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Circulation. 1995;92:3436-3444

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(Circulation. 1995;92:3436-3444.)
© 1995 American Heart Association, Inc.

Articles

Quantitative Relation Between Myocardial Viability and Improvement in Heart Failure Symptoms After Revascularization in Patients With Ischemic Cardiomyopathy

Marcelo F. Di Carli, MD; Farbod Asgarzadie, BA; Heinrich R. Schelbert, MD; Richard C. Brunken, MD; Hillel Laks, MD; Michael E. Phelps, PhD; Jamshid Maddahi, MD

From the Division of Nuclear Medicine, Department of Medical and Molecular Pharmacology, Laboratory of Nuclear Medicine, Laboratory of Biomedical and Environmental Sciences; the Crump Institute for Biological Imaging; and the Division of Cardiothoracic Surgery (H.L.), Department of Surgery, University of California at Los Angeles, School of Medicine.

Correspondence to Marcelo F. Di Carli, MD, Positron Emission Tomography Center, Children's Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201-2196. E-mail: mdicarli@pet.wayne.edu.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background Studies of patients with coronary artery disease and left ventricular dysfunction have shown that preoperative quantification of myocardial viability may be clinically useful to identify those patients who will benefit most from revascularization both functionally and prognostically. However, the relation between preoperative extent of viability and change in heart failure symptoms has not been documented carefully. We assessed the relation between the magnitude of improvement in heart failure symptoms after coronary artery bypass surgery (CABG) and the extent of myocardial viability as assessed by use of quantitative analysis of preoperative positron emission tomography (PET) images.

Methods and Results We studied 36 patients with ischemic cardiomyopathy (mean left ventricular ejection fraction, 28±6%) undergoing CABG. Preoperative extent and severity of perfusion abnormalities and myocardial viability (flow-metabolism mismatch) were assessed by use of quantitative analysis of PET images with 13N ammonia and fluorine-18-deoxyglucose. Each patient's functional status was determined before and after CABG by use of a Specific Activity Scale. Mean perfusion defect size and severity were 63±13% and 33±12%, respectively. Total extent of a PET mismatch correlated linearly and significantly with percent improvement in functional status after CABG (r=.87, P<.0001). A blood flow–metabolism mismatch >=18% was associated with a sensitivity of 76% and a specificity of 78% for predicting a change in functional status after revascularization. Patients with large mismatches (>=18%) achieved a significantly higher functional status compared with those with minimal or no PET mismatch (<5%) (5.7±0.8 versus 4.9±0.7 metabolic equivalents, P=.009). This resulted in an improvement of 107% in patients with large mismatches compared with only 34% in patients with minimal or no PET mismatch.

Conclusions In patients with ischemic cardiomyopathy, the magnitude of improvement in heart failure symptoms after CABG is related to the preoperative extent and magnitude of myocardial viability as assessed by use of PET imaging. Patients with large perfusion-metabolism mismatches exhibit the greatest clinical benefit after CABG.


Key Words: cardiomyopathy • myocardium • revascularization • tomography


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Symptomatic left ventricular dysfunction is associated with frequent hospitalizations and poor survival in patients with coronary artery disease. Previous studies1 2 indicate that myocardial revascularization in selected patients improves survival and may also improve heart failure symptoms. Alleviation of heart failure symptoms is of utmost importance in deciding the appropriate treatment strategy. Indeed, it is the primary reason that patients with left ventricular dysfunction seek medical attention. However, because surgical mortality in these patients is high, preoperative assessment of the amount of myocardial viability is crucial to identify patients who will benefit most from revascularization both prognostically and symptomatically.

PET with FDG has been used successfully to distinguish viable from infarcted myocardium.3 4 Increased glucose uptake in segments with reduced blood flow (flow-metabolism mismatch) indicates the presence of viable myocardium. A flow-metabolism mismatch identifies myocardium with a potentially reversible impairment of contractile function, average literature positive and negative predictive accuracies being 83% and 84%, respectively.5 6 7 8 9 10 Studies with either rest11 12 13 or exercise14 15 16 201Tl imaging protocols also demonstrated that they can provide clinically relevant information with respect to myocardial viability in patients with regional or global systolic dysfunction. In addition, previous clinical data acquired by use of resting 201Tl scintigraphy11 13 or metabolic imaging5 17 indicate that improvement in global LV systolic function is related to the anatomic extent of myocardial viability as assessed preoperatively. However, a quantitative correlation between the measured extent of viable myocardium and the change in heart failure symptoms has not been established.

