Reduced Oxidative Metabolic Response in Dysfunctional Myocardium with Preserved Glucose Metabolism but with Impaired Contractile Reserve

Study Population

Twenty sequential patients with old myocardial infarction were prospectively studied between May 2000 and April 2001. There were 17 men and 3 women with a mean age ± SD of 63.0 ± 8.8 y. These patients met the following criteria: (a) the presence of a Q wave infarction caused by total or subtotal occlusion of a coronary artery; (b) the presence of severe segmental dysfunction (severe hypokinesis, akinesis, or dyskinesis) on resting echocardiography; (c) the absence of unstable angina or acute myocardial infarction within the preceding 4 wk; (d) the absence of concomitant cardiopulmonary disease, severe valvular disease, or left ventricular aneurysm. Two patients (10%) were excluded from the final evaluation: 1 patient with inadequate ¹⁸F-FDG uptake due to severe diabetes, and 1 patient who did not reach the study protocol dose of 7.5 μg/kg/min dobutamine due to angina. Table 1 summarizes the clinical characteristics of the 18 patients with complete data. The mean left ventricular ejection fraction (LVEF) was 37.1% ± 16.5%. β-Adrenergic blocking agents were withdrawn at least 48 h before both the ¹¹C-acetate PET and the DSE studies. Other cardiac medications were not withheld before dobutamine stress studies to avoid myocardial ischemia. In the dysfunctional segments defined on the routine echocardiography, GM was evaluated using ¹⁸F-FDG PET and CR was evaluated using DSE. All patients underwent ¹¹C-acetate PET, ¹⁸F-FDG PET, and DSE within a period of 1 wk. ¹⁸F-FDG PET was performed on the first day and DSE was performed on the third or fifth day. ¹¹C-Acetate PET was performed on the seventh day. The study was approved by the Ethics Committee of Hokkaido University Hospital. Written informed consent was obtained from each patient.

Dobutamine Stress Test

Dobutamine was administered intravenously at a starting dose of 5 μg/kg/min for 3 min. It was then increased to a dose of 7.5 μg/kg/min as described previously (15,17). When the heart rate and blood pressure stabilized with a fluctuation of <5%, a second ¹¹C-acetate PET dynamic scan or echocardiogram was obtained. During dobutamine infusion, the 12-lead electrocardiogram and blood pressure results were recorded every minute.

¹¹C-Acetate PET Protocol

1-¹¹C-Acetate was synthesized according to the methods of Pike et al. (18).

For the resting study, the patients were studied after a 5-h fast. PET was performed using a whole-body scanner (ECAT/EXACT HR+; Siemens/CTI). Transmission images were obtained using an external ring of ⁶⁸Ga to enable correction of the emission images for photon attenuation.

After the 20-min transmission scan, 370 MBq (10 mCi) of ¹¹C-acetate were administered intravenously, and a dynamic PET acquisition was initiated (6 × 10, 4 × 15, 18 × 60 s) (15,17). Four hours after the resting study, a second dynamic scan under dobutamine infusion was performed.

¹⁸F-FDG PET Acquisition

The ¹⁸F-FDG PET studies were scheduled for the morning after an overnight fast. Images were corrected for attenuation using coefficients determined by a 20-min transmission scan. Sixty minutes after the start of the hyperinsulinemic–euglycemic clamp, 555 MBq (15 mCi) of ¹⁸F-FDG were injected. Forty minutes later, exogenous myocardial glucose utilization was determined from a 20-min static scan.

PET Data Analysis

Data analysis of the PET images was accomplished using an image analysis package (Dr. View; Asahi-Kasei) and special dedicated software. The images were iteratively reconstructed and resliced along the short axis (19). Regions of interest were defined for each of these images. The left ventricle was divided according to the 16-segment model recommended by the American Society of Echocardiography (20). These segments included the anterior, anteroseptal, septal, inferior, posterior, and lateral walls, each subdivided into the basal and midventricular portions, and the apical anterior, apical septum, apical inferior, and apical lateral regions. The same anatomic landmark (the insertion of the right ventricle into the interventricular septum) was used in all studies to optimize the image coregistration for the regions of interest in each study (¹¹C-acetate PET, ¹⁸F-FDG PET, and DSE) (21).

