Noninvasive Assessment of Myocardial Viability by Positron Emission Tomography With 11C Acetate in Patients With Old Myocardial Infarction
Usefulness of Low-Dose Dobutamine Infusion
Background When patients with severely depressed left ventricular function are treated, it is crucial to know in advance how much functional recovery is expected from coronary revascularization.
Methods and Results We compared the results of 11C acetate positron emission tomography (PET) with dobutamine infusion with changes in regional wall motion evaluated by left ventriculography in 28 patients with old Q-wave anterior myocardial infarctions. Dysfunctional but viable myocardium (group A, n=13) was separated from nonviable myocardium (group B, n=15) by echocardiographic assessments of regional wall motion before and after successful coronary revascularization. 11C acetate PET was performed to characterize normalized myocardial blood flow and oxidative metabolism (the clearance rate constant, k mono). While the baseline k monos of the infarct areas of the two groups were different with overlap, the responses to dobutamine infusion were directionally different. In addition, relative perfusion by 11C acetate PET could predict recovery of left ventricular function as well as or better than dobutamine 11C acetate kinetics. The extent of the increase in k monos of the infarct area with dobutamine infusion correlated well (P<.01) with the degree of the increase in the percentage of systolic segment shortening in the infarct area (left ventriculography) after coronary revascularization.
Conclusions 11C acetate PET with dobutamine infusion can predict not only the reversibility of dysfunctioning myocardium after coronary revascularization but also the extent of improvement of regional wall motion in patients with old Q-wave infarction.
The most important factor determining the short- and long-term survival of patients with myocardial infarction is the state of LV function. Revascularization to residual viable myocardium perfused by markedly obstructed vessels can reduce the threat to the jeopardized myocardium and improve LV function. Accordingly, accurate assessment of the presence and extent of viable yet poorly contractile myocardium and its discrimination from purely infarcted tissue are of paramount clinical importance. Myocardial viability is generally assessed with 201Tl scintigraphy. Delayed (18 to 72 hours) thallium imaging1 and a reinjection method2 have improved the detection of viable myocardium, but they cannot predict whether revascularization truly results in improvement in myocardial function. The assessment of myocardial viability with PET has provided new insights into this area. Scanning with a perfusion tracer (commonly 13N ammonia) to provide regional flow information in conjunction with a metabolic marker (18F-fluorodeoxyglucose) to demonstrate areas of altered glucose metabolism is the gold standard test of myocardial viability.3 4 It was recently reported that with use of echocardiography, the contractile response of akinetic myocardium to low-dose dobutamine infusion can accurately identify viable myocardium.5 The improvement of wall motion of the noncontractile but viable myocardium may be accompanied by increases in regional myocardial blood flow and oxidative metabolism. Accordingly, in the present study using 11C acetate PET,6 7 we evaluated regional myocardial perfusion in relative terms and oxidative metabolism of dysfunctioning myocardium at baseline and evaluated low-dose dobutamine infusion as a tool for predicting both myocardial viability and the extent of regional functional recovery after revascularization in patients with an old Q-wave infarction.
Between January 1992 and December 1994, we screened 83 patients with LV dysfunction caused by angiographically proven coronary artery disease who were referred to our institution for possible PTCA or CABG. From this group, we studied 28 patients who met the following inclusion criteria: (1) the presence of an old anterior Q-wave infarction caused by total or subtotal occlusion of the proximal left anterior descending coronary artery; (2) baseline LV ejection fraction ≤50%; (3) suitability of the culprit lesion for PTCA or CABG; and (4) no other concomitant cardiopulmonary or severe valvular disease or evidence of LV aneurysm and dyskinetic regions.
The age of the 28 patients included ranged from 43 to 73 years (mean, 62±8 years). Table 1⇓ summarizes the clinical characteristics of each patient. The decision to perform coronary angioplasty in these patients was based on the open artery concept8 regardless of the viability of the jeopardized myocardium. The study was approved by the institutional review board of Kyoto (Japan) University Hospital, and written informed consent was obtained from each patient. The procedures followed were in accordance with institutional guidelines.
