ORIGINAL ARTICLE 
Annals of Nuclear Medicine Vol.13, No.1, 33-41, 1999 

Abnormal fatty acid metabolism in patients with coronary vasospasm 

Kenichi WATANABE,* Yoshimi OHTA,* Ken TOBA,** Yusuke OGAWA,** Yoshifusa AIZAWA,** Naohito TANABE,** Kiminori KATO,** Yoichi HIROKAWA,** Satoru HIRONO,** Yuji OHKURA,** Koichi FUSE,** Masahiro ITO,** Makoto KODAMA,** Yuichi NAKAMURA,** Yoriko KUSANO,*** Seiichi MIYAJIMA*** and Takafumi NAGATOMO**** 

*Department of Clinical Pharmacology and ****Department of Phormacology, Niigata College of Pharmacy **First Department of Medicine, Niigata University, School of Medicine ***Division of Cardiology, Tsubame Rosai Hospital 

Although various noninvasive methods have been used to detect vasospasm, none of them are sensitive enough for patients with sporadic attacks. Since abnormal fatty acid metabolism is observed in ischemic myocardium, 123I-b-methyl-p-iodophenyl pentadecanoic acid (BMIPP), a radiolabeled fatty acid analog, has recently been proposed as a useful tracer for detecting myocardial damage. The aim of this study was to clarify the clinical implications of decreased myocardial BMIPP uptake in patients with vasospastic angina. We evaluated 53 patients with vasospastic angina (32 with clinically documented vasospasm [Group-A] and 21 with vasospasm induced by ergonovine provocation [Group-B]) and 27 control subjects, 20 in Group-A were re-evaluated 6 months after medical treatment. The territorial regions of vasospasm-induced coronary artery, the wall motion by left ventriculography, and BMIPP uptake were compared. Vasospasm was induced in multiple coronary arteries in 29 (55%) patients. Reduced wall motion and decreased BMIPP uptake were observed in 19 (36%) patients and 47 (89%) patients, respectively. The sensitivity and specificity of determination of vasospasm-induced coronary arteries with BMIPP scintigraphy were 71% (69/97 coronary arteries) and 88% (126/143), respectively. Vasospasm was re-induced by ergonovine provocation in 8 patients (Group-I) and not re-induced in 12 (Group-II) after treatment. In Group-I, improvement of decreased BMIPP uptake was lower than in Group-II ( 19+-11 vs. 59+-22%, mean+-SD, p < 0.001). The regions in which vasospasm was re-provoked exhibited decreased BMIPP uptake.
 Abnormal fatty acid metabolism was more often observed than wall motion abnormality in the vasospastic region in patients with vasospastic angina. BMIPP scintigraphy is a highly accurate and non-invasive technique for determining the presence and location of vasospasm. 

Key words: 123I-b-methyl-p-iodophenyl pentadecanoic acid (BMIPP) scintigraphy, fatty acids, vasospasm, myocardial stunning 

INTRODUCTION 

VASOSPASTIC ANGINA is characterized by resting anginal attacks occurring mainly at night and in the early morning, 

 Received October 12, 1998, revision accepted November 18, 1998.
 For reprint contact: Prof. Kenichi Watanabe, M.D., Ph.D., Department of Clinical Pharmacology, Niigata College of Pharmacy, Kamishinei-cho, Niigata 950-2081 , JAPAN.
 E-mail: watanabe @niigata-pharm.ac jp 

but asymptomatic ischemic attacks are more frequent in patients with vasospastic angina. Some patients may exhibit reduced left ventricular wall motion due to transient myocardial ischemia resulting from vasospastic attacks.1-4 Although various noninvasive methods have been used to detect vasospasm, none of them is sensitive enough for patients with sporadic attacks.
 Long-chain fatty acid is one of the major cardiac energy substrates, and decreased myocardial fatty acid metabolism has been demonstrated in some patients with ischemic heart disease. 123I-b-methyl-p-iodophenyl pentadecanoic acid (BMIPP) is a newly developed tracer for assessing myocardial fatty acid metabolism, and BMIPP is appropriate for use with single photon emission computed tomography (SPECT) because of its stable accumulation in the myocardium.5-8 Some recent studies have demonstrated regional abnormalities in myocardial fatty acid metabolism by visual assessment of BMIPP SPECT in patients with ischemic heart disease.9-11 In this study we performed myocardial BMIPP SPECT scintigraphy on patients with vasospastic angina before and after medical treatment. The aim of this study was to clarify the clinical implications of fatty acid metabolic imaging with BMIPP in patients with vasospastic angina. 

