¹¹C-Methionine PET of Acute Myocardial Infarction

MATERIALS AND METHODS

¹¹C-Methionine PET

¹¹C-methionine was synthesized by the reaction of ¹¹C-methyltriflate with an aqueous solution of l-homocysteine thiolactone on a Sep-Pak tC18 cartridge (Waters) followed by purification with ion exchange cartridges (9). The radiochemical purity of the ¹¹C-methionine was more than 99%, and its clinical use was approved by the Institutional Review Board.

After 6 h of fasting, the patients were intravenously injected with 370 MBq of ¹¹C-methionine. Twenty minutes after injection, PET/CT of the heart was performed with an 8-min emission scan per bed position and CT attenuation correction. The reconstruction of the PET data was the same as that used for ¹⁸F-FDG PET.

Before the patients had been examined, 3 healthy volunteers (2 men and 1 woman) were examined to determine the optimal timing of myocardial imaging after ¹¹C-methionine injection; dynamic data was acquired for up to 60 min after ¹¹C-methionine injection, and PET images of ¹¹C-methionine uptake in normal myocardium were thus obtained (Fig. 1A). In the normal myocardium, ¹¹C-methionine uptake was almost homogeneous, with a tendency toward a slight elevation in the basal anteroseptal area. In 2 volunteers, the average standardized uptake values (SUVs) of the basal anterior wall were 2.0 and 1.96 and those of the lateral wall were 1.71 and 1.78; the ratios of uptake in the basal anterior wall to the lateral wall were 1.17 and 1.10. Physiologic uptake in the liver was high, and this uptake masked some segments of the inferior wall. Patients with inferior-wall myocardial infarctions were also examined but were not included in the present study; instead, only cases of left anterior descendent infarction were chosen.

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FIGURE 1. 

(A) Time–activity curves of regions of interest after tracer administration: whole left ventricle (red) and left ventricular blood pool (green). Blood-pool activity decreased from initially steep curve to stable lower level at around 20 min after injection, resulting in higher and stable myocardium–to–left-ventricle contrast at 20 min and thereafter. Then, we determined imaging time of myocardium with ¹¹C-methionine at 20 min after injection. (B) Comparison of infarction-to-normal SUV ratios (SUV i/n) on ¹⁸F-FDG and ¹¹C-methionine images (P < 0.005 vs. ¹¹C-methionine imaging: mean ± SD, unpaired t test). (C and D) ²⁰¹Tl SPECT, ¹⁸F-FDG PET, and ¹¹C-methionine PET in 53-y-old man (patient 7) (C) and 71-y-old man (patient 9) (D). In ¹¹C-methionine images, physiologic uptake in liver was high. Infarction zone in anterior wall exhibited decreased uptake on ²⁰¹Tl and ¹⁸F-FDG images and increased uptake on ¹¹C-methionine images. ¹¹C-methionine uptake increased more in middle anterior wall than in apex: highest zone of uptake was almost next to spare zone in ²⁰¹Tl and ¹⁸F-FDG images. ²⁰¹Tl images were similar to ¹⁸F-FDG images visually. However, direct comparisons are difficult because of the different modalities. (E) Another instance of 3 orthogonal views of patient with segment 9 AMI (patient 8). Relative increase in¹¹C-methionine uptake is also apparent in this patient.

RESULTS

²⁰¹Tl and ¹⁸F-FDG uptake was decreased, whereas ¹¹C-methionine uptake was similar or increased, relative to the normal region on semiquantitative visual analysis (Table 1). Table 1 summarizes the clinical information and analyzed data of the 9 patients (mean age, 57.1 ± 15.1 y; female-to-male ratio, 0:9). All infarction-to-normal count ratios were lower than 1.0 in the ²⁰¹Tl images. All infarction SUVs were lower than normal SUVs in the ¹⁸F-FDG images, whereas all infarction SUVs were similar to or higher than normal SUVs in the ¹¹C-methionine images. Using the SUVs for all 9 patients, we determined the infarction-to-normal SUV ratio (mean ± SD) to be 0.39 ± 0.128 for the ¹⁸F-FDG images and 1.207 ± 0.095 for the ¹¹C-methionine images (Fig. 1B). Representative patients are shown in Figures 1C–1E. Two patients with segment 6 AMI (Figs. 1C and 1D) exhibited increased uptake of ¹¹C-methionine in the infarct zone, although uptake of the other tracers was decreased in the same zone. The greatest ¹¹C-methionine uptake was not in the core of the infarct region but in the border region between the infarct and normal tissue. Visually, relative ¹⁸F-FDG uptake was reduced in the infarction zone, and the ²⁰¹Tl uptake was the same. Three orthogonal views of another patient with no. 9 AMI are shown in Figure 1E. A relative increase in ¹¹C-methionine uptake is visible. Figure 2 shows the changes in ¹¹C-methionine uptake in studies performed 1 wk and 3 mo (patient 3) and 6 mo (patient 7) after AMI onset. At 3 mo after onset, uptake of ¹¹C-methionine was similar to that observed during the acute phase, whereas uptake was decreased or showed a partial defect at 6 mo after onset. The ¹¹C-methionine infarction-to-normal SUV ratio also decreased in 2 patients (Table 1). Thus, ¹¹C-methionine uptake changed during imaging studies performed over the course of 6 mo after AMI onset.

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FIGURE 2. 