Positron Emission Tomography
In the control study, each patient fasted for ≥5 hours. Approximately 370 MBq (10 mCi) 11C acetate was administered at rest, and serial dynamic PET scans were acquired. Four hours after the control study, dobutamine was infused intravenously, starting at 4 μg/kg body weight per minute, with increases of 2 μg·kg−1·min−1 every 2 minutes until 120% of heart rate or systolic blood pressure at rest had been reached. When these values became steady state with a fluctuation of <5%, a second dose of 11C acetate was administered intravenously, and serial PET scans were acquired.
Preparation of 11C Acetate
11C acetate was synthesized according to the procedures reported by Pike et al9 with a slight modification. 11C carbon dioxide was produced from the proton bombardment of nitrogen gas by the 14N (p, a)11C reaction by use of an ultracompact cyclotron (model 325, Sumitomo) and reacted with methyl magnesium bromide purchased from Tokyo Chemical Industry Co. After acidic hydrolysis of the reaction mixture with HCl and separation of the HCl layer, the ether layer was extracted with NaOH solution. Ether elimination from the aqueous layer was followed by neutralization with HCl and filtration through a 0.22-μm Millipore filter for injection.
PET was performed with a whole-body PET camera (Positologica III or PET 3600W, Hitachi Medico Co). The Positologica III has four rings that provide 7 tomographic slices at 16-mm intervals. The intrinsic spatial resolution in the tomographic plane was 7.6-mm FWHM at the center, and the axial resolution was 12-mm FWHM.10 The PET 3600W has eight rings that provide 15 tomographic slices at 7-mm intervals; the intrinsic resolution was 4.6-mm FWHM at the center, and the axial resolution was 7-mm FWHM. The effective resolution after reconstruction was ≈12 mm in the former case and 10 mm in the latter. Each subject was positioned on the PET camera by use of the ultrasound technique. Transmission scanning was performed for accurate correction of photon attenuation. Before each study, heart rate and blood pressure were measured to estimate the cardiac workload. Immediately after intravenous administration of 370 MBq (10 mCi) 11C acetate, serial dynamic scanning was performed, collecting 20 frames of 60-second duration each for 20 minutes.
Three transverse slices were selected for analysis. We adopted three slices in which the 11C activity in the anterior wall was the lowest on the basis of visual inspection. These slices usually were located in the middle one third of the LV. Three square regions of interest (7.5×7.5 mm each) were assigned in the centers of the infarct and the remote normal contractile (noninfarct) areas. Six regional myocardial time-activity curves of the two areas (infarct and remote noninfarct areas) were generated from the serial PET images after correction of dead time and physical decay of 11C activity. With an interactive least-squares fitting technique, regional time-activity curves were fitted monoexponentially for calculating the k mono. The linear portion of the first exponential fit was selected visually from semilogarithmic plots of the clearance curve. Because the clearance of blood pool activity was rapid, the spillover activity from the blood pool to the myocardium was considered minimal and was not corrected in this study. Because the blood activity was low and unchanged after 6 minutes of the tracer administration, the monoexponential fitting was started after 6 minutes.11 The summed time-activity curves of the three square regions of interest to every two myocardial areas were used to obtain mean rate constants for these two areas in all patients.
Regional myocardial perfusion in relative terms was based on the early myocardial uptake of 11C acetate. Results of previous studies12 13 have demonstrated that the regional distribution of activity within the myocardium from 60 to 180 seconds after the administration of 11C acetate accurately reflects regional myocardial perfusion in relative terms. Consequently, this method was used to measure normalized regional myocardial blood flow in the infarct area before and after revascularization.
Echocardiographic Analysis and Assessment of Myocardial Viability
Regional wall motion was quantified with the use of echocardiography as described in previous studies.14 15 For this purpose, the LV wall was divided into eight regions (septal, anterobasal, anterior, apical, lateral, posterolateral, inferior, and inferoposterior). Wall motion of the anterior infarct area was graded according to the scoring system recommended by the American Society for Echocardiography (1=normal, 2=hypokinetic, 3=akinetic, 4=dyskinetic, and 5=aneurysmal).16 The wall motion was analyzed by two observers blinded to both the PET results and the clinical data. Myocardial segments were then defined as (1) normal, (2) dysfunctional but viable (initially dysfunctional segments [wall motion score ≥2] that subsequently exhibited an improved wall motion score of at least one full grade after revascularization), or (3) nonviable (persistently dysfunctional segments that did not exhibit functional improvement).14 15 Our 28 patients were divided into group A (those with dysfunctional but viable myocardium, n=13) and group B (those with nonviable myocardium, n=15).
