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Detection of Myocardial Ischemia by a Radio-labeled Free Fatty Acid Analog, BMIPP

Hideo Kusuoka, M.D., Ph.D., FACC

Institute for Clinical Research
Osaka National Hospital
Osaka, Japan

Introduction
Intramyocardial metabolism of BMIPP
Clinical application of myocardial BMIPP SPECT
Conclusion

1. Introduction

Cardiac muscle mainly consumes free fatty acids (FFA) as an energy substrate at the normal, aerobic condition. When heart is subjected to hypoxia or ischemia, energy metabolism shifts from aerobic one to anaerobic one, and main energy substrates change from FFA to glucose
(Fig. 1). Lactate is used as an energy substrate at aerobic condition, but generated as the end product of glycolysis at anaerobic condition. Thus, the detection of lactate consumption or production at myocardium gives an useful index of cardiac ischemia, but it is necessary to perform cardiac catheterization to determine the lactate production rate. Myocardial glucose uptake is also used as the index of myocardial ischemia; a glucose analog, F-18 fluorodeoxyglucose (FDG) is widely used for this purpose. However, F-18 is a positron nucleus, and positron emission tomography or other specific equipment is required to get images of myocardial FDG uptake.

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It is reasonable to use FFA or their analogs to illustrate myocardial aerobic metabolism. C-11 palmitate or radioactive iodine-labeled FFA similar to palmitate has been used for this purpose. However, the straight-chain FFA is metabolized very rapidly in myocardium, thus only dynamic analysis can be performed. In contrast, branched-chain FFA has usually slower metabolism, and better to apply for single photon emission tomography (SPECT).b -methyl-p-iodophenylpendadecanoic acid (BMIPP, Fig. 2) is one of such radio-labeled branched FFA.

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2. Intramyocardial metabolism of BMIPP

BMIPP has the methyl branch at the b position. Previously, two different pathways were proposed for intramyocardial BMIPP metabolism. One is that BMIPP receives b oxidation first, then no further degradation goes on BMIPP. The other is that BMIPP receives a oxidation first, and then is processed by repeated b oxidation until paraiodophenyl acetate (PIPA) is generated as the end product. Recent study revealed that the latter pathway is the actual BMIPP metabolism in myocardium.

Based on the several studies, intramyocardial metabolic pathway of BMIPP is summarized as in Fig. 3. BMIPP is brought to heart by blood flow. Thus, the myocardial blood flow is one of the major determinants of myocardial BMIPP uptake. It is not yet clear whether BMIPP is taken up into myocytes by specific carrier in sarcolemma. Recently, CD36 has been considered as a long-chain FFA transporter in myocardium. CD36 is a multifunctional glycoprotein, and was originally discovered as the protein on the cell membrane of platelet, monocytes and macrophages. Recently, the correlation between CD36 deficiency (type 1) and the lack of myocardial BMIPP uptake has been reported. Thus, CD36 may be a specific carrier of BMIPP. When BMIPP is taken up into myocytes, it is phosphorylated by ATP and incorporated into triglyceride pool. Some of BMIPP directly receives a -oxidation, and some is degraded from triglyceride and receives a -oxidation. After  a -oxidation, repeat of b-oxidation degrades BMIPP until PIPA. If BMIPP is not incorporated into triglyceride pool, it seems to be removed from myocytes easily by back diffusion. Thus, intracellular ATP level is also one of major determinants of myocardial BMIPP uptake. When heart is in ischemic or hypoxic condition and intramyocardial ATP level is low, myocardial BMIPP uptake decreases compared with normal, normoxic condition. In clinical situation, combination of low blood flow and ischemia/hypoxia decreases myocardial BMIPP uptake.

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3. Clinical application of myocardial BMIPP SPECT

BMIPP was initially developed to detect myocardial ischemia in which energy substrate shifts from FFA to glucose. However, the shift in energy metabolism from oxidative phosphorylation to glycolysis occurs not only in ischemic myocardium but also in other pathologic conditions. Thus, now in Japan, myocardial SPECT with BMIPP is also widely used to determine the pathophysiological conditions of myocardium in congestive heart failure, hypertrophic cardiomyopathy, and diabetes mellitus.