Vertical long-axis images obtained 1 wk and 3 mo after AMI onset in 60-y-old man (patient 3) (A) and 1 wk and 6 mo after AMI onset in 53-y-old man (patient 7) (B). In both patients, ¹¹C-methionine uptake in region was higher than that in lateral wall at 1 wk after AMI onset (infarction-to-normal ratios, 1.12 and 1.10). However, uptake became similar to ¹⁸F-FDG uptake at 3 mo after AMI onset and almost undetectable after 6 mo (infarction-to-normal ratios, 0.80 and 0.77). Uptake was slightly increased around infarction zone in ¹⁸F-FDG images obtained at 3 mo after AMI onset, whereas decreased ¹⁸F-FDG uptake was observed at 6 mo.

DISCUSSION

¹¹C-methionine PET has been used for diagnosing brain tumors and evaluating their treatment (1–4). Because of the low physiologic uptake of ¹¹C-methionine in the brain, ¹¹C-methionine PET is currently used mainly to assess brain tumors. Numerous studies have examined ¹¹C-methionine uptake, and ¹¹C-methionine uptake is widely known to reflect amino acid transport, transmethylation, and protein synthesis. In particular, Ishiwata et al. reported that the amino acid transport system was dominant in the brain and in tumors (2). Kracht et al. demonstrated a correlation between ¹¹C-methionine uptake and microvessel density and showed a strong correlation between increased amino acid uptake and angiogenesis in evolving gliomas (4). In studies on brain infarction, Jacobs observed an increase in ¹¹C-methionine uptake in peripheral areas of acute cerebral infarction (5), and Nagano-Saito et al. concluded that ¹¹C-methionine uptake by damaged but viable brain tissue represented gliosis and angiogenesis (6).

However, few studies have examined the application of ¹¹C-methionine PET to myocardial imaging, especially using clinical PET images. Here, we presented ²⁰¹Tl SPECT and ¹⁸F-FDG/¹¹C-methionine PET images of AMI after successful reperfusion. All the ²⁰¹Tl and ¹⁸F-FDG images were typical of myocardial ischemia and exhibited similar uptake profiles. However, the ¹¹C-methionine images showed a different pattern of uptake. An increase in ¹¹C-methionine uptake was observed in regions exhibiting reduced or the absence of ²⁰¹Tl and ¹⁸F-FDG uptake.

As we had suspected on the basis of the pattern of ¹¹C-methionine uptake in the brain, ¹¹C-methionine uptake was observed in regions of myocardial infarction. Blankesteijn et al. separated the process of healing after myocardial infarction into 4 phases: myocardial cell death, acute inflammation, the formation of granulation tissue, and scar formation (10). ¹¹C-methionine uptake was observed in the second and third of these phases.

During the acute inflammatory reactions that occur during the early phase of healing, many inflammatory cells in the damaged region produce cytokines, which degrade the extracellular collagen matrix (11). In tumor tissue, ¹¹C-methionine uptake increases in granulation tissue and macrophages, but not as much as does ¹⁸F-FDG (1). Thus, ¹¹C-methionine uptake may reflect the activity of these inflammatory cells.

On the other hand, numerous small blood vessels are present during the formation of granulation tissue. Angiogenesis, a repair process after ischemic injuries (12), recently has become a field of molecular imaging research (13–17). ¹¹¹In-RP748 SPECT (13) and ¹⁸F-galacto-RGD PET (14) targeting α_vβ₃ integrin, an angiogenic factor, have been used to study animal models of myocardial infarction; these studies showed overexpression of α_vβ₃ integrin in activated endothelial cells during angiogenesis after hypoxia, and increased uptake was observed in infarcted areas. The time course of the ¹¹C-methionine images obtained after AMI was similar to the acute phase of angiogenesis described in these reports. Thus, the increased uptake of ¹¹C-methionine might reflect some angiogenic factors, as mentioned in the above studies on cerebral infarction and gliomas, suggesting a relation between ¹¹C-methionine uptake and angiogenesis. Possibly, the amino acid transport system might become active during remodeling of the heart, just as it does in the brain and in tumors.

This study had some limitations. ¹¹C-methionine uptake was elevated during early AMI. This elevated uptake may gradually decrease until it disappears in scar tissue. ¹¹C-methionine uptake after infarction may be useful for assessing the process of remodeling after AMI and for monitoring the effects of therapy. Further studies on ¹¹C-methionine uptake after myocardial infarction are needed.

The present findings were limited to only the early acute phase of myocardial infarction, and more data on long-term changes in ¹¹C-methionine uptake should be obtained.

In addition, although we compared ²⁰¹Tl uptake for perfusion images, ¹⁸F-FDG for glucose metabolism, and ¹¹C-methionine for amino acid metabolism, differences between the SPECT and PET modalities prevented us from determining whether the region of ¹¹C-methionine uptake better matched the region of low ¹⁸F-FDG uptake or the region of ²⁰¹Tl hypoperfusion.

Furthermore, because our ¹⁸F-FDG PET images were obtained after the oral administration of glucose, a comparison of ¹⁸F-FDG after fasting with heparin injection and ¹¹C-methionine uptake would be useful to confirm whether ¹¹C-methionine uptake actually reflects acute inflammation or ischemia.

Finally, from a technical viewpoint, the considerable physiologic uptake of ¹¹C-methionine in the liver makes a detailed assessment of the right coronary artery area difficult.

CONCLUSION

We have presented the first (to our knowledge) images of ¹¹C-methionine uptake in damaged myocardium after reperfusion for AMI. These images differ greatly from those of ²⁰¹Tl and ¹⁸F-FDG uptake. ¹¹C-methionine uptake might reflect an aspect of dynamic myocardial changes, such as remodeling during healing, after reperfusion for AMI.