Left Ventriculographic Analysis
Catheterization and Data Acquisition
All patients were referred for conventional diagnostic right ventricle and LV catheterization, together with left ventriculography and selective coronary angiography, to evaluate coronary atherosclerotic lesions and LV function. All medications were withheld for ≥24 hours before the procedure. Cardiac output was determined by the thermodilution technique. Pressures were measured under basal conditions with standard water-filled catheters. Selective coronary arteriography was performed by means of the femoral approach. Multiple projections of right and left coronary arteries were routinely obtained. After LV pressures had returned to baseline levels, LV cineangiography was performed in a 30° right anterior oblique projection with a 9-in image intensifier system. Two lead markers were placed on the image intensifier as fixed references for superimposition of the images. After the study, a 10-mm cross-hatched grid was filmed at the same distance from the x-ray tube and image intensifier, as was the LV cavity. Cardiac catheterization was repeated 106±14 days (range, 92 to 130 days) after successful coronary intervention.
The boundaries of two LV silhouettes (end diastole and end systole) were traced with a digitizer by an observer who was unaware of the data from coronary angiography. The end-diastolic frame was determined by the ECG recorded simultaneously on the cinefilm as the frame nearest the peak of the R wave. The frame of the smallest ventricular volume was taken as the end-systolic frame. The LV volumes were calculated by a modification of the formula of Kennedy et al.17 The ventricular silhouette at end systole was superimposed on the end-diastolic frame with two external reference markers.18 Thirty-six radial grids were drawn from the center of gravity of the end-diastolic silhouette to the endocardial margin. Of these 36 radial grids, 30 covered the outline of the LV cavity, which excluded the area of aortic and mitral valves. In the present study, changes in the mean value of the length of the 10 grids (Nos. 9 through 18) in the anterior segment were considered to denote the wall motion of the anterior infarct area.19 The percentage of systolic segment shortening of the anterior infarct area was also calculated with the following formula: (End-Diastolic Length−End-Systolic Length)×100/End-Diastolic Length.
Mean values and SDs were calculated. One-way ANOVA was used for comparison of intergroup differences. A paired Student's t test was used to compare observations within the same patient. ANOVA was used to compare the differences in k monos among the segments. Correlations between two variables were evaluated by least-squares linear regression analysis. A value of P<.05 was considered significant.
Data on Coronary Angiography and Revascularization Procedures
In group A (age, 61±10 years), 7% and 6% of the patients showed one- and two-vessel disease, respectively. Of the 15 patients in group B (age, 63±7 years), 12 had one-vessel disease and 3 had two-vessel disease. There were no significant differences in the extent of coronary artery disease between the two groups (Table 1⇑). Among the 13 patients with myocardial viability, 2 had well-developed collateral circulation (grade 2 CI20 ), 7 had inadequate collateral circulation (grade 1 CI), and the remaining 4 had no collaterals (grade 0 CI). Of the 15 patients without myocardial viability, only 3 had inadequate collateral circulation. The remaining 12 patients had no collateral circulation to the infarct area. The CI of group A was significantly higher than that of group B (0.8±0.7 versus 0.2±0.4, P<.01; Table 1⇑). In each group of patients, 2 underwent CABG, and the remaining 24 patients had PTCA.