The present study tested the hypothesis that improvement in heart failure symptoms after CABG in patients with ischemic cardiomyopathy would be related to the extent, magnitude, and location of viable myocardium, as determined by quantitative analysis of preoperative PET images.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Study Group
Forty-one consecutive patients with coronary artery disease and ischemic cardiomyopathy (mean LV ejection fraction, 27±7%; range, 15% to 42%) referred for assessment of myocardial viability and subsequent CABG were enrolled in the study. Global LV ejection fraction was obtained from contrast left ventriculography in 33 patients and echocardiography in 8 patients. Four patients died during the in-hospital postoperative period and 1 patient died suddenly before follow-up. The remaining 36 patients constitute the study cohort. Twenty-six of these 36 patients were part of a previous study in which we reported that patients with blood flow–metabolism PET mismatches have a survival benefit if they are revascularized.18 In the present study, we focused the analysis on the relation between the extent, intensity, and location of PET mismatches and the magnitude of heart failure symptom improvement after CABG. There were 31 men and 5 women, 49 to 81 years of age (mean, 66±8 years). Twenty-eight patients (78%) had a history of previous Q-wave myocardial infarction. None of the individuals had recent clinical infarctions. Nine patients (25%) had previous CABG. Thirty patients had >70% luminal narrowing of all three major epicardial coronary arteries, and the remaining 6 had two-vessel disease. The mean LV diastolic dimension by echocardiography was 64±7 mm (range, 50 to 75 mm).

Assessment of Functional Status
Functional status of patients was assessed before and after CABG (mean follow-up, 25±14 months) by use of a Specific Activity Scale previously described and validated by Goldman et al.19 The Specific Activity Scale is based on approximations of the metabolic costs of a variety of personal care, housework, occupational, and recreational activities.20 21 Goldman et al19 demonstrated a 68% agreement between the Specific Activity Scale system and exercise treadmill performance, which was significantly higher than that of the Canadian Cardiovascular Society system (59%) and New York Heart Association estimates (51%). Furthermore, in the same study,19 the Specific Activity Scale had a reproducibility of 73%. This was similar to the reproducibility observed with the Canadian Cardiovascular Society system but significantly higher than that obtained by use of the New York Heart Association criteria. Using a previously validated interview protocol,19 we determined whether specific activities were performed and, in particular, what symptoms were provoked by them. A patient was considered able to perform a given number of METS if the appropriate activity was performed to completion, with or without symptoms. Conversely, if the activity was not performed because of symptoms, fear of symptoms, or habit, and if no other activity of approximately equal or higher metabolic cost was performed, the patient was considered unable to attain the given metabolic load. Patients were placed into a Specific Activity Scale functional class according to the metabolic load associated with the most strenuous activity performed before and after myocardial revascularization.19 In each patient, the functional status before and after CABG was determined by interviews conducted either personally or by telephone contact with the patient by an investigator who was blinded to the PET data.

Positron Emission Tomography
Resting regional myocardial perfusion and glucose uptake were assessed with 13N-ammonia, FDG, and PET. Imaging was performed on a whole-body positron emission tomograph (model 931-108, Siemens-Computer Technology, Inc). Studies were acquired in the glucose-loaded state, after oral administration of 50 g glucose. A 20-minute transmission scan was recorded for correction of photon attenuation. Fifteen transaxial emission images were then obtained for 20 minutes, beginning 7 minutes after an intravenous injection of 20 mCi of 13N-ammonia. Then, 10 mCi of FDG was injected intravenously and, after 30 minutes (to allow for decay of 13N-ammonia and for metabolic trapping of FDG in the myocardium) another set of transaxial images was acquired for 20 minutes.