MATERIALS AND METHODS 

Subjects 
(1) Study-1 
Between January 1994 and June 1997, 156 patients with vasospastic angina were admitted to our institution. Fifty-three patients (46 males and 7 females, age 57+-8 years [mean+-SD], range 44 to 69 years) were prospectively selected for this study by using the following criteria. All 53 patients had angiographically normal coronary arteries (defined as < 25% stenotic) and angiographically documented coronary artery vasospasm. Coronary arteriograms were performed by the Judkins technique. Left ventriculography right and left anterior oblique projections were used to evaluate segmental contraction abnormalities. If coronary artery stenosis was more than 99% with ST-segment elevation or depression developing after intracoronary injection of methyl ergometrine maleate (ergonovine), coronary vasospasm was diagnosed as previously reported.4,12-15 Ambulatory electrocardiogram monitoring (SM-50, Fukuda Denshi Co., Japan) for at least 48 hours demonstrated that 32 patients (clinically documented definite vasospasm group, Group-A) had spontaneous vasospastic attacks (ST-segment elevation with or without chest pain) and 21 (vasospasm induced group, Group-B) did not have signs of spontaneous vasospastic attacks.
 This study also included 27 control subjects (Group-C) who were suspected of having coronary artery vasospasm because of characteristic chest pain (16 males and 11 females, mean age 56+-11 years, range 36 to 69 years). These control subjects underwent diagnostic cardiac catheterization for evaluation of chest pain. They had angiographically normal coronary arteries and did not have coronary artery vasospasm after injection of ergonovine. Ambulatory electrocardiogram monitoring of each subject did not detect any spontaneous vasospastic attacks.
 In all 80 subjects, medical treatment, except sublingual nitroglycerin, had not yet been administered, and chest pain attacks had occurred. 

(2) Study-2 
Twenty of 32 patients in Group-A underwent a second BMIPP myocardial scintigraphy, left ventriculography and ergonovine-provoked coronary arteriography after 6 months of single or combined administration of nifedipine at 40-120 mg/day, diltiazem at 90-300 mg/day, amlodipine at 5-20 mg/day and isosorbide dinitrate at 40-120 mg/ day. Ambulatory electrocardiogram monitoring for at least 48 hours did not detect any cardiac symptoms with ST-segment depression or elevation, comfirming that anginal attacks were completely suppressed by the medical treatment. Dosage and combination of medications were optimized and stabilized on suppression of cardiac symptoms, and all medications were continued during this study.
 Although exercise 201TICl myocardial scintigraphy was performed on all 80 subjects, no persistent abnormalities in 201TICl uptake were seen. No subject had myocardial infarction, cardiomyopathy, valvular heart disease, left ventricular hypertrophy, congenital heart disease or hypertensive heart disease.
 Written informed consent was obtained from each subject before the study. The protocol of this study was in agreement with the guidelines of the ethical committee of our institution. 

Myocardial BMIPP SPECT scintigraphy 
BMIPP scintigraphy on all 80 subjects in Group-A, B or C was performed within 2 weeks before diagnostic cardiac catheterization. BMIPP scintigraphy was performed the morning after an overnight fast. BMIPP (111 or 148 MBq) was intravenously injected into the subjects at rest. The BMIPP scintigram image was obtained 15 minutes after the injection. In 20 patients in Group-A, the second study was performed 6 months after the beginning of the medical treatment. The SPECT system used consisted of a single head, and a large field digital gamma-camera equipped with a general purpose, low energy, parallel hole collimator (ZLC-D-ORBITER, Siemens, German) connected to a microcomputer (Scintipak 24000, Shimadzu Co., Japan), as previously reported.4,12 Both image sequences consisted of 32 projections with 64 x 64 matrix acquired for 40 seconds (BMIPP) and 30 seconds (201TICl) over a 180deg. circular orbit, from 30deg. right anterior oblique to 60deg. left posterior oblique. 

