ORIGINAL ARTICLE 
Annals of Nuclear Medicine Vol. 9, No. 3, 125-130, 1995 

Impaired myocardial fatty acid metabolism detected by 123I-BMIPP in patients with unstable angina pectoris: Comparison with perfusion imaging by 99mTc-sestamibi 

Yasuchika TAKEISHI, Hiroyasu SUKEKAWA, Haruo SAITO, Shozo NISHIMURA, Takayuki SHIBU, 
Yasuhiko SASAKI and Hitonobu TOMOIKE 

Divisions of Cardiology and Radiology, Ishinomaki Red Cross Hospital 
First Department of Internal Medicine, Yamagata University School of Medicine 

The present study was undertaken to determine the potential diagnostic value of 123I-BMIPP scintigraphy for the detection of altered myocardial fatty acid metabolism in patients with unstable angina. Both myocardial metabolic imaging with 123I-BMIPP and perfusion imaging with 99mTc-sestamibi were performed at rest in 28 patients with unstable angina in the pain-free state. The regional uptakes of 123I-BMIPP or 99mTc-sestamibi were scored semiquantitatively (0 = normal, 4 = no activity) and compared with the coronary arteriographic findings. Decreased uptakes of 123I-BMIPP were observed in 18 patients, and 11 patients had abnormal 99mTc-sestamibi images. Defect scores of 123I-BMIPP were larger than those of 99mTc-sestamibi (7.8 +- 2.1 vs. 5.2 +- 1.9, p < 0.01). The sensitivity for the detection of patients with unstable angina was higher in 123I-BMIPP than in 99mTc-sestamibi (77% vs. 45% , p < 0.01 ). The site of the decreased 123I-BMIPP uptake corresponded to the most stenotic coronary artery lesion in all patients. 

Fatty acid metabolic imaging with 123I-BMIPP was more sensitive for detecting myocardial ischemia than perfusion imaging with 99mTc-sestamibi. 123I-BMIPP may be a clue to define the culprit lesion in unstable angina and be helpful to decide the best treatment and guide coronary angioplasty. 

Key words: 123I-BMIPP 99mTc-sestamibl unstable angina 

INTRODUCTION 

IN UNSTABLE ANGINA, there is a significant 1-year mortality rate and a high incidence of myocardial infarction.1 The diagnosis of the presence and extent of myocardial ischemia in patients with unstable angina is important, because this diagnosis carries with it the imminent danger of acute myocardial infarction or sudden death. A 12-lead electrocardiography is generally used for the detection of myocardial ischemia.2 Although electrocardiographic ischemic changes are considered to be the major indicator of myocardial ischemia, these changes are not sensitive enough for the satisfactory diagnosis.3-6 A noninvasive approach for the assessment of the presence and severity of myocardial ischemia is desirable, since a provocation test, such as exercise or pharmacologic stress, is usually contraindicated in unstable angina. Recently, myocardial perfusion imaging with thallium-201 (201Tl)3,7,8 or technetium-99m methoxy-isobutyl-isonitrile (99mTc-sestamibi)4-6 has been used for the diagnosis of unstable angina. 99mTc-sestamibi perfusion imaging is a reliable diagnostic tool for the noninvasive detection of myocardial ischemia and the identification of the involved coronary artery stenoses, but perfusion imaging often yields false negative results when the isotope is injected in the pain-free state.3-5 

In the fasting state, fatty acids are account for more than 70% of myocardial energy requirements at rest under normal aerobic conditions . With positron emission tomography, 11C-palmitate has been used for the evaluation of myocardial fatty acid metabolism.9,10 For practical purposes, single photon emitting radionuclides that can assess myocardial metabolism have long been desired.11-18 Recently, iodine-123 beta-methyl-iodophenyl-pentadecanoic acid (123I-BMIPP) has been developed and used as a tracer for myocardial fatty acid metabolism.19,20 

The goal of the present study was to evaluate the potential diagnostic value of 123I-BMIPP at rest in patients with unstable angina. We hypothesized that fatty acid metabolic imaging was more sensitive than perfusion imaging for the detection of myocardial ischemia. To test this hypothesis, myocardial single photon emission computed tomography (SPECT) with both 123I-BMIPP and 99mTc-sestamibi were performed at rest during the pain-free period in patients with unstable angina. 