Regional Oxidative Metabolism

Regional oxidative metabolism was determined from the monoexponential function (k mono) fit to the linear portion of the semilogarithmic plot. The start of the curve was visually defined corresponding to when the blood-pool activity had cleared (usually 3–5 min) as previously described (22). The curve fitting was automated (17,22,23). The oxidative metabolic reserve was defined by change in the k mono with stress as follows: k mono during dobutamine infusion minus the k mono at baseline (15,16).

Regional Myocardial Perfusion

Regional myocardial perfusion was based on the early myocardial uptake of ¹¹C-acetate (14,24). The regional tracer distribution in the myocardium, 60–180 s after the administration of ¹¹C-acetate, has been shown to reflect regional perfusion in relative terms (24). Segments with reduced perfusion were defined as relative tracer uptake < 50% of the maximum uptake (1,25).

Quantitative Assessment of Segmental ¹⁸F-FDG Uptake

Quantitative assessment of segmental ¹⁸F-FDG uptake was performed as previously described (6). Preserved GM for a given segment was defined when the mean segmental ¹⁸F-FDG uptake was ≥50% of the maximal myocardial uptake taken from a region with normal wall motion (6).

DSE

Ventricular function was assessed by 2-dimensional echocardiography using a Sonos 5500 ultrasound system (Phillips Medical Systems) equipped with a 2- to 4-MHz transducer. Echocardiography was performed under resting conditions and during the last 3 min of each dobutamine infusion rate. Images were obtained in the standard parasternal long-axis and short-axis views.

Echocardiographic images were recorded digitally in quadscreen, cine loop format on magnetic optical disks using an echocardiographic image analysis system (Prism 5000; Tom Tec Imaging Systems).

Echocardiograms were read by 2 experienced investigators who were unaware of the clinical data and the results of PET. For the analysis of wall motion, the left ventricle was divided into 16 segments as previously described (20). The basal and middle thirds are divided into 6 segments for the short-axis image. Apical 2- and 4-chamber views were used to visualize the apical segments. Wall motion was assessed visually, using both endocardial motion and wall thickening, and was quantified using a 5-point scoring system: 1, normal; 2, mild hypokinesia; 3, severe hypokinesia; 4, akinesia; 5, dyskinesia. In the dysfunctional segments, improvement of segmental wall motion by at least one grade was considered significant. The interobserver and intraobserver variabilities for the wall motion score were 94% and 96%, respectively.

LVEF Assessment

LVEF was defined from available measurements for a given patient using radionuclide angiography (n = 11) or quantitative gated SPECT (n = 7) (26,27).

Subgroups

On the basis of the results of ¹⁸F-FDG PET and DSE, dysfunctional segments (grade 3, 4, or 5 on resting echocardiography) were divided into 3 groups: group A, segments with preserved CR and GM (n = 26); group B, segments without CR but with preserved GM (n = 15); and group C, segments without CR and without preserved GM (n = 41).

Statistical Analysis

All data are presented as the mean ± SD. The ¹¹C-acetate PET-derived parameters (k mono and change in k mono) were compared among the 3 groups using repeated-measures ANOVA, with the Scheffé F test applied when ANOVA results were statistically significant. A comparison of proportions was made using the χ² test or the Fisher exact probability test where appropriate. P < 0.05 was considered statistically significant.

Hemodynamics

The heart rate, systolic blood pressure, and rate · pressure product were similar for DSE and ¹¹C-acetate PET both at rest and during dobutamine infusion. The heart rate, systolic blood pressure, and rate · pressure product significantly increased during dobutamine infusion in both studies (Table 2).

Oxidative Metabolism

The resting k mono value, used as a measure of oxidative metabolism, was similar in group A (0.052 ± 0.011/min) and group B (0.051 ± 0.012/min, P = not significant). The resting k mono was lower in group C (0.040 ± 0.015/min) than that in group A (P < 0.005) or group B (P < 0.03; Fig. 1). In addition, the k mono during dobutamine infusion in group C (0.048 ± 0.020/min) was significantly lower than that in group A (0.070 ± 0.017/min, P < 0.001) and tended to be lower than that in group B (0.059 ± 0.015/min, P = 0.15; Fig. 1). There was no significant difference between group A and group B.