Imaging analysis 
Locations where reduced wall motion and vasospasm occurred, as revealed by left ventriculography and coronary angiography, were described according to the American Heart Association classification.16 The left ventriculogram was analyzed by means of the CAA-lO ELK cine-angio system (Nishimoto Co., Japan) and the region of reduced wall motion was the area that deviated from the lower limit of the normal range as defined by our institution.4,12 BMIPP scintigrams of the basal short axis, the middle short axis, the vertical long axis and the horizontal long axis patterns were obtained by SPECT and fractionated into 17 segments by coronary arterial territory (Fig. 1).17 The left ventricle was divided into the three major coronary territories. Coronary arteries perfusing 2 overlapping areas were determined by the methods of Segar et al.18 The defect score of BMIPP uptake (graded as normal uptake = O, mildly decreased uptake = l, moderately decreased uptake = 2, severely decreased uptake or defect pattern = 3) were visually assessed by 2 physicians blinded to the results of the coronary angiogram (Fig. 1). Differences of opinion were resolved by consensus, A summational point of a defect score of more than 3 in the respective coronary territories was defined as decreased BMIPP uptake. The total defect score was calculated as the summation of all counts. We assessed the improvement in the total defect score from initial and second BMIPP scintigrams (initial score - second score/initial score x 100%).
 The intraobserver and interobserver variations for determining the defect score were tested in 50 coronary territories, and the correlation coefficients were 0.95 and 0.90, respectively. 

Statistical analysis 
Fisher's exact probability test and Student's t-test were used to compare the defect score and abnormalities in BMIPP uptake and wall motion in patients with vasospastic angina and the control subjects. A p value < 0.05 was considered significant. Values are presented as mean+-SD. 

RESULTS 

Provocation of coronary vasospasm at cardiac catheterization 
Vasospasm was induced in the right coronary artery (RCX) of 42 patients, in the left anterior descending artery (LAD) of 32, and in the left circumflex artery (LCX) of 23. Multiple coronary artery vasospasm occurred in 29 (55%) patients (18 [56%] in Group-A and 11[52%] in Group-B). Overall, 97 of 159 coronary arteries in all 53 patients in Groups-A and B developed coronary vasospasm after intracoronary administration of ergonovine (i.e., vasospasm-induced coronary artery) and 62 did not (i.e., non-vasospasm induced coronary artery). 

Left ventriculography 
Reduced wall motion was observed in 19 (36%) patients in Groups-A and B (13 [41%] patients in Group-A and 6 [29%] in Group-B, p < 0.05) by left ventriculography. Location of reduced wall motion coincided with territorial regions of the vasospasm-induced coronary artery (Table 1). Reduced wall motion was more frequently associated with patients having multiple coronary artery vasospasm than with single coronary arterial vasospasm (15 [52%] of 29 patients and 4 [17%] of 24, p < 0.01). Reduced wall motion was observed in 3(11%) subjects in Group-C. 

