused by infarct-related vessels. The ischemia in the infarcted areas was proof of significant ST-T change on the electrocardiogram by bicycle ergometer test or redistribution by exercise myocardial scintigraphy. The interval between the onset of myocardial infarction and the operation was 3.4 ± 2.9 years. Coronary artery bypass grafting was performed with the use of cardiopulmonary bypass with moderate hypothermia and cold potassium cardioplegic arrest. Intraoperative myocardial contrast echocardiography. The method of intraoperative myocardial contrast echocardiography has been described previously.4 When the hemodynamic status became stable after termination of cardiopulmonary bypass (blood pressure 102 ± 12/ 58 ± 13 mm Hg; heart rate 100 ± 15 beats/ min without pacing), an epicardial crosssectional view was obtained at the papillary muscle level of the left ventricle before and after a bolus injection of 2 ml of 5% sonicated human albumin directly into the SVGs through a 24-gauge catheter. The mean size of microbubbles prepared with sonicated 5% human albumin was 4.6 ± 2.6 ~m (range 1.8 to 9.0 ~m). Echocardiographic images were recorded by videotape recorder from approximately 10 seconds before injection of the contrast agent until the contrast enhancement was no longer evident. Analysis of myocardial contrast echocardiography. The method of analysis has been described previously.4 End-diastolic echocardiographic images were used for analysis. A microprocessor-based offline echocardiographic viewing system, consisting of a personal computer and a high-speed image processor capable of digitizing echocardiographic fields in real time, was used. The system converted each two-dimensional echocardiographic image on videotape into a 512 X 512 pixel matrix image with 256 Gy levels per pixel and quantified the intensity of the echocardiographic signals in the regions of interest outlined by the operator. The region of interest was defined as an area in which myocardial enhancement was obtained by injection of the contrast agent into SVGs. The regions of interest were traced by hand, excluding the endocardium and epicardium. So that regional myocardial blood flow distribution was assessed, each area was divided into two layers of epicardial and endocardial halves, and intensities were measured for each half of each area. The background-subtracted peak intensity (i.e., peak intensity) was measured in all OMI areas. The ratio of endocardial to epicardial intensity (endocardial/ epicardial intensity ratio) was calculated. This analysis was performed by two observers. Fig. 1 presents a diagram. Assessment of regional wall motion and myocardial scintigraphy. To quantitatively assess regional wall motion in the grafted areas, we measured the percent increase in segmental wall thickening during systole on two-dimensional echocardiographic images. For this purpose, the cross-sectional view at the papillary muscle level of the left ventricle, which was the same area assessed by myocardial contrast echocardiography, was used. After the endocardium and epicardium were traced, wall thickness of the area with myocardial contrast enhancement was measured for end-systolic and end-diastolic images by means of a modified centerline method,6 and the percent increase in segmental wall thickening was calculated. This study

3 The Journal of Thoracic and Volume 108, Number 6 Hirata et al Relative Ti-201 activity (%) o Background Count of MI-Count of Background Count of Normal-Count of Background Xl 00 Fig. 2. Method for measuring relative 20lTI uptake in the short-axis view on 20lTI spectroscopy. MI, Myocardial infarction. was performed 30 minutes before the beginning of cardiopulmonary bypass and simultaneously with myocardial contrast echocardiography after termination of cardiopulmonary bypass. Myocardial 201 TI scintigraphy during exercise was performed within 1 month before the operation in all. All patients underwent symptom-limited treadmill exercise testing according to the Bruce protocol. 7 The exercise was continued until achievement of at least 85% of the maximal heart rate, chest pain, development of 1 mm of horizontal or downsloping ST depression on the electrocardiogram, or patient fatigue. Near peak exercise, 2.0 mci of 20lTI was injected intravenously and the patient continued to exercise for at least 1 minute. Myocardial imaging was obtained within 10 minutes after the injection and repeated 4 hours later. Images were obtained from 45- or 70-degree left anterior oblique projections with a gamma scintillation camera equipped with a high-resolution collimator (GCA-601E, Toshiba Corp., Tokyo, Japan). Delayed images were acquired during the same time required to record the initial images. Relative 20ln activity is the value obtained from quantitative analysis of myocardial 20ln distribution in the short-axis view, which is almost the same view as in myocardial contrast echocardiography, on the delayed image. 