Image Analysis
Transaxial images were reoriented on a Macintosh IIci personal workstation (Apple Computer Inc) into six contiguous short-axis and three modified apical slices of the LV.22 23 Analysis of relative myocardial perfusion, glucose uptake, and their relation was performed by use of a method described previously in detail.22 Briefly, volume-weighted polar maps were generated from circumferential profiles of the maximal myocardial count activity obtained along 60 equally spaced radii generated from the center of the LV cavity. The circumferential profiles were constrained by elliptical regions of interest encompassing the LV myocardium on each of the six short-axis slices. The "raw" 13N-ammonia and FDG polar maps were normalized to myocardial regions with the highest 13N concentration. Extent of a perfusion abnormality was computed as the number of pixels with relative myocardial 13N-ammonia activity below the lower limit of normal (mean-2 SD) in the entire LV. Severity of a perfusion abnormality was assessed by computing the average percent reduction of the relative myocardial 13N-ammonia uptake below the lower limit of normal (mean-2 SD). To identify myocardial regions with increases in glucose uptake relative to blood flow, the FDG polar maps were then compared with the 13N-ammonia maps, resulting in a difference polar map. These difference maps were subsequently compared with a database of normals. Depending on the FDG uptake, hypoperfused regions were categorized into PET mismatch and PET match. A concordant reduction in FDG and 13N activities was defined as a flow-metabolism match, whereas an FDG/13N difference of >2 SD above the normal mean was defined as a flow-metabolism mismatch. Scintigraphic extent of a PET mismatch was expressed as percent of the entire LV and of each coronary vascular territory (LAD, left circumflex artery, and right coronary artery territories). Average severity of a PET mismatch (FDG/13N difference) in the entire LV myocardium and in each vascular territory was expressed as the average number of SD above the normal mean.

Statistical Analysis
All continuous data are presented as mean±SD. Survival probability of the entire patient population was estimated by use of the Kaplan-Meier method. Paired comparisons between preoperative and follow-up data were performed with Student's t test or Fisher's exact test as appropriate. Multiple groups were compared with a single-factor ANOVA and the F test. For significant F values, the Tukey test (with correction for group size) was used to identify differences between pairs of groups. Linear regression analysis was performed by least-squares fitting. The effect of covariates on heart failure symptom improvement was assessed by use of multiple logistic regression analysis.24 ROC curves were derived according to the method described by Metz.25 A probability of less than .05 was considered significant.


*    Results
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 up arrowAbstract
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 up arrowMethods
*Results
down arrowDiscussion
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Coronary Artery Bypass Grafting
All patients underwent complete revascularization that was based on the anatomic distribution of coronary stenosis and review of operative reports. The mean number of grafts per patient was 4±0.8. In addition, no patient had mitral valve replacement or aneurysmectomy. Four of the 41 patients died during the in-hospital postoperative period (30-day operative mortality of 10%). Two of these 4 patients had ECG changes compatible with a postoperative infarction. All postoperative deaths were primarily due to worsening of heart failure. In patients who died within the 30-day postoperative period, preoperative PET imaging demonstrated flow-metabolism mismatches extending from 29% to 54% of the LV in 3 of 4 patients and a predominantly matched defect in 1 patient. In addition, 1 patient died suddenly before follow-up (20 months after CABG). In this patient, preoperative PET imaging demonstrated a flow-metabolism mismatch of 22%. The Kaplan-Meier estimate of the 2-year survival probability for the entire study group was 87%. The remaining 36 patients were free from ischemic events (nonfatal myocardial infarction or unstable angina); however, all patients had some degree of functional limitation during follow-up, as assessed by the Specific Activity Scale.

Relation Between Preoperative Symptoms and PET Imaging Findings
At the time of hospitalization leading directly to CABG, all patients had symptoms of congestive heart failure. Thirty-two patients were in class III and 4 patients were in class IV heart failure according to the Specific Activity Scale classification.19 Thirteen patients also had angina pectoris. Thirty-four patients (94%) were receiving angiotensin-converting enzyme inhibitors, 30 patients (83%) furosemide, 28 patients (78%) digoxin, 20 patients (56%) oral nitrates, 12 patients (33%) calcium channel blockers, and 5 patients (14%) ß-blockers.