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FIGURE 1.

Comparison of myocardial oxidative metabolism at rest and during dobutamine (7.5 μg/kg/min) infusion. *P < 0.03; **P < 0.005; ***P < 0.001.

Change in the k mono with dobutamine (as a measure of metabolic reserve) was significantly greater for group A patients (0.018 ± 0.012) than that for group B patients (0.0075 ± 0.0096, P < 0.03) or group C patients (0.0080 ± 0.012, P < 0.005). There was no significant difference between group B and group C (Fig. 2).

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FIGURE 2.

Oxidative metabolic response to dobutamine (change in k mono). *P < 0.03; **P < 0.005.

Myocardial Perfusion

In the regions with dysfunctional myocardium, 3 of 26 segments (12%) had reduced perfusion in group A compared with 8 of 15 segments (53%) in group B (P < 0.01) and 37 of 41 segments (90.2%) in group C (P < 0.001). Reduced perfusion was more often seen in group C (90.2%) than in group B (53%) (P < 0.01) (Table 3).

Discrepancy Between Accuracy of DSE and ¹⁸F-FDG PET Findings

Although ¹⁸F-FDG imaging and DSE are considered accurate noninvasive methods for identifying viable myocardium, previous reports indicate that there are discrepancies between the 2 methods in the evaluation of myocardial viability (9–11,28). In the present study, there were 15 segments with a loss of CR in spite of preserved GM.

It has been suggested that segments with both preserved CR and GM have improved regional function earlier after revascularization. In contrast, segments without CR but with preserved GM may require a longer period before improvement in regional function becomes apparent after revascularization (29). Camici and Dutka (30) suggested that there are 2 phases of myocardial hibernation: “functional hibernation” with preserved CR and “structural hibernation” without CR in segments with preserved GM. In the present study, group A would correspond to functional hibernation and group B would correspond to structural hibernation as defined by Camici and Dutka (30).

The present data suggest that, in addition to a loss of CR, there is a reduction in the oxidative metabolic response in the structural hibernating-type myocardium. To the best of our knowledge, the oxidative metabolic response in myocardium with preserved CR and in myocardium without CR but with preserved GM has not been previously described.

Oxidative Metabolism in Hibernating Myocardium

¹¹C-Acetate PET permits the evaluation of flux through the tricarboxylic acid cycle (TCA) in mitochondria and, therefore, reflects oxidative metabolism and myocardial oxygen consumption (11). Using ¹¹C-acetate PET, oxidative metabolism has been shown to be significantly greater in hibernating myocardium than that in scar tissue (13,15,31). Budinger et al. (32) reported that the mitochondrial potential was maintained during hypoxia in dysfunctional but viable myocardium in cultured myocytes. This may account for the preserved oxidative metabolism observed in the current study.

Inotropic Response in Hibernating Myocardium

Inotropic stimulation using dobutamine increases regional myocardial blood flow and oxygen consumption (15,16,33). Therefore, myocardial contraction can improve in both normal and viable myocardium. Myocardial oxidative metabolism increases during low-dose dobutamine infusion in viable segments (15,16). Data from the current study are consistent with these previous reports. However, in the current study, the value for change in the k mono in segments without CR but with preserved GM was lower than that in segments with preserved CR and GM in spite of preserved resting oxidative metabolism.

The metabolic responses observed in this study are lower than those previously reported by Hata et al. (15). These differences may relate to a variation in the patient population. In the present study, 13 patients (72%) had multivessel disease (39% with 2-vessel disease and 33% with triple-vessel disease). Hata et al. evaluated oxidative metabolism in patients with single-vessel disease. The mean LVEF in the present study was 37.1% and was lower than that in the Hata et al. study (LVEF of the “viable” group was 45%). Our study extended the assessment of oxidative metabolic responses by comparing ¹¹C-acetate PET in segments with CR measurements using DSE as well as GM using ¹⁸F-FDG PET.