8-1O That is, a region of interest of a 3 X 3 matrix was established in the infarct area, a normal area, and the upper mediastinal area as the background. Relative 201 Tl activity (A) is calculated as follows: Relative A (%) = (A of infarct areas - A of the background)/ (A of normal areas - A of the background) X 100 (Fig. 2). In this study, the relative 201 Tl activity was calculated on the seven anteroseptal infarct areas in seven patients with no significant stenosis in the left circumflex artery and on the three inferior infarct regions in three patients with no significant stenosis in the left circumflex artery. Normal areas were treated as left circumflex artery areas. Reproducibility of results. The reproducibility of the peak intensity was assessed in II patients by repeated injection. No difference between the values (20 ± 7 versus 19 ± 6) was 0.~... ro... >-. iii c C1l... c cti :0... ro (,).c- C1l... ro "C... ro (,) 0 -C C C1l r = P < 0.01 peak intensity O 30 Fig. 3. A correlation (r = -0.63, P < 0.01) existed between the background-subtracted peak intensity (peak intensity) and the endocardial/epicardial intensity ratio: the greater the peak intensity of myocardial enhancement, the lower the endocardial/epicardial intensity ratio. observed, the absolute difference being 2 ± 2. The reproducibility of the endocardial/ epicardial intensity ratio was assessed in the same 11 patients by repeated injection. Again, no difference between the values (0.87 ± 0.17 versus 0.86 ± 0.15) was observed, the absolute difference being 0.03 ± The peak intensity measured by the same observer at two different times was 18 ± 7 each time (absolute difference: 2 ± 1), and that measured by two observers was 18 ± 7 and 18 ± 8 (absolute difference: 2 ± 1). The percent increase in segmental wall thickening during systole measured by the same observer at two different times was 18.0 ± 8.6 and 18.1 ± 8.2 (absolute difference: 1.2 ± 1.1), and that measured by two observers was 18.0 ± 8.6 and 17.8 ± 8.9 (absolute difference: 1.6 ± 0.5). Statistical analysis. All data are expressed as the mean ± standard deviation_ The unpaired t test was used to compare the values among groups. Correlations among groups were analyzed by means of linear regression. Results Background-subtracted peak intensity and endocardial/epicardial intensity ratio in infarct areas. An inverse correlation (r = -0.63,p < 0.01) existed between peak intensity and endocardial/ epicardial ratio in infarct areas (Fig. 3): the greater the peak intensity (8 to 30, 18 ± 7), the lower the endocardial/epicardial ratio (0.4 to 1.1, 0.88 ± 0.17). Relation between percent increase in segmental wall thickening during systole after revascularization and the background-subtracted peak intensity in infarct

4 Hirata et al. The Journal of Thoracic and December >- +-' 'Ci) c 220 c..::,t!. co 0) r = 0.73 P < >- +-' 'Ci) C 220.S..::,t!. co 0) r = 0.81 P < o % increase in segmental wall thickening Fig. 4. A correlation existed between the percent increase in segmental wall thickening during systole after revascularization and the background-subtracted peak intensity (peak intensity) (r = 0.73, P < 0.005). areas. The values of percent increase in segmental wall thickening during systole were 14.3% ± 6.5% (5% to 24%) before myocardial revascularization. A significant correlation existed between those values and wall motion analysis assessed by preoperative left ventriculography (scoring below; hypokinesis = I, severe hypokinesis = 2, akinesis = 3)(r = -0.89,p < 0.01). The values improved to 18.2% ± 8.2% after revascularization (p < 0.01). A significant correlation (r = 0.73, p < 0.005) existed between the percent increase in segmental wall thickening during systole after revascularization (5% to 33%, 18% ± 9%) and the peak intensity (8 to 30, 18 ± 7) (Fig. 4). Relation between relative 20lTI activity obtained preoperatively and background-subtracted peak intensity in infarct areas. A good correlation (n = 10, r = 0.81, p < 0.005) existed between the relative 20lTI activity (34% to 78%, 65% ± 9%) and the peak intensity (8 to 30,18 ± 7) (Fig. 5). Discussion Assessment of myocardial perfusion in old infarct areas. In the acute infarct areas during sustained coronary occlusion, myocardial contrast echocardiography was used to assess regional myocardial perfusion by disclosing echocardiographic contrast defects. I I. 12 However, a few reports have been published concerning evaluation of regional myocardial perfusion in OMI areas. Lim relative T.e activity Fig. 5. A significant correlation existed between the relative 201TI activity and the background-subtracted peak intensity (peak intensity) (r = 0.81, p < 0.005). and colleagues 13 described either contrast defects or slight echo enhancement in OMI areas. We previously showed that echo enhancement was obtained in OMI areas, but it was poorer than that in the noninfarcted areas. 