Preoperative findings in the 36 patients with LV dysfunction are summarized in Table 1Down. For the entire study group, the mean perfusion defect size was 63±13%, whereas the mean perfusion defect severity was 33±12%. Similarly, the extent of flow-metabolism match was 41±23%, indicating extensive areas of myocardial infarction. However, despite the presence of class III or class IV (Table 1Down, patients 4, 9, 31, and 35) heart failure on the Specific Activity Scale, preoperative PET imaging demonstrated significant areas of flow-metabolism mismatch averaging 23±22% of the LV, suggesting that advanced heart failure symptoms do not exclude the presence of significant myocardial viability.


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  		Table 1. Clinical and Scintigraphic Findings of 36 Patients With LV Dysfunction

Average extent and mean severity of preoperative resting perfusion defects were similar in patients with and without angina (Table 1Up). Of note, the extent of flow-metabolism mismatch in the 13 patients with angina did not differ from that of the 23 patients without angina (15±22% versus 27±21%, P=NS). Thus, the presence of angina was not associated with more extensive areas of viable but hibernating myocardium.

Correlation Between Postoperative Specific Activity Scale and Exercise Tolerance
Fig 1Down depicts the correlation between postoperative Specific Activity Scale classification and exercise capacity in 15 patients who performed treadmill exercises concurrently with the interviews. All patients were clinically stable between both assessments, and there were no changes in heart failure medications. There was a significant correlation between the METS of activity estimated by use of the Specific Activity Scale and those calculated by use of exercise treadmill data (y=2.3+0.5x, r=.73, SEE=1.02, P=.002).



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  		Figure 1. Scatterplot showing the relation between METS of activity estimated from treadmill data (abscissa) and Specific Activity Scale (ordinate). The relation was y=2.32+0.57x, r=.73, SEE=1.02, P<.001.

Preoperative PET Findings and Change in Heart Failure Symptoms
Univariate analysis. Results of univariate analysis relating the extent and severity of a perfusion defect, the extent and severity as well as the product of the extent and severity (mismatch index) of a PET mismatch, LV size, LV ejection fraction, and age are given in Table 2Down. Total scintigraphic extent of a PET mismatch was related linearly to percent improvement in functional status after CABG (r=.87, P<.0001, Fig 2Down); patients with larger mismatches had the greatest improvement in symptoms of heart failure. Furthermore, the anatomic location of a PET mismatch also correlated with the change in functional status after CABG. The extent of a PET mismatch in the territory of the LAD (r=.61, P=.0001, Table 2Down) and the severity of a PET mismatch in the territory of the right coronary artery (r=.62, P=.0001, Table 2Down) showed the highest correlations with the change in functional status after CABG.


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  		Table 2. Univariate Predictors of the Change in Heart Failure Symptoms



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  		Figure 2. Scatterplot showing the relation between the anatomic extent of blood flow–metabolism mismatches, expressed as percent of the LV myocardium, and the change in functional status after CABG, expressed as percent improvement from baseline. The relation was y=24.27+2.04x, r=.87, SEE=10.8, P<.001.

Multivariate analysis. To determine the independent contribution of each variable for predicting a change in functional status after CABG, a multivariate analysis that used a stepwise procedure was performed. Results indicated that total extent of a PET mismatch (F=40.2, P=.0001) and age (F=4.1, P=.05) were the only two independent predictors of the change in functional status after CABG. Of note, neither the severity of a mismatch nor the mismatch index (product of its extent and severity) added information once the extent of mismatch was entered into the model. The regression equation for the predicted improvement in METS was -0.86+0.0356 · total extent of PET mismatch+0.0308 · age.