BMIPP SPECT scintigraphy 
Decreased BMIPP uptake was observed in 47 (89%) patients in Groups-A and B (29 [91%] patients in Group-A and 18 [86%] in Group-B, NS). The regions with decreased BMIPP uptake were consistent with territorial regions of the vasospasm-induced coronary artery. In most patients, decreased BMIPP uptake was observed in regions where reduced wall motion was indicated by left ventriculography. Decreased BMIPP uptake was also observed in 5 ( 19%) of 27 control subjects. Based on these results, the sensitivity and specificity for the identification of the vasospastic angina with BMIPP scintigraphy were 89%(47/53) and 81% (22/27), respectively (Table 2).
 In 53 patients in Groups-A and B, the regions with decreased BMIPP uptake in each territorial region of the vasospasm-induced coronary artery were 25 (78%) of 32 arteries in LAD, 6 (26%) of 23 arteries in LCX and 38 (90%) of 42 arteries in RCX, as shown in Table 1 . In the control subjects, the regions were 2 (7%) of 27 arteries in LAD, O (O%) of 27 arteries in LCX and 3 (11 %) of 27 arteries in RCX. Overall, decreased BMIPP uptake was detected in 69 (71%) of 97 myocardial regions that were perfused by vasospasm-induced coronary arteries in 53 patients in Groups-A and B. In addition, decreased BMIPP uptake was detected in 17 (27%) of 62 regions that were perfused by non-vasospasm-induced coronary arteries in Groups-A and B, and in 5 (6%) of 81 regions in Group-C. The sensitivity and specificity of BMIPP scintigraphy for the identification of vasospastic coronary artery was 71 % (69/97) and 88% (126/143), respectively (Table 2). 

Re-evaluation by left ventriculography, coronary arteriography and BMIPP scintigraphy 
Twenty patients in Group-A were re-evaluated 6 months after medical treatment. Vasospasm was re-induced by ergonovine provocation in 8 patients (Group-I) and not re-induced in 12 (Group-II) (Table 3). Medications were continued during this study, and the dosage and combination of medications did not differ significantly in the two groups. In all 8 patients in Group-I, higher dosages of ergonovine were required to induce vasospasm as compared with pre-treatment provocation (31+-5 and 16+-6 ug for each coronary artery, p < 0.01). Although there were many patients with multiple coronary artery vasospasm and reduced wall motion in Group-I, the total defect score for Group-I was not higher than that of Group-II (17+-7 vs. 12+-6, respectively, NS) before medical treatment.
 After medical treatment, reduced wall motion was observed in 2 patients in Group-I and in O in Group-II by left ventriculography, and the region of its occurrence corresponded to the region in which vasospasm was re-induced and in which decreased BMIPP uptake was observed. Table 3 shows that decreased BMIPP uptake still remained in 8 ( 100%) of 8 patients in Group-I and in 4 (33%) of 12 patients in Group-II. In Group-I, the total defect score (13+-6 vs. 4+-3, p < 0.01) was higher, and improvement in the total defect score was poorer than in Group-II (19+-11% vs. 59+-22%, p < 0.01). 