MATERIALS AND METHODS 

Subjects and study protocol 
All patients with suspected unstable angina admitted to the coronary care unit of Ishinomaki Red Cross Hospital from April, 1993 to June, 1994 were enrolled. Chest pain suggestive of myocardial ischemia had to occur within one week before admission. The exclusion criteria consisted of a previous well documented myocardial infarction, known coronary anatomy, previous coronary angioplasty or aortocoronary bypass surgery and refused consent. Blood levels of total creatine kinase and its MB fraction were obtained on admission and every 6 hr for 48 hr. Patients with acute myocardial infarction determined by a doubling of the creatine kinase levels with the presence of MB fraction or the appearance of a new Q wave were also excluded from the present study. 

During this period, 39 patients with suspected unstable angina were admitted and satisfied the criteria. All patients were treated with nitroglycerin, heparin, aspirin, beta blockers or calcium antagonists. However, in 11 out of these 39 patients, medical therapy was unsuccessful in controlling chest pain, and angiography was performed without scintigraphy. Therefore, 28 patients were examined in the present study. The subjects consisted of 18 male and 10 female with a mean age of 69 years. 

After receiving medication and controlling chest pain, scintigraphy was performed at rest in the pain-free state. Myocardial perfusion imaging with 99mTc-sestamibi was performed 1 to 3 days after admission and myocardial fatty acid metabolic imaging with 123I-BMIPP was obtained 2 days after the 99mTc-sestamibi imaging, because 99mTc was always available in our laboratory. Written informed consent was obtained from all subjects. The study protocol was approved by the Committee of Human Research of Ishinomaki Red Cross Hospital. 

Myocardial perfusion imaging with 99mTc-sestamibi 
A dose of 740 MBq of 99mTc-sestamibi was administered intravenously in the resting supine position after an overnight fast. Data acquisition was carried out I hr after the 99mTc-sestamibi injection. All studies were obtained on a large field-of-view rotating gamma camera (Siemens, ZLC-7500 DIGITRAC) equipped with a parallel-hole, high-resolution collimator. Energy discrimination was provided by a 20% window centered at 140 keV.21 Thirty-two images were obtained over a 180-degree arc from the 30-degree right anterior oblique to the 60-degree left posterior oblique position. Each image was accumulated for 30 seconds. The data were stored on a 64 x 64 matrix. Data processing was performed on a nuclear medicine computer system (Shimadzu, Scintipac-700). A series of contiguous transaxial images of 6 mm thickness were reconstructed by means of a filtered back-projection algorithm without attenuation correction. These transaxial images were then oriented in the short axis, vertical long axis, and horizontal long axis of the left ventricle.22 

Myocardial metabolic imaging with 123I-BMIPP After an overnight fast, a dose of 148 MBq of 123I-BMIPP was injected intravenously in the resting supine position. The patients were carefully repositioned by a laser positioning device at the same position as in the 99mTc-sestamibi studies. Data acquisition was performed 20 min after the injection of 123I-BMIPP. The process of image acquisition was the same as for 99mTc-sestamibi with the following exceptions23: 1 ) the imaging time per projection was 40 sec; and 2) a 20% window was centered at the 159 keV photopeak of 123I. The accumulated data were processed in a manner identical to that for the 99mTc-sestamibi studies. 

Image interpretation 
The distribution of 99mTc-sestamibi and 123I-BMIPP in the myocardium was analyzed in the three standard orthogonal tomographic imaging planes as follows: the anterior, septal, inferior, and lateral regions in the short axis view; the anterior, apical, and inferior regions in the vertical long axis view; and the septal, apical, and lateral regions in the horizontal long axis view.24 The left ventricular myocardium was divided into 9 segments by splitting the anterior, septal, inferior, and lateral walls into a basal and apical segment, including an extra segment for the apex.25,26 The anterior, septal and apical walls were assumed to represent the territory of the left anterior descending artery; the inferior wall, the territory of the right coronary artery ; and the lateral wall, the left circumflex artery territory. The images were interpreted by two independent observers who were unaware of the clinical history and the angiographic findings of the patients. A 5-point scoring system was used for evaluating the myocardial uptakes of the tracer25,26: 0 = normal, 1 = slightly reduced, 2 = moderatelyreduced, 3 = severely reduced, 4 = no activity. Scores of >: 2 were considered to be significant. The grading was settled by consensus between the two observers. When they disagreed on the results, the third observer reviewed the images, and his judgment was chosen.

Echocardiography 
Two-dimensional echocardiography was performed on admission for the assessment of left ventricular wall motion by an experienced cardiologist. Standard parasternal short- and long-axis views and an apical four-chamber view were recorded. The echocardiograms were analyzed by two independent observers who had no knowledge of the patients' clinical data. The left ventricle was divided into 5 segments in each view, and the level of segmental wall motion was scored as follows: 0 = normal , 1 = hypokinesis, 2 = akinesis, 3 = dyskinesis. 