3-1. Normal images of BMIPP SPECT

Figure 4 shows BMIPP SPECT images in a healthy volunteer with Tl-201 SPECT. BMIPP SPECT images (the lower panels) are almost equivalent to those with Tl-201 (the upper and the middle panels). As indicated, myocardial blood flow is one of major determinants of myocardial BMIPP uptake. Thus, it is not surprising that BMIPP SPECT images are equal to myocardial perfusion images in normal, aerobic condition.

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3-2. Old myocardial infarction

Figure 5 shows BMIPP and Tc-99m tetrofosmin SPECT images in the patient with old myocardial infarction at antero-septal region. As myocardial perfusion images (the right panels) indicated, there were neither viable myocardium nor ischemic myocardium in infarcted region. At that time, BMIPP images was also similar to those of myocardial perfusion images.

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3-3. Effort angina and unstable angina

In case of stable effort angina, BMIPP SPECT sometimes shows the images allocated to those with Tl-201 between exercise-stress ones and delayed ones (Fig. 6). BMIPP SPECT is performed at rest conditions, so its images should be closed to perfusion images at rest if BMIPP uptake is determined only by myocardial blood flow. However, BMIPP SPECT shows defect or low uptake at ischemic regions. This reduction of BMIPP uptake may be caused by the after-effect of ischemia on FFA metabolism. When myocardial blood flow was re-established, BMIPP images returned to normal (Fig. 7).

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The case shown in Fig. 6 suggests that BMIPP SPECT may be used to detect previous ischemic episode even though the patient showed no ischemic event at the acquisition of BMIPP images. Figure 8 shows the BMIPP and Tl-201 images at rest in the patient with unstable angina. Both images shows significant discrepancy; Tl-201 images shows a small, little defect, but BMIPP images shows much larger, more severe defects. The examination was performed not during the anginal attack, but this patient frequently developed attacks at that time. These results suggest that the recovery after the ischemic insult is significantly different between blood flow and FFA metabolism; blood flow recovers very quickly, but FFA metabolism delays in recovery. The dissociation of BMIPP images from the perfusion images strongly suggests the previous ischemic events. One of the advantages of BMIPP myocardial SPECT is high sensitivity (85 %) and specificity (95 %) to unstable angina. In contrast, the sensitivity to stable angina is not so high.

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3-4. Acute myocardial infarction

As indicated in previous figures, BMIPP images can give the information about previous ischemic insult. This characteristics can be applied to determine the risk area in a patient with acute myocardial infarction. The correct way to determine the risk area is to take perfusion images before reperfusion therpy. But, actual application of this method is limited due to several practical reasons. BMIPP SPECT after intervention gives not exactly the same but very close feature as the risk area. Figure 9 shows the comparison among three images to detect the risk area in acute myocardial infarction. BMIPP images obtained the 2nd day after the onset of infarction with revascularization (the right, lower panel) gives the defect smaller than the actual risk area determined by Tc-99m tetrofosmin images obtained before (the left panel) or after (the right, upper panel) the intervention. It is necessary to take the underestimation into the account, but BMIPP imaging is practically applicable to determine the risk area.

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Another advantage of BMIPP imaging in acute myocardial infarction is applicability for diagnosis of stunned myocardium. Figure 10 illustrates one example of stunned myocardium. The patient with acute myocardial infarction received successful reperfusion, and perfusion images with Tl-201 at acute phase (the 2nd panel in the left column) showed good recovery. However, the left ventricular wall motion at antero-apical region was still depressed (the lower panels in the left column). At that time, BMIPP images (the upper panel in the left column) showed severe defects at the corresponding regions. During the chronic phase, wall movement recovered well with the decreased defects in BMIPP image (the right column). The left ventriculograms indicate that the region where BMIPP images showed the discrepancy with perfusion images were stunned myocardium. These results indicate that BMIPP images are helpful to diagnose stunned myocardium and estimate the prognosis. BMIPP uptake may suggest the contractile ability of the regional myocardium.