To further correlate the anatomic location of mismatches on PET imaging with the degree of heart failure symptom improvement after CABG, the extent and intensity of a mismatch and their interaction in the three major coronary territories (LAD, left circumflex artery, and right coronary artery) were investigated in a separate multivariate model. Results indicated that the combination of the extent and severity of a flow-metabolism mismatch in the LAD territory (F=22.39, P=.0001) and the severity of a flow-metabolism mismatch in the right coronary artery territory (F=12.04, P=.002) were the only two independent predictors of change in heart failure symptoms after CABG.

Flow-Metabolism PET Mismatch for Predicting Improvement in Symptoms of Heart Failure
As shown in Fig 2Up, the greatest improvement in heart failure symptoms occurred in patients with the largest mismatches on quantitative analysis of the blood flow and glucose metabolism PET images. To determine the total extent of a PET mismatch that best predicted an improvement in functional class of at least one grade, a ROC analysis was performed. On the basis of this analysis, the optimum operating point on the curve corresponded to or was greater than an 18% PET mismatch on quantitative analysis. This operating point was associated with a sensitivity of 76% and a specificity of 78% for predicting an improvement in functional class of at least one grade (Fig 3Down).



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  		Figure 3. ROC curve demonstrating the sensitivity-specificity pairs for different anatomic extent of perfusion-metabolism PET mismatches. The arrow points at the operating point associated with the best trade-off between sensitivity (76%) and specificity (78%). The area under the fitted curve was 82%.

Accordingly, patients were divided into three groups. Group A consisted of 11 patients with minimal (<5%) or no PET mismatch before CABG (mean, 1.5±1.4%). Group B consisted of 8 patients with modest preoperative mismatches involving between 5% and 17% of the LV (mean, 13±4%). Group C comprised 17 patients with large mismatches involving >=18% of the LV myocardium (mean, 41±19%). Fig 4Down demonstrates that all groups of patients exhibited some improvement in heart failure symptoms after CABG. Patients in group C (>=18% mismatch) achieved a modest but significantly higher functional state compared with patients in groups A and B (5.7±0.8 METS in group C versus 4.9±0.7 and 4.9±0.5 METS in groups A and B, respectively, P=.009). More importantly, the higher level of estimated METS achieved by patients in group C after CABG resulted in an average improvement of 107% (2.8±0.7 METS to 5.7±0.8 METS, P<.001, Fig 4Down). In contrast, patients without significant mismatches (<5%) or with relatively small mismatches (5% to 17%) exhibited only relatively small improvements in METS of activity after CABG of 34% and 42% compared with baseline, respectively (ANOVA, P<.001) (Fig 4Down).



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  		Figure 4. Scatterplot of changes in METS of activity after CABG (Follow-up) grouped by anatomic extent of blood flow–metabolism mismatch (ie, group A, <5%; group B, 5–17%; and group C, >=18%). Pre-op indicates preoperative.

Patients in groups A, B, and C did not differ with respect to age, prior CABG, prior myocardial infarction, LV end-diastolic diameter, LV ejection fraction, and extent of angiographic coronary disease. Furthermore, the three groups of patients did not differ with respect to medications affecting the severity of heart failure symptoms after CABG (Table 3Down). However, patients in group C had more severe symptoms of heart failure before CABG than those in groups A and B (2.8±0.7 versus 3.7±0.6 and 3.6±0.7 METS, P<.05, Fig 4Up), presumably due to the presence of larger resting perfusion abnormalities (68±9% versus 59±10% and 58±8%, P<.05) and flow-metabolism mismatches (Fig 4Up).


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  		Table 3. Medications Used Before and After CABG


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
An accurate, noninvasive determination of myocardial viability is clinically important to identify coronary artery disease patients with severely depressed LV function who will benefit most from revascularization. Previous studies indicate that preoperative imaging with myocardial perfusion, metabolism, or both can provide clinically useful information for identifying patients with coronary artery disease and LV dysfunction who will benefit from revascularization both functionally5 6 7 8 9 10 11 12 13 14 15 16 17 and prognostically.18 26 27 28 Nonetheless, the question of whether revascularization will alleviate heart failure symptoms in these patients, which is often the primary functional limitation, remains an important concern for patients and physicians. The findings in the present study suggest that the magnitude of improvement in heart failure symptoms after CABG in patients with ischemic cardiomyopathy is related to the quantitative extent of myocardial viability as determined preoperatively. Furthermore, our results also suggest that the beneficial gain in functional capacity after CABG is related to the preoperative extent, magnitude, and anatomic location of a mismatch between blood flow and metabolism on PET imaging.