Coronary arteriography 
Coronary arteriography was performed in multiple projections with the standard Judkins' technique. Coronary arteriograms were interpreted by 3 experienced observers unaware of the clinical conditions and scintigraphic data of the patients. Stenoses of large diagonal or marginal branches were considered as lesions of the left anterior descending artery or circumflex artery, respectively. Stenoses with > 50% luminal diameter reduction was considered significant. 
Statistics 
Data were reported in mean +- SD. Continuous variables were compared by Students' t-test, and the differences in proportion (categoric variables) were examined by a chi-square test. A p value < 0.05 was considered significant. 

RESULTS 

Case presentation 
Figure 1 shows myocardial images with 123I-BMIPP and 99mTc-sestamibi in a patient with unstable angina. The patient was a 69-year-old male who was admitted with worsening effort angina. In the 123I-BMIPP images, decreased uptake was observed in the anterior, septal and apical regions of the left ventricle. However, myocardial uptake of 99mTc-sestamibi was homogeneous. Coronary arteriography demonstrated 90% coronary stenosis in the proximal left anterior descending artery. 

Comparison with coronary arteriographic findings 
Out of 28 patients, 10 patients had normal 99mTc-sestamibi and normal 123I-BMIPP images, 11 patients had abnormal 99mTc-sestamibi and abnormal 123I-BMIPP images, and 7 patients had normal 99mTc-sestamibi and abnormal 123I-BMIPP images. Coronary arteriography revealed that significant coronary stenosis of > 50% was observed in 22 out of 28 patients. The sites of coronary stenosis were left anterior descending artery in 15 patients, right coronary artery in 12 patients and left circumflex artery in 4 patients. The sensitivity and specificity for the detection of patients with significant coronary stenosis are shown in Figure 2. The sensitivity of 123I-BMIPP was higher than that of 99mTc-sestamibi (77% vs. 45%, p < 0.01), although specificity was comparable (83% vs. 83%. The regions of decreased 123I-BMIPP uptake coincided topologically well with those of most severe coronary stenosis in all patients. 

The sensitivity for the detection of individual coronary 
stenosis was compared between the coronary stenoses of graded severity (Fig. 3). The sensitivities of 123I-BMIPP and 99mTc-sestamibi were O% and O% with mild stenosis, 38% and 25% with moderate stenosis, and 79% and 47% with severe stenosis (p < 0.01, 123I-BMIPP vs. 99mTc-sestamibi), respectively. 

Comparison of regional 123I-BMIPP and 99mTc-sestamihi uptakes 
Regional 123I-BMIPP uptakes in each segment were compared with those of 99mTc-sestamibi (Fig. 4). Defect scores of 123I-BMIPP were concordant with those of 99mTc-sestamibi in 172 segments (69%). In 64 segments (25 %), defect scores of 123I-BMIPP were higher than those of 99mTc-sestamibi. 99mTc-sestamibi had higher defect scores than 123I-BMIPP in only 16 segments (6%). The sum of defect scores in each patient was greater in 123I-BMIPP than in 99mTc-sestamibi (7.8 +- 2.1 vs. 5.2 +- 1.9, p < 0.01). 

Relationship to the presence of a wall motion abnormality 
Hypokinetic or akinetic wall motion abnormality was observed in 13 of 28 patients. In patients with normal wall motion, the sum of defect scores of 99mTc-sestamibi and 123I-BMIPP was 3.7 +- 0.9 and 4.4 +- 1.1, respectively (Fig. 5). In patients with a wall motion abnormality, the sum of defect scores was 6.6 +- 2.0 in 99mTc-sestamibi (p < 0.01, vs. normal motion) and 8.4 +- 2.2 in 123I-BMIPP (p < 0.01 , vs. normal wall motion). The sum of defect scores of 123I-BMIPP was higher than that of 99mTc-sestamibi in patients with a wall motion abnormality (p < 0.01 ). The sensitivity for detecting the presence of a wall motion abnormality was 85% by 123I-BMIPP and 62% by 99mTc-sestamibi (p = ns). 

DISCUSSION 

Impaired fatty acid metabolism in patients with unstable angina was detected as a decrease of myocardial uptake of 123I-BMIPP. The sensitivity of 123I-BMIPP for the detection of unstable angina was 77%, that is higher than that of 99mTc-sestamibi (45%). The site of decreased 123I-BMIPP uptake corresponded to the most stenotic coronary artery in all cases, and 123I-BMIPP imaging identified the left ventricular wall motion abnormality in 85% of patients.
 In the present study, 6 patients without significant coronary artery stenosis were included. The presence of a coronary artery spasm might be related to the occurrence of chest pain in these patients. Induction of a coronary artery spasm by intracoronary injection of acetylcholine was performed in only 2 of 6 patients, and a spasm was not induced in these patients. 