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3-5. Heart failure due to dilated cardiomyopathy

BMIPP imaging can be applicable to assess the effects of treatment in heart failure. Figure 11 shows the BMIPP images before and after the treatment in a patient with dilated cardiomyopathy (DCM). Before the treatment, BMIPP uptake was poor, especially at posterior region (panel A), whereas BMIPP uptake increased when cardiac function was improved by the treatment (panel B). DCM usually shows low BMIPP uptake, and BMIPP imaging has no advantage to diagnose dilated cardiomyopathy. However, when the therapy against heart failure is effective and improves cardiac function, BMIPP images are also improved. Effective treatment may affect the shift in myocardial energy metabolism, and depict the improved BMIPP images. The precise mechanisms for this phenomenon are still not revealed, but BMIPP imaging can be applicable to assess the treatment against heart failure.

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3-6. Hypertrophic cardiomyopathy

BMIPP imaging has also no contribution in the diagnosis of hypertrophic cardiomyopathy (HCM). However, BMIPP imaging is useful to estimate the prognosis of this disease. Some of the patients with HCM show regional defects in BMIPP images (Fig. 12, the left panel), although the myocardial perfusion is not impaired (the right panel). Ito, et al. reported that the regions showing the defect in BMIPP imaging depict FDG uptake without ischemia. These results indicate that energy metabolism shifts from aerobic one to anaerobic one in some of HCM. It was also reported that some of HCM showed DCM-like clinical feature as the pattern of end-stage, and this change was coupled with the shift in energy metabolism. Thus, the change in BMIPP imaging provides good information about the prognosis of HCM.

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3-7. Diabetes mellitus

Recent study by Sakamoto, et al. reported that reduced BMIPP uptake was observed in patients with diabetes mellitus and no coronary lesion, and these defects were correlated with the abnormality in left ventricular wall motion. As shown in Fig. 13, BMIPP images (the lower panel) was dissociated from those of Tl-201 images (the upper panel) in a patient with diabetic cardiomyopathy. Contractile dysfunction was observed at the regions showing the defect in BMIPP image but not in perfusion image. They concluded that impairment of FFA metabolism rather than small vessel abnormalities is responsible for modest left ventricular (LV) dysfunction in the patients with diabetes mellitus. It is still unknown whether the shift in the energy metabolism is the cause or the result for the LV dysfunction. Nevertheless, it is important to know the metabolic abnormality by BMIPP imaging to estimate the possibility of LV dysfunction.

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4. Conclusion

BMIPP was developed to illustrate myocardial FFA metabolism with SPECT, but the precise pathway of BMIPP metabolism is not equal to those for natural FFA. Nevertheless, BMIPP has the characteristics suitable to detect the shift of energy metabolism in myocardium. One of the clinical utilities of BMIPP is based on the disturbance in myocardial uptake that continues for a while even after the re-establishment of myocardial perfusion. This characteristics enables BMIPP to diagnose unstable angina and stunned myocardium and to determine the risk area after reperfusion therapy. BMIPP also contributes the assessment of abnormal energy metabolism in hypertrophic, failing, and diabetic hearts. BMIPP can be applicable to assess the therapeutic results of clinical cardiology.

 Acknowledgment

The author thanks to Tsunehiko Nishimura, Toshiisa Uehara, Shinji Hasegawa, and Yasushi Ito in Osaka University Medical School, Kazuki Fukuchi and Yoshio Ishida in National Cardiovascular Center, Tatsuo Ito in Osaka Rosai Hospital, Takakazu Morozumi, Shinsuke Nanto, Kenya Sakamoto, and Tsuyoshi Shimonagata in Kansai Rosai Hospital, Hideki Kobayashi in Tokyo Women’s Medical College, and Kenichi Watanabe in Niigata Pharmaceutical University for their kind permission to present the their work in this lecture.

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© CETIFAC
Bioengineering
UNER
Update
Dic/08/1999