Data on Cardiac Catheterization
Table 2⇓ summarizes the hemodynamics and global LV functional data before and after coronary revascularization. The baseline LV peak systolic pressure was comparable between the two groups (136±16 and 130±19 mm Hg in groups A and B, respectively). Coronary reperfusion did not cause detectable changes in either group. The baseline LV end-diastolic pressure was also comparable between the two groups (14±5 and 16±8 mm Hg in groups A and B). Coronary intervention for group A patients decreased the LV end-diastolic pressure from 14±5 to 10±3 mm Hg (P<.05), whereas in group B, the LV end-diastolic pressure remained unchanged despite the successful revascularization. The cardiac index of group A patients was increased significantly (P<.001), from 2.4±0.4 to 3.2±0.6 L·min−1·m−2, by reperfusion of the infarct-related coronary artery, whereas that of group B was not changed by reperfusion. The baseline cardiac size was comparable between the two groups (86±16 and 96±18 mL/m2 in groups A and B, respectively). The successful reperfusion resulted in a significant reduction in cardiac size in group A but not in group B. The baseline LV ejection fraction was also comparable between the two groups (45±4% and 43±5% in groups A and B). The LV ejection fraction of group A was improved from 45±4% to 62±6% (P<.001) as a result of successful revascularization but remained unchanged in group B. A significant difference was observed in the baseline percentage of systolic segment shortening of the infarct area between the two groups (10.8±5.1% versus 4.1±5.2%, P<.01). Although the percentage of systolic segment shortening in group B remained unchanged, it was significantly increased in group A to 24.2±4.9% after revascularization.
Echocardiographic Assessment of Segmental Wall Motion
Table 3⇓ summarizes the changes in average wall motion scores in the infarct areas of the two groups. Before revascularization, both groups of patients exhibited similar resting regional wall motion abnormalities (2.5±0.5 and 2.7±0.5 in groups A and B, respectively). In group A, dobutamine infusion significantly (P<.001) improved the wall motion scores to 1.6±0.4, and successful revascularization also decreased the resting wall motion scores to 1.4±0.5 (P<.001). In group B, the wall motion scores remained unchanged despite dobutamine infusion and the revascularization procedure (2.8±0.4 and 3.1±0.6, respectively).
Although the baseline k mono of the infarct region was significantly higher in group A than in group B (0.052±0.010 min−1 [COV, 18.2±6.6%] versus 0.033±0.010 min−1 [COV, 27.4±10.1%], P<.001), there was considerable overlap between the two groups. In group A, dobutamine infusion significantly increased the k mono to 0.097±0.018 min−1 (COV, 16.1±5.1%), whereas the k mono of group B was 0.030±0.011 min−1 (COV, 33.0±12.1%) during dobutamine infusion, which was not different from baseline values (Fig 1A⇓). Because the responses to dobutamine infusion were directionally different, this overlap consequently disappeared. The baseline k mono of the remote noninfarct region was significantly higher than that of the infarct region in each group (group A, 0.075±0.013 min−1 [COV, 14.3±4.7%] versus 0.052±0.010 min−1, P<.001; group B, 0.077±0.011 min−1 [COV, 12.1±3.8%] versus 0.033±0.010 min−1, P<.001). In group A, dobutamine infusion increased the k mono to 0.117±0.017 min−1 (COV, 13.1±2.8%, P<.001). Similarly, in group B the k mono was augmented to 0.113±0.014 min−1 (COV, 8.6±3.2%, P<.001; Fig 1B⇓).
Normalized Oxidative Metabolism and Normalized Blood Flow
Fig 2A⇓ demonstrates normalized oxidative metabolism at the infarct area of the two groups before and during the treatment with dobutamine. The baseline oxidative metabolism in the infarct area of group A was 70.7±15.8% of that in the remote noninfarct area. In contrast, in nonviable myocardium of group B, oxidative metabolism was 43.1±13.0% of that in the noninfarct myocardium. The difference in the baseline normalized oxidative metabolisms of the two groups was significant (P<.001), with considerable overlap. The normalized k monos in the infarct area of group A were increased significantly (P<.05), from 70.7±15.8% to 83.2±9.9%, with the administration of dobutamine, indicating that the increase in the k monos of the infarct area was more prominent than that of the remote nonischemic area. In contrast, in group B the normalized k monos were decreased significantly (P<.001), from 43.1±13.0% to 26.9±10.3%, despite treatment with dobutamine. Thus, the changes in the normalized k monos were directionally different in the two groups.