In histopathologic studies, sarcomere loss and myocardial fibrosis were observed in the segments with hibernating myocardium. The presence of sarcomere loss and fibrosis correlated inversely with functional recovery after revascularization (31,32). The degree of fibrosis is also associated with loss of CR (34). Mitochondria structure is altered. Small mitochondria and degenerative mitochondria are seen in hibernating myocardium (35,36). Although the pathophysiologic significance of mithochondrial degeneration has not been well established, the degeneration might be one possible explanation of our findings.

¹¹C-Acetate clearance from the myocardium via the TCA cycle in mitochondria has been shown to correlate with myocardial oxygen consumption (12). Decrease of the metabolic response in the segments without CR but with preserved GM may be due to the mitochondrial dysfunction including a reduction of TCA cycle activity.

Limitations

We did not assess the recovery of regional wall motion abnormalities or global function after revascularization. This study did not provide any information on the relative merits of dobutamine stimulation versus PET for predicting improvement in contractile function after revascularization. This topic is important for investigation but was not the aim of this study. The primary purpose of the present study was to examine oxidative metabolism and metabolic responses of myocardium with and without CR in the setting of preserved GM. In addition, some patients could not be revascularized; therefore, wall motion recovery data were not available. However, evaluation of wall motion recovery after revascularization is important and requires further investigation in future studies.

Although, the study population was small (n = 20), the current study demonstrated impaired metabolic response in the segments without preserved CR but with preserved GM. Large clinical trials may be required for a more comprehensive comparison of the GM, CR, and metabolic responses and their role in understanding dysfunctional myocardium and its recovery.

Previous studies reported that CR correlated with regional myocardial blood flow and flow reserve in the dysfunctional myocardium (16). The current study did not quantify flow. Therefore, stress flow and reserve could not be determined. Thus, their contribution to the blunted oxidative metabolic response was not evaluated.

In the present study, we analyzed segmental myocardial conditions. This segmental analysis is a well-established method applied in many previous studies. Viability assessment is also helpful for predicting improvement in overall patient outcome. Therefore, patient-related analysis becomes an important method to evaluate myocardial viability and should be considered in future studies.

The anatomic correlation between echocardiographic segment location, ¹¹C-acetate PET, and ¹⁸F-FDG PET segment location may not be precise. However, we used the same standard 16-segmentation model and the same anatomic landmark for the 3 studies to minimize anatomic mismatching—thus reducing misalignment among these studies (20,21).

Partial-volume effects due to differences in wall motion may affect imaging data. To address this potential limitation, we performed subsequent analysis considering the wall motion score. The mean regional wall motion score in group A was lower than that in group B (P < 0.05) and group C (P < 0.01), but there was no significant difference between group B and group C. This may have impacted the partial-volume effect. However, as all segments in all 3 groups had a regional wall motion score ≥ 3, this effect was likely small.

¹¹C-Acetate PET k mono data have a narrow range. Due to this narrow range in data, many groups have suggested several parameters, such as segmental ratio, clearance rate, normalized oxidative metabolism, and percentage increase. In the present study, we evaluated the metabolic response by change of the k mono, which was k mono during dobutamine infusion minus k mono at rest (15,16). This parameter is a relatively simple measurement to perform and reflects the metabolic response of the myocardium to dobutamine. Therefore, we adopted this parameter for the present study.

DSE was performed at baseline and during the low-dose dobutamine infusion (7.5 μg/kg/min). The ability of low-dose DSE to detect the hibernating myocardium has been reported in several studies. These studies evaluated the response of regional wall motion during the dobutamine infusion of 5–10 μg/kg/min. Afridi et al. reported that the optimal dose of dobutamine for the prediction of myocardial hibernation was 7.5 μg/kg/min (3). Therefore, we used this dose to evaluate the wall motion by the DSE. We did not evaluate the biphasic response to dobutamine, which can also be useful as a predictor for the functional recovery after revascularization (1). Evaluation of the oxidative metabolic reserve in the segments with biphasic response would also be relevant but requires further clinical studies.