6 The present study revealed that echo enhancement obtained in OMI areas distributed mainly in the epicardial halves, which suggested that myocardial damage was greater in the subendocardial halves than in the epicardial halves even in OMI areas. Keller and colleagues l4 reported that peak contrast intensity did not correlate with absolute blood flows measured with radioactive microspheres because of the variability in the concentration and rate of injection of the microbubbles during each stage of the experiment. However, a recent clinical study has shown that measurement of peak contrast intensity after intracoronary injections of contrast agents provides a relative index of the regional myocardial perfusion that allows assessment of regional coronary reserve in patients with coronary artery disease,15 Lim and colleagues l6 reported that the collateral perfusion expressed angiographic grades corresponding to the peak contrast intensity even in OMI areas. Possibility of assessment of myocardial viability with myocardial contrast echo cardiography. The regional myocardial perfusion in OMI areas was poorer than that in the noninfarcted areas in our previous study.4 Therefore, we compared our findings to those by using the usual methods, the improvement in the regional wall motion after myocardial revascularization and myocar-

5 The Journal of Thoracic and Volume 108, Number 6 Hirata et al. 1 I 2 3 dial scintigraphy performed before the operation. The property of 201 T1 to redistribute in the myocardium has led to its widespread application for the assessment of myocardial viability. I?, 18 Initial defects provide information regarding regional blood flow, whereas the subsequent filling in or reversibility of the perfusion defects has been used to differentiate viable from infarcted myocardium. 19, 20 In consequence, good correlations were found between the peak intensity of myocardial enhancement and the index of the aforementioned two usual methods, which indicated that myocardial viability may be assessable from the peak intensity measured by myocardial contrast echocardiography. We have speculated that the myocardium is viable only because the microvasculature in the OMI area was previously.developed to the point that survival of cells was ensured. Echo enhancement in OMI areas was obtained in response to myocardial viability, and myocardial viability in OMI areas was mainly in the epicardial halves. Antecedent myocardial infarction routinely has been diagnosed clinically when pathologic Q waves are noted on the electrocardiogram. Although Q waves have been associated with transmural infarction, prior pathologic studies have demonstrated that they do not reliably differentiate transmural from subendocardial infarction In the 0 MI areas, we speculate that myocardial damage existed in the epicardial halves, which had been subject to greater ischemia. We further speculate that mainly the myocytes in the endocardial halves should have been damaged if myocardial ischemia had not been greater, because endocardial halves tend to be exposed to greater ischemic damage. Myocardial contrast echocardiography enabled us to assess myocardial transmural distribution, which could not be assessed by myocardial 201TI scintigraphy. Clinical implication. In the present study, we can assess the effectiveness of myocardial revascularization to OMI areas during surgery. Moreover, the present study revealed the possibility of assessing myocardial viability with myocardial contrast echocardiography if adequate echo images are obtained. In the future, myocardial contrast echocardiography during coronary arteriography may enable the preoperative assessment of regional myocardial viability in the infarct areas, that is, the decision making affecting the indication for revascularization. Methodologic limitations of the study. Enhancement of the gray level is influenced by several factors, such as the gain setting, angle of incidence, axial and lateral resolution, the ultrasound attenuation, and the injection volume and speed of contrast agent. Therefore, measurement of the absolute myocardial blood flow has significant limitations. 24, 25 We must take into consider- ation that echo dropout is brought out because of the orientation of myocardial fibers on echocardiographic images and causes difficulty in identifying the border of enhancement, especially in the lateral wall areas. 26 We think that subendocardial hypoperfusion was not due to any technical artifacts. We 4 previously reported on noninfarcted areas after myocardial revascularization. In such noninfarcted areas, we could obtain myocardial enhancement not only in the epicardial but also in the endocardial halves. Moreover, we used sonicated albumin microbubbles, which behaved like intravascular tracers of red cell flow. 3 Conclusion. Myocardial viability may be assessable from the peak background-subtracted intensity measured by myocardial contrast echocardiography. Myocardial viability in infarct areas may be mainly in the epicardial half. REFERENCES 1. 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