Fig 2B⇑ demonstrates the normalized blood flow in the infarct region of the two groups. The baseline normalized blood flow in the dysfunctional but viable myocardium of group A was 67.9±9.6%. In the nonviable myocardium of group B, it averaged only 32.7±5.8%. The difference in the baseline normalized blood flow between the two groups was statistically significant (P<.001) without overlap, in contrast to the baseline normalized oxidative metabolism. The normalized blood flow in the infarct area of group A was increased slightly, from 67.9±9.6% to 70.4±7.5%, with the administration of dobutamine. In contrast, in group B the normalized blood flow was decreased significantly (P<.001), from 32.7±5.8% to 21.1±5.3%, despite treatment with dobutamine. Thus, the normalized blood flow and the kinetics of 11C acetate after dobutamine administration were different in the two groups.
Relationship of Changes in k monos to LV Regional Functional Recovery
The extent of the increases in k monos in the infarct area with dobutamine infusion correlated well (P<.01) with the degree of the increases in LV regional wall motion after the successful revascularization (Fig 3⇓).
This study described metabolic mechanisms that have not been previously reported and illustrated a new paradigm for assessing myocardial viability and providing mechanistic insights. The salient findings of the study were that in this small number of patients, the relative flow reductions were as accurate as the dobutamine k mono and the response of regional wall motion to dobutamine stimulation in identifying myocardial viability and that 11C acetate PET combined with low-dose dobutamine infusion could predict not only the reversibility of dysfunctioning myocardium after revascularization but also the extent of improvement of wall motion in patients with old Q-wave infarctions.
Data Analysis of 11C Acetate PET
In our analysis of acetate washout curves, we applied a monoexponential curve fit for the data during dobutamine and at rest. It has been demonstrated that a biexponential curve fit was superior to a monoexponential curve fit in the analysis of acetate washout curves during dobutamine infusion.6 21 In our analysis of the data during dobutamine infusion, however, the correlation coefficient was higher in a monoexponential fit than in a biexponential fit. This disparity may, at least in part, be accounted for by the different doses of dobutamine.
Baseline Oxidative Metabolism
Average baseline k monos of the remote noninfarct region in both groups of patients were higher than those of previous studies.14 15 22 The disparity may be due, at least in part, to the patient selection. Although we studied patients with extensive anterior Q-wave infarctions and baseline LV ejection fractions ≤50%, patients with non–Q-wave infarctions were included in previous studies. Therefore, the Frank-Starling mechanism may have operated more intensively in our patients with more depressed LV functions. The baseline oxidative metabolism of the infarct area of group A was significantly better than that of group B. This finding is in agreement with that of Gropler et al.14 However, there was considerable overlap in baseline k monos between the two present groups of patients.
Changes in Oxidative Metabolism by Dobutamine
In the present study, the responses of the k mono of the infarct area to dobutamine infusion were directionally different in the two groups (Fig 3⇑). In group A, the increase in the k mono of the infarct area was larger than in the k mono of the remote noninfarct area, resulting in the increase in the percent k mono. In these patients, echocardiographic study revealed that the improvement in the regional akinesis of the infarct area was comparable to that in the wall motion of the noninfarct area with dobutamine treatment. In contrast, group B did not show any detectable improvement in the wall motion of the infarct area, which was accompanied by the unchanged k mono and the decreased percent k mono of the infarct zone.
Normalized Blood Flow
A significant difference was observed in the present study in the baseline normalized blood flow of the infarct area between the two groups as well as or better than dobutamine 11C acetate kinetics (Fig 2⇑). These findings are in agreement with previous reports. Schelbert,23 in a preliminary study, noted that infarct regions with 13N ammonia uptake ≤20% of control generally exhibited reduced 18F-fluorodeoxyglucose uptake, whereas zones with 13N ammonia uptake ≥40% of control invariably exhibited 18F-fluorodeoxyglucose activity. Zones with 13N ammonia uptake between 20% and 40% of control exhibited an unpredictable pattern of 18F-fluorodeoxyglucose uptake. Gewirtz et al24 reported on absolute measurements of regional myocardial blood flow in patients with chronic myocardial infarction. In that report, myocardial viability was unlikely when basal regional myocardial blood flow was ≤0.25 mL·min−1·g−1 (about 30% of that of normal myocardium), which is almost consistent with our present results. Thus, PET measurement of regional myocardial blood flow in relative or absolute terms is helpful in identifying nonviable myocardium in these patients.