Significance of a Flow-Metabolism PET Mismatch
In humans, the combined evaluation of regional myocardial blood flow and glucose metabolism allows identification of specific metabolic patterns that occur in ischemic but viable as well as in infarcted myocardium.3 4 Increased glucose uptake in segments with reduced blood flow (flow-metabolism mismatch) indicates the presence of viable myocardium. Conversely, a segmental concordant reduction in glucose utilization and blood flow reflects necrosis and scar tissue formation. Previous studies have confirmed extensively that a flow-metabolism mismatch on PET imaging successfully identifies potentially reversible myocardial dysfunction after revascularization.5 6 7 8 9 10 17 Moreover, the study by Tillisch et al5 reported a correlation between scintigraphic extent of preoperative mismatch, as assessed qualitatively, and improvement in LV ejection fraction after CABG. For example, LV ejection fraction remained unchanged in patients with one or fewer of eight anatomic segments with PET mismatch. In contrast, in patients with two or more segments with mismatch before CABG, LV ejection fraction improved from 30±11% to 45±14% 6 weeks after CABG.

Observations
Our results suggest that the preoperative extent of a flow-metabolism mismatch is correlated linearly and significantly with the magnitude of postrevascularization improvement in heart failure symptoms (Fig 2Up). Patients with large mismatches (>=18%), particularly in the LAD territory, had the greatest clinical benefit, improving their functional status by 107%, which had an important impact on the patients' quality of life. Before CABG, these patients generally were not able to shower without experiencing significant functional limitation; after CABG, they were able to walk at a rate of 4 miles per hour on level ground without significant functional limitation. This change in functional status was significantly greater than the improvement observed in patients without significant (<5%) or with relatively small preoperative flow-metabolism mismatches (5% to 17%), whose improvement was only 34% and 42%, respectively. Although the absolute level of METS achieved by patients in group C after CABG was statistically higher than that observed in patients in groups A and B, the difference was only modest. Thus, the greater improvement of patients in group C also was due to their lower preoperative functional capacity (Fig 4Up). This difference may relate to the fact that patients in group C had significantly larger areas of flow-metabolism mismatch, which likely influenced their preoperative functional state. Nonetheless, our findings suggest that patients presenting with advanced heart failure symptoms as the primary functional limitation should not be presupposed as not having clinically relevant areas of myocardial viability and thus be kept from realizing a significant symptomatic (and probably prognostic) benefit of revascularization. The selected threshold of 18% of the LV with a flow-metabolism mismatch was associated with the best trade-off between sensitivity (76%) and specificity (78%) on the ROC curve for predicting a change in functional capacity after CABG (Fig 3Up). Our results agree with previous reports1 2 demonstrating a significant improvement in heart failure symptoms after CABG in patients with severely depressed LV function. However, our findings contrast with those reported in the Coronary Artery Surgery Study (CASS).29 In the CASS registry, the percentage of patients presenting with predominant heart failure symptoms who were alive and free from severe functional limitation at 5-year follow-up was not statistically different between medical therapy and revascularization. Of note, in the CASS study, patients were not categorized according to the absence or presence of myocardial viability. The latter might explain the lack of significant improvement in symptoms of heart failure in the surgical group.