DISCUSSION 

Although vasospasm can be induced by various kinds of stress in daily life, attacks usually occur at night or in the early morning and can often be suppressed by calcium antagonists 19 However, as in case 14 in Group-A (Fig. 3), some patients experience a recurrence of chest pain, acute myocardial infarction or sudden death despite receiving treatment.1,12 Provocation tests of coronary vasospasm are consequently important in the diagnosis and treatment of this disease. Infusion of ergonovine into the coronary arteries can safely induce vasospasm with a high degree of probability and good reproducibility.4,12-15 It is expected that administration of drugs which can suppress ergonovine-provoked vasospasm can eliminate attacks and prevent sudden death during treatment.
 Some patients with vasospastic angina develop abnormal left ventricular wall motion resulting from repeated vasospastic attacks. This suggests that metabolic disorders occur in these patients.20,21 Fatty acid is one of the major substrates for normal myocardial energy metabolism. It is therefore important to determine the state of myocardial fatty acid metabolism in order to determine the viability and ischemic condition of the myocardium. Although positron computed tomography has been useful for evaluating fatty acid metabolism in the myocardium, BMIPP, a recently developed 123I-labeled fatty acid with side chains, has been employed to clarify stunned myocardium and pathological conditions related to the viability of the myocardium during acute myocardial infarction.5-8 As decreased BMIPP uptake can be detected for about 1-3 months, it is expected to be utilized in the diagnosis of vasospastic angina.5-10 We therefore performed BMIPP scintigraphy within 2 weeks before cardiac catheterization in this study.
 In the present study, regional wall motion was reduced in 19 (36%) of 53 patients with vasospastic angina. This suggests that the so-called stunned myocardium resulted from vasospasm, though no coronary stenosis was observed in the coronary arteriography, and the 201TICl myocardial scintigram was normal. In 7 of the 9 patients who could be re-examined during treatment, reduced left ventricular wall motion was alleviated 6 months after starting treatment in the initially exhibited region. These results also support the above hypothesis.
 On the other hand, BMIPP uptake decreased in 47 (89%) of the 53 patients. In addition, the territorial region of vasospasm-induced coronary artery was consistent with the region with decreased BMIPP uptake, and BMIPP uptake was decreased in the region where left ventricular wall motion was reduced in most patients. Reduced wall motion was more frequently associated with patients having multiple artery vasospasm than patients having single vasospasm, and more frequently found in Group-A than in Group-B. Abnormalities were more frequently revealed by BMIPP scintigraphy than by left ventriculography. In some patients who had a long interval after the chest pain attack, wall motion was normal despite decreased BMIPP uptake. Two reasons are suggested for these results. Although moderate or severe ischemic attacks cause abnormal left ventricular wall motion and decreased BMIPP uptake, mild ischemic attacks may cause only decreased BMIPP uptake. Secondly, abnormal BMIPP uptake may last longer than abnormal ventricular wall motion.
 Although non-invasive diagnosis of vasospastic angina has been performed by defect pattern identification or redistribution with 201TICl during a vasospastic attack induced by exercise or hyperventilation. Koyanagi et al.22 reported that the sensitivity for the diagnosis of vasospasm with exercise 201TICl scintigraphy was 44%.21,22 In this study, the sensitivity and specificity for detecting vasospasm-induced coronary artery with BMIPP scintigraphy (determined by analyzing the location of the decreased BMIPP uptake region, and coronary vasospasm induced by ergonovine provocation as a reliable standard) were 71% and 88%, respectively. Our results are therefore comparable to those obtained with invasive techniques.12-14 This strongly suggests that BMIPP reflects myocardial damage resulting from vasospasm more accurately than 201TICl scintigraphy or left ventriculography.
 In the 12 (Group-II) of 20 patients re-examined by BMIPP scintigraphy 6 months after starting medical treatment, the decreased BMIPP uptake regions improved. This suggests that myocardial damage involving fatty acid metabolism might recover within 6 months. If decreased BMIPP uptake is not alleviated after 6 months of treatment, patients with vasospastic angina should be given additional treatment irrespective of cardiac symptoms.
 Decreased BMIPP uptake was observed in some of our control subjects, especially in conjunction with reduced wall motion, as indicated by left ventriculography. We suspect that these patients had coronary vasospasm and were false-negative for ergonovine provocation. In all 5 subjects in Group-C who had decreased BMIPP uptake and could be re-examined during medical treatment, decreased BMIPP uptake was alleviated 6 months after treatment, supporting our hypothesis.
 We had previously encountered patients with vasospastic angina which appeared to be completely suppressed, but some of them subsequently experienced sudden death or myocardial infarction (Fig.3), and those incidences prompted this study. It is extremely difficult to frequently repeat invasive tests such as left ventriculography or coronary angiography. The effects of treatment can be more effectively judged, therefore, by observing the regions with decreased uptake in non-invasive BMIPP myocardial imaging. Non-invasive BMIPP scintigraphy should be remarkably useful. We now judge the effect of medical treatment for vasospasm by using ambulatory electrocardiogram monitoring and BMIPP scintigraphy before and after 6 months of treatment.
 In conclusion, the territorial regions in which vasospasm was induced by ergonovine provocation, regions with abnormal left ventricular wall motion, and BMIPP myocardial scintigrams were compared in patients with vasospastic angina before and after medical treatment. Fatty acid metabolic imaging with BMIPP SPECT permitted the evaluation of vasospastic regions and non-invasive judgement of the effects of medical treatment. 

ACKNOWLEDGMENT 

This research was supported by grants from 'the Promotion and Mutual Aid Corporation for Private Schools of Japan' and 'Ministry of Education, Science, Sports and Culture.' 

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