Advantages of 11C Acetate PET With Low-Dose Dobutamine Infusion Over Previous Approaches
In addition to improved accuracy in differentiating dysfunctional but viable from nonviable myocardium,25 PET with 11C acetate offers logistic advantages relative to PET with 18F-fluorodeoxyglucose. The duration of a complete tomographic study with 11C acetate is ≈70 minutes. In contrast, a viability study with 18F-fluorodeoxyglucose requires 2 hours and the use of another radiopharmaceutical (eg, 15O water, 13N ammonia, or 82rubidium) for the assessment of myocardial perfusion. The insensitivity of 11C acetate kinetics in myocardium to the pattern of substrate delivery26 is an additional advantage. However, these advantages are somewhat counterbalanced by the need for more frequent synthesis of the radiopharmaceutical (physical half-life, 20.3 and 109.9 minutes for 11C and 18F, respectively) and slightly more intensive computer processing and data analysis.
Low-dose dobutamine stress echocardiography has been proposed as a useful tool for evaluating reversible dysfunction in patients with myocardial infarction.5 However, it may be difficult to assess subtle regional wall motion improvement during low-dose dobutamine infusion, especially in quantitative terms.27 In addition, many patients are not suitable for the echocardiographic approach because of inadequate echocardiograms for visualization of all segments owing to a poor acoustic window. In contrast, the assessment of myocardial viability with 11C acetate PET with low-dose dobutamine infusion was quite successful in all patients who were candidates for coronary revascularization.
In interpreting our findings, we must take several limitations into account. First, in myocardium subjected to Q-wave infarction, our estimates with 11C acetate PET may have been impaired by limited counting statistics, partial volume averaging, and spillover effects. However, evaluation with two-dimensional echocardiography has disclosed that the wall thickness of the infarct area is well maintained in all patients in this study, indicating that the range of interest accurately reflects the information on myocardium. Second, dobutamine may induce ischemia of hibernating myocardium, especially in the presence of severe reduction of coronary flow reserve. To rule out the possibility of the occurrence of myocardial ischemia, we monitored the wall motion using echocardiography during the dobutamine test. There was no evidence of the deterioration of wall motion, which was indicative of the appearance of myocardial ischemia. Third, in our patients baseline akinetic segments may have included stunned myocardium. To rule out myocardial stunning, we prospectively performed serial echocardiographic evaluations until coronary intervention and confirmed that the segmental akinesis was persistent. Finally, because of the small number of cases representing a limited spectrum of disease, the clinical utility in comparison to other methods will require larger studies of patients with mixed scars and viability that reflect a wider spectrum of disease.
One of the most important determinants of the prognosis of patients with myocardial infarction is the functional state of the LV. Therefore, the indication for revascularization procedures such as PTCA and CABG depends primarily on the presence or absence of viable myocardium. In the treatment of patients with severely depressed LV systolic function, it is crucial to know in advance what extent of functional recovery is expected by coronary intervention, because the surgical burden is not disregarded in these patients. In the clinical setting, our new diagnostic approaches to myocardial viability would play an important role in determining the therapeutic strategy for patients with severe coronary artery disease.
11C acetate PET combined with dobutamine infusion gives important quantitative information for identifying infarct patients with improvement in LV performance after coronary artery revascularization. This information can be obtained at little cost in time and manpower compared with the usual PET method for myocardial viability assessment.
Selected Abbreviations and Acronyms
|CABG||=||coronary artery bypass graft|
|COV||=||coefficient of variation|
|k mono||=||clearance rate constant|
|LV||=||left ventricle/left ventricular|
|PET||=||positron emission tomography|
|PTCA||=||percutaneous transluminal coronary angiography|
We thank Kazuto Yamanishi, MD, for analyzing left ventriculograms; Yasuhiro Magata, MD, and the cyclotron staff for their technical assistance; and Daniel Mrozek, Naoko Takemoto, and Kumiko Tsuru for preparation of the manuscript and technical advice.
- Received February 7, 1996.
- Revision received July 29, 1996.
- Accepted July 31, 1996.
- Copyright © 1996 by American Heart Association
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