Although the overall relation between scintigraphic extent of a flow-metabolism mismatch and functional improvement after CABG was statistically significant, our data show that change in heart failure symptoms can vary appreciably among patients with comparable extent of flow-metabolism mismatch. Additionally, there was some degree of improvement in heart failure symptoms in patients without significant (<5%) or with relatively small (<18%) mismatches (Fig 4Up). Of note, use of cardiac medications affecting the severity of heart failure symptoms was similar in groups A, B, and C (Table 3Up). The reason for this variability is unknown but may relate to physiological limitations and/or limitations in some of the methodologies applied in the present study. One possible explanation for the variable postoperative change in heart failure symptoms among individual patients with large mismatches may be the lack of effective improvement in tissue perfusion despite a successful grafting of the stenotic arteries, due to the presence of target vessels with poor distal runoff. Indeed, in the study by Ragosta et al,13 there was substantial improvement in the accuracy of rest-redistribution thallium-201 scintigraphy for predicting an improvement in systolic ventricular function after adjusting for the adequacy of revascularization, as assessed by postoperative perfusion imaging. Another possible explanation for this variable response to revascularization may be that our definition of PET mismatch (preserved FDG activity in a region with reduced perfusion) may have underestimated the presence of stunned myocardium. Indeed, repetitive bouts of silent or symptomatic ischemia superimposed on hibernating myocardium or regions with normal or nearly normal blood flow at rest, which went undetected by our definition of PET mismatch, may have led to myocardial stunning with further impairment of contractile function and worsened heart failure.30 Thus, improvement in ventricular function due to stunning may have contributed to the variable improvement of heart failure symptoms among patients with comparable mismatches and to the observed functional improvement in patients without significant or with relatively small mismatches. A third possible explanation is that improvement in LV diastolic function also may have contributed to the observed interindividual variability in functional status after CABG among patients with comparable extent of flow-metabolism mismatches. LV diastolic function is markedly impaired in chronic heart failure31 32 and has been shown to improve after successful myocardial revascularization.33 34 35 In addition, improvement in LV diastolic function, systolic function due to stunning, or more likely a combination of both may account for the improvement in heart failure symptoms observed in patients with relatively small or no mismatches before CABG.

Unlike previous studies, which have concentrated on the functional outcome of hibernating myocardial regions after revascularization,5 6 7 8 9 10 11 12 13 15 16 17 the present study did not include a systematic assessment of LV function after CABG. Rather, the present study focused on the relation between myocardial viability as assessed preoperatively by FDG imaging and the postoperative change in heart failure symptoms by use of a readily accessible, valid, and reproducible clinical scale. Nevertheless, the linear relation between the change in functional status after CABG and the scintigraphic extent of a flow-metabolism mismatch on FDG imaging suggests an improvement in LV function as a possible mechanism. This hypothesis is supported by previous observations demonstrating an improvement in ventricular function after CABG only in patients with extensive areas of flow-metabolism mismatch (approximately 20% of the LV).5 17 Further support is provided by the results of Ragosta et al,13 who demonstrated a positive and significant correlation between improvement in systolic LV function and extent of myocardial viability as determined by rest-redistribution 201Tl imaging.

In the present study, patients with heart failure and angina did not exhibit more extensive areas of viable myocardium as assessed by the flow-metabolism mismatch pattern. In fact, our data showed that the extent of perfusion-metabolism mismatches tended to be larger in patients without angina. A flow-metabolism mismatch refers to dysfunctional myocardium that, at rest, exhibits reduced blood flow but preserved metabolic activity, a pattern that many believe represents the metabolic expression of hibernating myocardium. The clinical manifestation of angina in patients with coronary artery disease and LV dysfunction reflects a transient imbalance between supply and demand in viable but not necessarily hibernating myocardial regions. Alternatively, the presence of angina in these patients may represent residual inducible ischemia in regions with prior nontransmural infarction (which will be matched on PET) or in regions with normal blood flow and metabolism at rest (which will be normal on PET). Although it is conceivable that regional blood flow in mismatched regions may worsen during stress and be manifested clinically as angina, previous observations from our laboratory36 suggest that only a fraction (49% in our experience) of mismatched segments will display such a worsening in regional perfusion during stress. Furthermore, our findings agree with those of Ragosta et al13 in patients with coronary artery disease and depressed LV function. They reported a lack of correlation between the presence of angina and improvement in global LV function after CABG. Our data also showed that advanced symptoms of heart failure did not exclude the presence of extensive areas of myocardial viability (Table 1Up). However, because only four patients were in class IV heart failure, definitive inferences regarding the relation between the severity of heart failure and the presence of viable myocardium must be limited.