A noninvasive evaluation of myocardial metabolism in addition to perfusion has long been desired. 123I-BMIPP has been applied to clinical as well as experimental studies for the assessment of myocardial fatty acid metabolism.23,27-30 123I-BMIPP has the following favorable biological properties for myocardial SPECT imaging.19,20: 1) high uptake and prolonged retention in the m yocardium; 2) relatively higher heart-to-background count ratio; and 3) rapid blood clearance. 123I-BMIPP is not metabolized by beta-oxidation but is trapped into the triglyceride fraction in the myocardium. Although, 123I-BMIPP is not an ideal tracer for myocardial fatty acid metabolism, the myocardial accumulation of 123I-BMIPP is associated with triglyceride synthesis, which in part reflects fatty acid utilization and depends on the level of adenosine triphosphate concentration in the myocardium.28 The safety and potential usefulness of this isotope have now been confirmed clinically in patients with myocardial infarction,29 stable angina pectoris,30 and cardiomyopathy,23 but not in those with unstable angina. 

Two radiopharmaceutical agents, 201Tl and 99mTcsestamibi , are currently available for myocardial perfusion imaging. The characteristics of 99mTc-sestamibi make this agent more appropriate than 201Tl for emergency use. 99mTc is produced with a generator and is more readily available than 201Tl. Furthermore, 99mTc-sestamibi shows minimal redistribution and its properties allow the delayed imaging acquisition after tracer administration. Scintigraphic acquisition does not prevent any delay in the initiation of medical treatment. This has important implications in patients with unstable angina in whom immediate medical therapy is required. Gregoire and Theroux have reported high accuracy of 99mTc-sestamibi studies for the detection of coronary artery disease in patients with unstable angina.4 99mTc-sestamibi SPECT has a sensitivity of 96% during a episode of chest pain, that is much higher than that of electrocardiography (35%). 99mTc-sestamibi is also useful to rule out acute myocardial ischemic events in patients with nondiagnostic electrocardiograms.6 However, sensitivity of 99mTcsestamibi in unstable angina decreased to 65% in the pain-free state.4,5 

Extensive reports have shown that fatty acid metabolism is altered in the ischemic myocardium.9-18,29,30 In patients with unstable angina, repeated episodes of transient ischemia may result in the depletion of fatty acid metabolism. However, metabolic state of the diseased myocardium in patients with unstable angina has not been rigorously examined. We showed that decreased uptakes of 123I-BMIPP were more frequently observed than those of 99*Tc-sestamibi, and the reduction of 123I-BMIPP uptake was more extensive in most patients. The sensitivity for unstable angina was higher in 123I-BMIPP than in 99mTc-sestamibi, although 99mTc-sestamibi studies were performed before 123I-BMIPP scans. These findings suggest that in patients with unstable angina impaired fatty acid metabolism, which is independent of myocardial perfusion, is present in the pain-free period, and that can be detected by 123I-BMIPP SPECT at rest. Because patients in whom medical therapy was unsuccessful in controlling chest pain were excluded from the present study, it was considered that the sensitivity of 77% by 123I-BMIPP was good enough. The mechanisms for the decreased 123I-BMIPP uptake in the presence of normal 99mTc-sestamibi uptake are still controversial. The following two possible mechanisms might be suggested: 1) the repeated transient reduction of coronary blood flow lead to the depletion of fatty acid metabolism, and this post ischemic metabolic disturbance may be prolonged after the recovery of myocardial perfusion; 2) mild ischemia due to coronary artery narrowing, which is sufficient to alter myocardial metabolism, is present during the painfree period, but this is not detected by perfusion scintigraphy with 99mTc-sestamibi. 

In the present study, the location of decreased 123I-BMIPP uptake coincided with the region of the most stenotic coronary artery. It is often difficult to determine the culprit coronary artery lesion by coronary arteriography alone in some patients with multi-vessel coronary involvement. Myocardial metabolic imaging with 123I-BMIPP may be a clue to define culprit lesion, because it can provide functional information concerning the severity of myocardial ischemia. This can help to decide the best treatment and guide coronary angioplasty . Metabolic imaging with 123I-BMIPP may provide a new approach for better understanding of myocardial ischemia. 

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