Because the aim of the present study was to define the physiological relations between the response of heart failure symptoms to myocardial revascularization and the preoperative extent and magnitude of myocardial viability, no other imaging approaches were considered in the study design. For example, rest-redistribution thallium-201 scintigraphy alone,11 12 13 14 in combination with radiolabeled synthetic fatty acid imaging,37 or perhaps FDG,38 and single photon emission computed tomography have been shown to be useful in detecting clinically relevant myocardial viability. Although it seems conceivable that a similar relation between heart failure symptoms and myocardial viability could be found with different imaging modalities, this needs to be investigated further.

Study Limitations
Several potential methodological limitations might have influenced the results of the present study. First, the study population was a selected group referred for assessment of myocardial viability and subsequent CABG and not a consecutive group of patients with ischemic cardiomyopathy. The applicability of our findings to a cohort of patients with ischemic cardiomyopathy who were not considered primarily for CABG is less certain. Furthermore, due to the relatively small number of patients, especially with class IV heart failure, definitive inferences regarding the relation between the severity of heart failure symptoms and myocardial viability must be limited.

Second, the functional status of patients was assessed by use of a Specific Activity Scale rather than more objective descriptors of exercise tolerance such as treadmill exercise or estimates of oxygen consumption. However, the Specific Activity Scale used in the present study has been shown previously to be a simple, reproducible, and valid system to assess the functional status of patients when compared with treadmill exercise data, even more so than widely adopted systems such as the New York Heart Association and Canadian Cardiovascular Society classifications.19 Moreover, the significant linear correlation between postoperative functional capacity as assessed by the Specific Activity Scale and the treadmill exercise data in the present study further supports the validity of the Specific Activity Scale as a measure of the patients' functional status. Third, the present report did not include a systematic assessment of regional or global LV function after CABG. Although the observed linear relation between improvement in heart failure symptoms and quantitative extent of a flow-metabolism mismatch on FDG imaging suggests an improvement in systolic LV function as an important mechanism, the relation between systolic function and heart failure symptoms after CABG needs to be investigated further.

Conclusions
The present study demonstrates that in coronary artery disease in patients with depressed LV function, preoperative quantification of the extent and magnitude of myocardial viability is predictive of the degree of improvement in heart failure symptoms after CABG. Importantly, our results suggest that the beneficial gain in functional capacity after CABG is related to the preoperative extent of viable myocardium, magnitude of glucose uptake, and anatomic location of a flow-metabolism mismatch on PET imaging. The linear relation between the preoperative extent of viable myocardium and improvement in functional status after CABG suggests that the magnitude of functional improvement can be predicted. These findings may be clinically useful for assessing the risk-to-benefit ratio of myocardial revascularization in patients with coronary artery disease, severe LV dysfunction, and heart failure symptoms.


*    Selected Abbreviations and Acronyms
 
CABG = coronary artery bypass graft surgery
FDG = fluorine-18-fluorodeoxyglucose
LAD = left anterior descending artery
LV = left ventricle (ventricular)
METS = metabolic equivalents
PET = positron emission tomography
ROC = receiver operating characteristic


*    Acknowledgments
 
This study was supported in part by the Director of the Office of Energy Research, Office of Health and Environmental Research, Washington, DC, and NIH research grant HL-29845, Bethesda, Md. This work was completed during Dr Di Carli's tenure of a Research Fellowship Award from the American Heart Association, Los Angeles, Affiliate. The authors are indebted to Ron Sumida, Lawrence Pang, Francine Aguilar, Marc Holgan, and DerJenn Liu for their technical assistance in performing the PET studies; to Jeffrey A. Gornbein for his statistical assistance; and to Diane Martin for preparing the artwork.


*    Footnotes
 
The Laboratory of Nuclear Medicine is operated for the US Department of Energy by the University of California under contract No. DE-FC03-87ER60615.

Received January 23, 1995; revision received June 12, 1995; accepted August 1, 1995.


*    References
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*References
 

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